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May 13, 2024

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Source of sugar may be more important than amount when it comes to the development of obesity in children

by European Association for the Study of Obesity

New research presented at the European Congress on Obesity (ECO) in Venice, Italy (12–15 May) suggests that the source of sugar is more important than the amount of sugar when it comes to the development of obesity in children.

The study found that the total amount of sugar consumed when very young was not associated with weight at age 10 or 11.

However, children who got a higher proportion of their sugar from unsweetened liquid dairy products (milk and buttermilk) were less likely to go on to live with overweight or obesity.

Similarly, getting more sugar from fruit was associated with less weight gain. However, getting a lot of sugar from sweet snacks such as cakes, confectionery and sweetened milk and yogurt drinks, such as chocolate milk, was linked to being of higher weight.

"The high consumption of sugary foods is considered a risk factor for childhood overweight and obesity and so children are advised to consume less sugar-rich foods, such as confectionery, cakes and sugar-sweetened drinks, and eat more fruit and unsweetened dairy products, such as milk and yogurt," says lead researcher Junyang Zou, of the Department of Epidemiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

"But while fruit and unsweetened dairy products are considered healthy, they contain high amounts of intrinsic sugars—sugar that occurs naturally in the food, rather than being added. We wanted to know if the source of sugar, added versus intrinsic, as well as the amount, affects the likelihood of developing overweight or obesity.

"While this has been studied before, the results are inconsistent and there is a lack of high quality research on the topic."

To address this, Zou and colleagues used data from the GEKCO Drenthe study, an ongoing longitudinal study of a cohort of children born in Drenthe, in the northern Netherlands, between April 2006 and April 2007, to explore the association between total sugar intake in early childhood and the intake of sugar from different sources on weight, weight gain and the development of overweight and obesity.

The answers to a food intake questionnaire filled in by the parents of 891 children (448 males) when the children were 3 years were used to calculate daily total sugar intake and the daily sugar intake from 13 food groups [vegetables; fruits (whole fruit only); cereals; starchy vegetables; nuts; legumes; meat, eggs, vegetarian meat substitutes, and oil, butter, and margarines; milk and milk products ; coffee and tea, and coffee and tea-based drinks; sugar-sweetened beverages (including fruit juice , lemonade and sweetened milk and yogurt drinks); savory products including homemade and ready meals and soup; sugary snacks such as cakes, confectionery and chocolate; toppings/sauces/sugars].

Height and weight, as measured by trained nurses, were used to calculate BMI Z-scores, the change in this score between 3 and 10/11 years and weight status at 10/11 years (normal weight/overweight/obese, as defined by International Obesity Task Force 2012 criteria).

BMI Z-scores are a widely used measure of weight in childhood and adolescence. They show how a young person's BMI compares to the average BMI for their age and sex, with higher values representing a higher weight.

All 891 children were included in the BMI-Z score at 10/11y and change in BMI-Z score analyses. 817 of the children (414 males) were included in the weight status analysis (74/891 were living with overweight or obesity at age 3 and were excluded from this analysis).

Average total daily sugar intake was 112g. This made up around a third (32%) of the total daily energy intake of 1,388 calories.

The main sources of sugar were fruit (average daily intake = 13g), dairy products (18.6g), sugar-sweetened beverages (41.7g) and sugary snacks (13.1g).

At 10/11 years of age, 102 children with normal weight at the age of 3 had developed overweight or obesity.

Total sugar intake at 3 years was not related to BMI Z-score, weight gain or weight status 10/11 years.

However, a higher intake of sugar from sugary snacks was related to a higher BMI Z-score at 10/11.

In contrast, a higher daily sugar intake from fruit (whole fruit only) was related to a lower BMI Z-score at 10/11 years and less weight gain. (No significant association was found between fruit juice and weight.)

And a higher sugar intake from unsweetened liquid dairy products (milk and buttermilk) was related to a lower odds of developing overweight/obesity at age 10/11. Children with the highest intake of these products aged 3 had a 67% lower risk of going on to have overweight/obesity, compared to those with the lowest intake.

The study didn't look at why these foods affected weight differently. However, possible explanations include slower release of sugar from pieces of fruit than from sugary snacks and differences in how the sugars in the different foods (sucrose in cakes and confectionery, fructose in fruit and lactose in dairy) act on the body.

The researchers conclude that when it comes to developing obesity in childhood, the source of sugar seems to be more important than the amount.

Zou adds, "Children should be encouraged to have fruit and milk instead of sweetened milk and yogurt drinks, sweets, cakes and other foods rich in added sugar."

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• Dietary sugar...

Dietary sugar consumption and health: umbrella review

• Related content
• Peer review
• Yin Huang , doctoral student 1 ,
• Zeyu Chen , resident physician 1 ,
• Bo Chen , doctoral student 1 ,
• Jinze Li , doctoral student 1 ,
• Xiang Yuan , masters student 2 ,
• Jin Li , doctoral student 1 ,
• Wen Wang , associate professor 3 ,
• Tingting Dai , attending physician 4 ,
• Hongying Chen , consultant physician 5 ,
• Yan Wang , consultant physician 5 ,
• Ruyi Wang , attending physician 1 ,
• Puze Wang , masters student 1 ,
• Jianbing Guo , attending physician 1 ,
• Qiang Dong , professor 1 ,
• Chengfei Liu , professor 6 ,
• Qiang Wei , professor 1 ,
• Dehong Cao , associate professor 1 ,
• Liangren Liu , associate professor 1
• 1 Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
• 2 Department of Oncology, West China Hospital, Sichuan University, Chengdu, China
• 3 Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
• 4 Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, China
• 5 Research Core Facility, West China Hospital, Sichuan University, Chengdu, China
• 6 Department of Urologic Surgery, UC Davis School of Medicine, Sacramento, CA, USA
• Correspondence to: L Liu liuliangren{at}scu.edu.cn
• Accepted 28 February 2023

Objective To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary sugar consumption and health outcomes.

Design Umbrella review of existing meta-analyses.

Data sources PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, and hand searching of reference lists.

Inclusion criteria Systematic reviews and meta-analyses of randomised controlled trials, cohort studies, case-control studies, or cross sectional studies that evaluated the effect of dietary sugar consumption on any health outcomes in humans free from acute or chronic diseases.

Results The search identified 73 meta-analyses and 83 health outcomes from 8601 unique articles, including 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials. Significant harmful associations between dietary sugar consumption and 18 endocrine/metabolic outcomes, 10 cardiovascular outcomes, seven cancer outcomes, and 10 other outcomes (neuropsychiatric, dental, hepatic, osteal, and allergic) were detected. Moderate quality evidence suggested that the highest versus lowest dietary sugar consumption was associated with increased body weight (sugar sweetened beverages) (class IV evidence) and ectopic fatty accumulation (added sugars) (class IV evidence). Low quality evidence indicated that each serving/week increment of sugar sweetened beverage consumption was associated with a 4% higher risk of gout (class III evidence) and each 250 mL/day increment of sugar sweetened beverage consumption was associated with a 17% and 4% higher risk of coronary heart disease (class II evidence) and all cause mortality (class III evidence), respectively. In addition, low quality evidence suggested that every 25 g/day increment of fructose consumption was associated with a 22% higher risk of pancreatic cancer (class III evidence).

Conclusions High dietary sugar consumption is generally more harmful than beneficial for health, especially in cardiometabolic disease. Reducing the consumption of free sugars or added sugars to below 25 g/day (approximately 6 teaspoons/day) and limiting the consumption of sugar sweetened beverages to less than one serving/week (approximately 200-355 mL/week) are recommended to reduce the adverse effect of sugars on health.

Systematic review registration PROSPERO CRD42022300982.

Introduction

As an important component of the human diet, sugars have been shown to be harmfully associated with a variety of risk factors for decades, mainly including obesity, 1 2 3 diabetes, 4 5 6 cardiovascular disease, 7 8 9 10 hyperuricaemia, 11 gout, 11 12 13 ectopic fatty accumulation, 14 15 16 dental caries, 17 and some cancers. 18 19 20 21 According to the latest report of the World Health Organization and the Food and Agriculture Organization of the United Nations, sugars include monosaccharides, disaccharides, polyols, and free sugars, of which free sugars are identified as all monosaccharides and disaccharides added to foods by the manufacturer, cook, or consumer and sugars naturally present in honey, syrups, and fruit juices. 3 22 In addition, another important group of sugars, added sugars, has been proposed in the Dietary Guidelines for Americans and has been defined as all monosaccharides and disaccharides used in processed and prepared foods and drinks and sugars added to foods but not naturally occurring sugars such as in fruits and fruit juices ( table 1 ). 23

Classification of dietary sugars 3 23

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In recent years, many studies have focused on the adverse effects of sugar sweetened beverages on human health, given the substantial contribution of these drinks to total added sugar or free sugar intake and the rapidly increasing rate of their consumption. 24 25 26 Generally, sugar sweetened beverages are the largest source of added sugars, including carbonated and noncarbonated soft drinks, fruit drinks, and sports and energy drinks. 27 Previous surveys have shown that consumption of sugar sweetened beverages is declining in many developed countries, although consumption levels remain high. 27 28 However, the consumption of sugar sweetened beverages is still increasing in many developing countries, which may be attributed to their increased availability accompanied by economic development. 29 The 2007 annual report of the Coca-Cola company revealed that the consumption of sugar sweetened beverages in India and China increased by 14% and 18%, respectively, in one year. 30 In 2018 a cross sectional survey conducted among Chinese primary and junior high school students showed that sugar sweetened beverages provide 10-15% of the total calorie consumption of school students. 31 Data from the National Health and Nutrition Examination Survey (NHANES) showed that, in 2009-10, sugar sweetened beverage consumption contributed 8% and 6.9% of daily energy intake among children/adolescents and adults, respectively, in the US. 32 Additionally, a global survey conducted in 2010 reported that a total of 180 000 adiposity associated deaths could be attributed to the consumption of sugar sweetened beverages around the world. 33 All of these findings promote the development of policies worldwide to limit sugar consumption, including sugars taxes, food labelling laws, and restrictions on advertising and marketing. 34 35 36 37 Meanwhile, national and international organisations such as WHO, the US Department of Agriculture, and the US Department of Health and Human Services have recommended reducing the consumption of free sugars or added sugars to less than 10% of total daily energy intake. 23 38

Although many meta-analyses of observational studies and randomised controlled trials focused on the associations between sugar consumption and a range of health outcomes have been published in recent decades, deficiencies in the study design, varying measurements of dietary sugar consumption, inconsistent findings, and different definitions of exposure make drawing definitive conclusions difficult. Therefore, before developing detailed policies for sugar restriction, the quality of existing evidence on the associations of dietary sugar consumption with all health outcomes needs to be comprehensively evaluated. To evaluate the quality of evidence, potential biases, and validity of all studies available on dietary sugar intake and any health outcomes, we did an umbrella review of meta-analyses on this topic.

Umbrella review methods

We systematically searched, extracted, and analysed large amounts of data from published systematic reviews and meta-analyses that research the associations between various health outcomes and dietary sugar consumption. 39 40 Generally, dietary sugar consumption could be measured through the specific proportions of sugars in foods or a percentage of total energy and combined in meta-analyses. 3 Therefore, we excluded simple systematic reviews without meta-analyses from our umbrella review. We prospectively registered this umbrella review in PROSPERO (CRD42022300982) ( https://www.crd.york.ac.uk/PROSPERO/ ).

Literature search

We searched PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews from inception through January 2022 (last update) for systematic reviews and meta-analyses of randomised controlled trials and observational studies. We searched the databases through a combination of Medical Subject Headings terms, keywords, and variations of text words associated with sugars following the Scottish Intercollegiate Guidelines Network’s guidance for literature searching: (sugars OR sugar) AND (systematic review OR meta-analysis). 41 Two authors (YH and ZYC) separately conducted electronic searches to screen the titles and abstracts retrieved from the databases and identified meta-analyses that met the inclusion criteria by full text reading. Any discrepancy in the literature screening between the two reviewers was resolved by a third author (LRL). We hand searched meta-analyses and reviews from the reference lists of all included articles to identify studies that might have been missed.

Eligibility criteria

We identified dietary sugar consumption as the intake of total sugars and the consumption of a component of total sugars (monosaccharides, disaccharides, polyols, free sugars, or added sugars), which are expressed in absolute amounts or as a percentage of total energy, or the intake of sugar sweetened beverages or foods ( table 1 ). 3 We included systematic reviews and meta-analyses of randomised controlled trials, cohort studies, case-control studies, or cross sectional studies that evaluated dietary sugar consumption in humans free from acute or chronic diseases. Meta-analyses were eligible for inclusion when they compared the effects of different dietary sugar consumption on the same health outcome through relative risks, odds ratios, hazard ratios, weighted mean differences, or standardised mean differences. We included meta-analyses when the exposure was total sugars, monosaccharides, disaccharides, polyols, free sugars, added sugars, or sugar sweetened beverages or foods. We extracted data on individual outcomes separately if two or more health outcomes were reported in a study. If more than one study published more than 24 months apart was conducted on the same dietary sugar exposure and health outcomes, we included the most recent study for data extraction, which is generally the study with the largest sample size. If more than one study was conducted within the same 24 month period, we included the meta-analysis with the largest number of prospective cohort studies and randomised controlled trials (a study with a higher AMSTAR score was included if the number of prospective studies was equal). 42 43 Furthermore, if the most recent study did not do dose-response analysis, whereas another study did, we included both studies for data extraction.

The exclusion criteria for these umbrella reviews included meta-analyses of the association between carbohydrates, non-nutritive sweeteners, and artificially sweetened beverages and health outcomes; meta-analyses evaluating the therapeutic or metabolic effects of short term sugar supplementation; meta-analyses that evaluated the effects of dietary sugar consumption on health outcomes in certain disease populations; randomised controlled trials that aimed to achieve isoenergetic replacement of sugars with other forms of carbohydrate; studies with insufficient data to evaluate sugar consumption from sugar containing foods (such as honey, apples, chocolate, ice cream, 100% fruit juice); and non-English studies and animal and cell culture studies.

Data extraction

Two reviewers (YH and ZYC) independently extracted the following information from each eligible study: first author’s name, publication year, type of dietary sugar consumption (total sugars, monosaccharides, disaccharides, polyols, free sugars, added sugars, sugar sweetened beverages or foods), measurement of dietary sugar consumption, health outcome, number of included studies, number of cases and total participants, study design (cross sectional, case-control, cohort, and randomised controlled trial), comparison (high versus low, never/low versus moderate/high, any versus none, or extra increment of sugars per day (or week) versus none), and estimated summary effect (risk ratio, odds ratio, weighted mean difference, and standardised mean difference with 95% confidence intervals). Furthermore, we extracted the model of effect (random and fixed), heterogeneity (I 2 statistic and Cochran’s Q test P value), and publication bias assessment (P value of Egger’s test or funnel plot). If dose-response analysis and subgroup analysis were conducted, we also extracted the non-linearity tests’ P value and results of subgroup analysis in meta-analyses. If a meta-analysis was conducted on both cohort and case-control/cross sectional studies and stratification analysis was conducted through study design, we selected the cohort design subanalysis results for data extraction or reanalysed. Any disagreement was determined by a third author (LRL).

Quality assessment of methods and evidence

Two reviewers (YH and ZYC) evaluated the methodological quality of the included articles by using AMSTAR (a measurement tool to assess systematic reviews), a valid and dependable measurement tool in assessing the quality of systematic reviews and meta-analyses. 42 44 In addition, according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), we evaluated evidence of each health outcome and graded it as “high,” “moderate,” “low,” or “very low” quality to draw conclusions. 45 Additionally, we classified evidence of outcomes into four categories following the evidence classification criteria: class I (convincing evidence), class II (highly suggestive evidence), class III (suggestive evidence), class IV (weak evidence), and NS (non-significant). 46 47 48 Table 2 shows detailed criteria of evidence classification.

Evidence classification criteria 46 47 48

Data analysis

We reanalysed the risk ratio, odds ratio, weighted mean difference, or standardised mean difference with 95% confidence intervals through random or fixed effects models and calculated the I 2 statistic, P value of Cochran’s Q test for heterogeneity, and P value of Egger’s regression test (at least 10 studies were included) for small study effects in each included meta-analysis that reported the metric, number of cases, and participants of the included original studies. 49 50 51 For outcomes classified as class I or II, we did sensitivity analysis if sufficient data were available to assess whether the credibility of the evidence varied when some component studies were excluded. We also extracted dose-response associations between dietary sugar consumption and various health outcomes from the included meta-analyses, if available. Moreover, if the latest meta-analysis did not include the original articles that were included by other meta-analyses, we combined the data of these meta-analyses and did a reanalysis. We assessed agreement statistics between two authors (YH and ZYC) regarding study selection by using Cohen’s κ statistics and associated 95% confidence interval. We interpreted magnitude of agreement by following guidelines reported by Landis and Koch: slight (0.00-0.20), fair (0.21-0.40), moderate (0.41-0.60), substantial (0.61-0.80), and almost perfect agreement (0.81-1.00). 52 In addition, if a meta-analysis reported the estimated effect by combining observational studies with randomised controlled trials, we reanalysed the estimated effects for observational studies and randomised controlled trials separately. If we could not do a reanalysis from a meta-analysis, we extracted summary data and assessed heterogeneity and publication bias from the meta-analysis as far as possible. We identified a P value <0.10 as statistically significant for heterogeneity tests. For other tests, we considered a P value <0.05 to be significant. We used Review Manager version 5.3 for evidence synthesis, Stata version 12.1 for Egger’s test and sensitivity analysis, and IBM SPSS Statistics version 25 for Cohen’s κ statistics.

Patient and public involvement

Patients and the public were not involved in the planning, design, and implementation of the study, as this study used secondary data. No patients were asked to advise on interpretation or writing up of the manuscript.

Characteristics of meta-analyses

Figure 1 shows the flowchart of the literature search and selection process. After a systematic literature search, we identified 8601 unique articles. Application of our inclusion criteria yielded total of 73 meta-analyses, including 67 meta-analyses of observational studies and six meta-analyses of randomised controlled trials. Agreement between the two reviewers (YH and ZYC) for study selection was almost perfect (κ=0.906, 95% confidence interval 0.859 to 0.953; P<0.001). We extracted 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials. Meta-analyses of randomised controlled trials included only change in body weight (sugar sweetened beverages), liver fat accumulation, muscle fat accumulation, change in body mass index, change in body weight (fructose), postprandial triglycerides, serum uric acid, intrahepatocellular lipids, and alanine aminotransferase. Figure 2 shows the significant dose-response relations between dietary sugar consumption and multiple health outcomes. The other forest plots show the significant non-dose-response relations between dietary sugar consumption and endocrine/metabolic ( fig 3 ), cardiovascular ( fig 4 ), cancer ( fig 5 ), and other outcomes ( fig 6 ). The full versions of the associations between dietary sugar consumption and each outcome are shown in supplementary tables A-D.

Flowchart of systematic search and selection process

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Significant dose-response relations between dietary sugar consumption and multiple health outcomes. Estimates are relative risks, summary mean difference is weighted mean difference, and effect models are random unless noted otherwise. Δ=final value – baseline value; AMSTAR=a measurement tool to assess systematic reviews; C=cohort studies; CHD=coronary heart disease; CI=confidence interval; CVD=cardiovascular disease; GRADE=Grading of Recommendations Assessment, Development and Evaluation; NA=not available; P=population based case-control and/or cross sectional studies; SSB=sugar sweetened beverage; T=total No of studies; T2DM = type 2 diabetes mellitus. *1 serving/week increment. †355 mL/d increment. ‡250 mL/d increment. §1 serving/d increment. ¶25 g/d increment. **Hazard ratio. †Children

Significant non-dose-response relations between dietary sugar consumption and endocrine and metabolic outcomes. Comparisons are highest versus lowest, estimates are relative risks, summary mean difference is weighted mean difference, and effect models are random unless noted otherwise. Complete associations between dietary sugar consumption and endocrine and metabolic outcomes are shown in supplementary table A. Δ=final value – baseline value; AMSTAR=a measurement tool to assess systematic reviews; C=cohort studies; CI=confidence interval; GRADE=Grading of Recommendations Assessment, Development and Evaluation; HDL-C=high density lipoprotein cholesterol; LADA=latent autoimmune diabetes in adults; LDL-C=low density lipoprotein cholesterol; NA=not available; P=population based case-control and/or cross sectional studies; R=randomised controlled trials; SSB=sugar sweetened beverage; T=total No of studies. *Odds ratio. †Children. ‡Any versus none. §Fixed effects model. ¶Standardised mean difference

Significant non-dose-response relations between dietary sugar consumption and cardiovascular outcomes. Comparisons are highest versus lowest, estimates are relative risks, summary mean difference is weighted mean difference, and effect models are random unless noted otherwise. Complete associations between dietary sugar consumption and cardiovascular outcomes are shown in supplementary table B. Δ=final value – baseline value; AMSTAR=a measurement tool to assess systematic reviews; C=cohort studies; CI=confidence interval; CVD=cardiovascular disease; GRADE=Grading of Recommendations Assessment, Development and Evaluation; NA=not available; P=population based case-control and/or cross sectional studies; SBP=systolic blood pressure; SSB=sugar sweetened beverage; T=total No of studies. *Children and adolescents. †Odds ratio

Significant non-dose-response relations between dietary sugar consumption and cancer outcomes. Comparisons are highest versus lowest, estimates are relative risks, and effect models are random unless noted otherwise. Complete associations between dietary sugar consumption and cancer outcomes are shown in supplementary table C. AMSTAR=a measurement tool to assess systematic reviews; GRADE=Grading of Recommendations Assessment, Development and Evaluation; C=cohort studies; CI=confidence interval; NA=not available; P=population based case-control and/or cross sectional studies; SSB=sugar-sweetened beverage; T=total No of studies

Significant non-dose-response relations between dietary sugar consumption and other outcomes. Comparisons are highest versus lowest, estimates are relative risks, summary mean difference is weighted mean difference, and effect models are random unless noted otherwise. Complete associations between dietary sugar consumption and other outcomes are shown in supplementary table D. ADHD=attention deficit/hyperactivity disorder; AMSTAR=a measurement tool to assess systematic reviews; BMD=bone mineral density; C=cohort studies; CI=confidence interval; GRADE=Grading of Recommendations Assessment, Development and Evaluation; IHCL=intrahepatocellular lipids; NA=not available; NAFLD=non-alcoholic fatty liver disease; P=population based case-control and/or cross sectional studies; R=randomised controlled trials; SSB=sugar-sweetened beverage; T=total No of studies. *Children. †Odds ratio. ‡Fixed effects model. §Never/low versus moderate/high consumption. ¶Standardised mean difference. **Any versus none

Most of the included meta-analyses focused on the associations between dietary sugar consumption and endocrine/metabolic diseases (n=28), followed by cancer (n=25), cardiovascular diseases (n=17), neuropsychiatric diseases (n=3), dental diseases (n=2), and other diseases (n=8) ( fig 7 ). Dietary sugar exposure included sugar sweetened beverages (n=58), fructose (n=11), sucrose (n=4), lactose (n=1), added sugars (n=4), free sugars (n=1), and total sugars (n=4). Significance was reached for 45 harmful associations and four beneficial associations. The remaining 34 outcomes were either harmfully or beneficially associated but did not reach significance. After quality assessment of evidence through GRADE and evidence classification criteria, most of the 83 outcomes were classified as “low” or “very low” quality and III, IV, or NS evidence class. Only four (5%) endocrine/metabolic outcomes were classified as “moderate” quality. Three (4%) endocrine/metabolic outcomes, two (2%) cardiovascular outcomes, and three (4%) other outcomes were graded as class IIB. No “high” quality or class I evidence was found in this umbrella review.

Map of outcomes associated with dietary sugar consumption

Endocrine and metabolic outcomes

Low and moderate quality evidence.

A meta-analysis of six randomised controlled trials found that sugar sweetened beverage consumption was significantly associated with increased body weight for highest versus lowest consumption (weighted mean difference 0.85, 95% confidence interval 0.50 to 1.20) (moderate; IV (the quality of evidence is expressed as “GRADE, evidence class”)). 53 In addition, any versus no added sugar consumption was associated with increased liver fat accumulation (standardised mean difference 0.93, 95% confidence interval 0.64 to 1.21) (moderate; IV) and muscle fat accumulation (standardised mean difference 0.63, 0.23 to 1.04) (moderate; IV). 54 Another dose-response meta-analysis showed that a one serving/week increment in artificially sweetened beverages was associated with a 4% higher risk of gout (risk ratio 1.04, 95% confidence interval 1.02 to 1.07) (low; III). 13 Furthermore, comparison of higher sugar sweetened beverage consumption with non-sugar sweetened beverage consumption indicated a 55% (odds ratio 1.55, 95% confidence interval 1.32 to 1.82) increased risk of obesity in children associated with higher consumption (low; II). 3 Sugar sweetened beverage consumption was also linked with an increased body mass index in children. 53 The authors conducted a dose-response analysis and showed that body mass index in children increased by 0.07 units for every one serving/day increment of sugar sweetened beverages (weighted mean difference 0.07, 0.01 to 0.12) (low; IV). 53 Evidence from this umbrella review suggests that fructose intake was not associated with serum uric acid (moderate; NS) 55 or changes in body weight (low; NS) ( fig 2 ; fig 3 ). 56

Very low quality evidence

Dose-response analysis based on seven cohort studies showed that a one serving/day increment of sugar sweetened beverages was associated with a 0.22 kg weight gain in one year (weighted mean difference 0.22, 0.09 to 0.34). 53 Furthermore, the risk of gout increased by 35% (risk ratio 1.35, 1.18 to 1.55) for the highest versus lowest sugar sweetened beverage consumption. 11 The highest versus lowest sugar sweetened beverage consumption was also significantly associated with a 35% (risk ratio 1.35, 1.19 to 1.52) higher risk of hyperuricaemia. 11 In addition, another pooled analysis found that participants with the highest sugar sweetened beverage consumption had 0.18 mg/dL greater concentrations of serum uric acid than did those with the lowest consumption (weighted mean difference 0.18, 0.11 to 0.25). 57 Similarly, the highest fructose intake could also increase the risk of gout (risk ratio 1.62, 1.28 to 2.03) 58 and hyperuricaemia (odds ratio 1.85, 1.66 to 2.07) 59 compared with the lowest consumption.

The most recent meta-analysis found a 1.46 mg/dL (weighted mean difference −1.46, −2.25 to −0.67) decrement of high density lipoprotein cholesterol for the highest versus lowest sugar sweetened beverage consumption. 60 Subgroup analysis indicated that the highest versus lowest sugar sweetened beverage consumption was associated with lower high density lipoprotein cholesterol in studies conducted in the US (weighted mean difference −2.85, −4.09 to −1.61) but was associated with higher high density lipoprotein cholesterol in studies conducted in Europe/Oceania (weighted mean difference 1.65, 0.26 to 3.05). 60 The highest versus lowest sugar sweetened beverage consumption was also significantly associated with increased low density lipoprotein cholesterol (weighted mean difference 1.21, 0.23 to 2.20) and decreased total cholesterol (−2.49, −2.89 to −2.10). 60 After stratification by region, no significant association between sugar sweetened beverage consumption and low density lipoprotein cholesterol was detected in the US, Europe/Oceania, and Asia, 60 whereas the highest versus lowest sugar sweetened beverage consumption was associated with lower total cholesterol concentrations in studies conducted in the US/Europe (weighted mean difference −2.47, −2.88 to −2.07) but not in Asia. 60

The risk of metabolic syndrome was increased by 14% (risk ratio 1.14, 1.05 to 1.23) for a 355 mL/day increment of sugar sweetened beverages, with no evidence for departure from linearity. 61 In addition, a meta-analysis including 56 579 participants and 11 821 incident cases of obesity showed an adverse linear dose-response association between sugar sweetened beverage consumption and the risk of obesity. 1 Each 250 mL/day increment in sugar sweetened beverage consumption was associated with a 12% (risk ratio 1.12, 1.05 to 1.19) higher risk of obesity, and this association also remained after adjustment for energy intake (1.13, 1.09 to 1.18) and physical activity (1.14, 1.05 to 1.25). 1 Moreover, a meta-analysis of 16 cohort studies found that with each one serving/day increment of sugar sweetened beverage consumption, the risk of developing type 2 diabetes mellitus increased by 27% (risk ratio 1.27, 1.15 to 1.41). 6 By contrast, an 8% (risk ratio 0.92, 0.85 to 0.99) lower risk of type 2 diabetes mellitus for each 25 g/day increment in sucrose intake was confirmed in dose-response analysis based on six cohort studies. 62 The highest versus lowest sugar sweetened beverage consumption was also significantly associated with a higher risk of latent autoimmune diabetes in adults (odds ratio 1.26, 1.12 to 1.41) ( fig 2 ; fig3 ). 30

We found no significant association between sugar sweetened beverage consumption and changes in body mass index in adults, 63 triglycerides, 60 or large waist circumference. 64 Fructose intake was not associated with postprandial triglycerides or type 2 diabetes mellitus. 62 65 Total sugar consumption was also not associated with type 2 diabetes mellitus (supplementary table A). 62

Cardiovascular outcomes

Low quality evidence.

In a single article, 10 a positive association between sugar sweetened beverage consumption and the risk of coronary heart disease was observed. Dose-response analysis showed that each 250 mL/day increment of sugar sweetened beverage consumption was positively associated with a 17% (risk ratio 1.17, 1.11 to 1.23) higher risk of coronary heart disease (low; II). 10 In addition, extreme category analysis showed that the highest versus lowest sugar sweetened beverage consumption was associated with an increased risk of myocardial infarction (risk ratio 1.19, 1.09 to 1.31) (low; III). 66 Low quality evidence suggests that fructose intake was not associated with the risk of hypertension (low; NS) ( fig 2 ; fig 4 ). 67

Except for a beneficial association between sucrose intake and cardiovascular disease mortality, all categories of dietary sugar exposure were adversely associated with various cardiovascular outcomes. A recent dose-response meta-analysis showed that each 250 mL/day increment of sugar sweetened beverage consumption was positively associated with a 7% (risk ratio 1.07, 1.02 to 1.12) higher risk of stroke. 10 Another meta-analysis of seven cohort studies with 329 791 participants and 16 999 cases found that each one serving/day increment of sugar sweetened beverage consumption was linearly associated with an 8% (risk ratio 1.08, 1.02 to 1.14) increased risk of cardiovascular disease. 8 For cardiovascular disease mortality, each serving/day increment of sugar sweetened beverage consumption was also linearly associated with a higher risk (hazard ratio 1.08, 1.04 to 1.12). 68 However, subgroup analysis found that the association between sugar sweetened beverage consumption and cardiovascular disease mortality was not statistically significant among participants from Asia. 68 In a separate meta-analysis in children and adolescents, 69 the highest versus lowest sugar sweetened beverage consumption was shown to be associated with a 1.67 mm Hg (weighted mean difference 1.67, 1.02 to 2.32) increase in systolic blood pressure and a 36% (odds ratio 1.36, 1.14 to 1.63) higher risk of hypertension. In adults, the results from pooled analysis of 13 prospective cohort studies indicated a harmful dose-response association between sugar sweetened beverage consumption and incidence of hypertension. 70 The risk of hypertension was increased by 11% (risk ratio 1.11, 1.09 to 1.13) for a 355 mL/day (1 serving/day) increment in sugar sweetened beverage consumption. 70 Moreover, both fructose (risk ratio 1.08, 1.01 to 1.15) and total sugars (risk ratio 1.09, 1.02 to 1.17) were harmfully associated with the risk of cardiovascular disease mortality for highest versus lowest consumption, 71 whereas a beneficial association between sucrose intake and cardiovascular disease mortality was observed ( fig 2 ; fig 4 ). 71

We observed no significant association between sugar sweetened beverage consumption and changes in diastolic blood pressure (children and adolescents) 69 or heart failure. 10 We also observed no significant association between sucrose intake or total sugar consumption and the risk of cardiovascular disease. 71 In addition, added sugar consumption was not associated with the risk of cardiovascular disease mortality (supplementary table B). 71

A dose-response meta-analysis showed that the risk of hepatocellular carcinoma increased by 100% (risk ratio 2.00, 1.33 to 3.03) for the highest sugar sweetened beverage consumption compared with the lowest (low; IV). 18 Additionally, a meta-analysis conducted by Aune and colleagues found that 25 g/day of fructose intake was linearly associated with a 22% higher risk of pancreatic cancer (risk ratio 1.22, 1.08 to 1.37) (low; III). 72 The association between fructose intake and incidence of pancreatic cancer remained significant in the subgroups of studies that adjusted for smoking, body mass index, red and processed meat consumption, and energy intake, whereas the association was diminished in the subgroups of studies that adjusted for alcohol consumption, diabetes status, or physical activity ( fig 2 ; fig 5 ). 72

A recent meta-analysis of six observational studies showed a higher risk of breast cancer for highest versus lowest sugar sweetened beverage consumption (risk ratio 1.14, 1.01 to 1.30). 19 In a separate meta-analysis, Li and colleagues found that the highest sugar sweetened beverage consumption might increase the risk of breast cancer mortality by 17% (risk ratio 1.17, 1.03 to 1.34) compared with the lowest. 18 Moreover, a meta-analysis of six cohort studies showed that participants with the highest sugar sweetened beverage consumption had a higher risk of prostate cancer than those with the lowest intake (risk ratio 1.17, 1.07 to 1.28). Dose-response analysis did not detect a significant association. 18 However, we observed a protective association between sugar sweetened beverage consumption and glioma in our umbrella review (risk ratio 0.81, 0.66 to 0.99). 18 In addition, a meta-analysis including 20 cohort studies with 5 505 812 participants observed a positive linear dose-response relation between sugar sweetened beverage consumption and overall cancer risk. 18 The risk increased by 4% for every serving/day increment of sugar sweetened beverage consumption (risk ratio 1.04, 1.01 to 1.09). 18 Furthermore, pooled analysis of 10 cohort studies with 1 239 183 participants found that the highest versus lowest sugar sweetened beverage consumption was significantly associated with a higher risk of overall cancer mortality (risk ratio 1.06, 1.00 to 1.12), without a significant dose-response relation. 18 Stratification by region produced a positive association between sugar sweetened beverage consumption and overall cancer mortality in the North American population (odds ratio 1.08, 1.01 to 1.15) but not in Asia (0.99, 0.81 to 1.22) ( fig 2 ; fig 5 ). 18

We observed no significant association between sugar sweetened beverage consumption and the risk of biliary track cancer, 18 bladder cancer, 18 colon cancer, 73 colorectal cancer, 18 colorectal cancer mortality, 18 endometrial cancer, 18 oesophageal cancer, 18 gastric cancer, 18 haematological malignancy, 18 kidney cancer, 18 lung cancer mortality, 18 nasopharyngeal carcinoma, 18 pancreatic cancer, 18 and prostate cancer mortality. 18 In addition, added sugar consumption was not associated with the risk of colorectal cancer. 74 We observed no significant association between sucrose intake and pancreatic cancer. 72 Moreover, lactose intake was not associated with the risk of ovarian cancer (supplementary table C). 75

Other outcomes

A recent meta-analysis of 11 cohort studies suggested that an increment in sugar sweetened beverage consumption of 250 mL/day was associated with a 4% (hazard ratio 1.04, 1.02 to 1.06) higher risk of all cause mortality (low; III). 76 Moreover, a harmful association between sugar sweetened beverage consumption and the risk of depression was observed in a meta-analysis of 10 observational studies (risk ratio 1.31, 1.24 to 1.39) (low; II). 77 No significant association was observed between fructose intake and alanine transaminase concentration (low; NS) ( fig 2 ; fig 6 ). 78

The highest versus lowest sugar sweetened beverage consumption might increase the risk of asthma in children by 26% (odds ratio 1.26, 1.07 to 1.48). 79 In a single article, 80 both sugar sweetened beverage consumption (odds ratio 1.80, 1.23 to 2.63) and total sugar consumption (1.22, 1.04 to 1.42) were associated with an increased risk of attention deficit/hyperactivity disorder. In addition, the results from a meta-analysis of 10 observational studies showed a significant inverse association between sugar sweetened beverage consumption and bone mineral density in adults (standardised mean difference −0.66, −1.01 to −0.31). 81 Subgroup analysis according to sex showed a significant harmful effect of sugar sweetened beverage consumption on bone mineral density in females (standardised mean difference −0.50, −0.87 to −0.13) but no association in males. 81 For dental diseases, a single article found a harmful association between sugar sweetened beverage consumption and the incidence of dental caries (odds ratio 1.72, 1.41 to 2.09) and dental erosion (1.77, 1.28 to 2.43) when comparing never/low with moderate/high consumption. 17 Additionally, sugar sweetened beverage consumption was positively associated with the risk of non-alcoholic fatty liver disease (risk ratio 1.39, 1.29 to 1.50). 16 Fructose intake was associated with increased intrahepatocellular lipids (standardised mean difference 0.45, 0.18 to 0.72) ( fig 2 ; fig 6 ). 78

Sugar sweetened beverage consumption was not associated with the risk of chronic kidney disease. 82 In addition, maternal increased free sugar intake during pregnancy was not associated with the risk of asthma in offspring (supplementary table D). 83

Heterogeneity

We reanalysed the heterogeneity in 69% of all health outcomes by a random or fixed effects model. Reanalysis found that approximately 46% of the health outcomes that we reanalysed had significant heterogeneity (I 2 >50% or P value of Cochran’s Q test <0.1). The heterogeneity of most outcomes could be explained by some potential factors, including setting, region, ethnicity, sex, age, study quality, study design, sample size, duration of follow-up, and adjustment for confounding factors. Of the 26 outcomes that we could not reanalyse, approximately 54% had significant heterogeneity and 4% did not report the results of the heterogeneity evaluation.

Assessment of risk of bias

We conducted Egger’s test for 23% of the outcomes in our reanalysis, which found evidence of publication bias in three outcomes—type 2 diabetes mellitus (sugar sweetened beverages) (P=0.016), overall cancer risk (P=0.005), and hypertension in adults (sugar sweetened beverages) (P=0.02). For outcomes that we could not reanalyse, publication bias was detected for cardiovascular disease mortality (sugar sweetened beverages), non-alcoholic fatty liver disease, obesity in adults, and change in body weight (one year) by statistical test or funnel plot. The remaining outcomes did not show significant publication bias or did not report an evaluation for publication bias.

AMSTAR, GRADE, and evidence classification

The median AMSTAR score of all health outcomes was 8 (range 3-11; interquartile range 8-9.25) (supplementary table E). Supplementary table F provides the detailed AMSTAR scores for each outcome. All evidence from meta-analyses of cohorts, population based case-control studies, and cross sectional studies is graded as “low” or “very low” quality owing to the observational study design and factors for quality downgrade (significant risk of bias, inconsistency, indirectness, imprecision, and potential publication bias). Among the nine meta-analyses of randomised controlled trials, four (liver fat accumulation, muscle fat accumulation, serum uric acid (fructose), and change in body weight (sugar sweetened beverages)) were downgraded as “moderate” quality given the imprecision, and the remaining (alanine transaminase, intrahepatocellular lipids, postprandial triglycerides, change in body mass index in adults, and change in body weight (fructose)) were downgraded as “low” or “very low” owing to the risk of bias, inconsistency, indirectness, or imprecision (supplementary table E). Supplementary Table G shows the detailed GRADE classification for each outcome. In terms of evidence classification, type 2 diabetes mellitus (sugar sweetened beverages), hyperuricaemia (fructose), obesity in children (sugar sweetened beverages), coronary heart disease, hypertension in adults (sugar sweetened beverages), dental caries, depression, and non-alcoholic fatty liver disease were graded as class II. For the remaining 75 outcomes, 15 (18.1%) were graded as class III, 26 (31.3%) were graded as class IV, and 34 (41.0%) were identified as non-significant (supplementary table E). Sensitivity analyses of each outcome graded as class II did not alter the direction or significance of the association.

Principal findings and possible explanations

Dietary sugar consumption is harmfully associated with multiple health outcomes across various measurements of exposure, including high versus low, never/low versus moderate/high, any versus none, or an extra increment of sugars per day (or week) versus none. We identified 73 meta-analyses and 83 health outcomes from 8601 unique articles, including 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials.

Dietary sugar consumption had harmful associations with endocrine and metabolic outcomes, including changes in body mass index in children, 53 changes in body weight, 53 changes in body weight (one year), 53 gout, 11 13 58 high density lipoprotein cholesterol, 60 hyperuricaemia, 11 59 latent autoimmune diabetes in adults, 30 low density lipoprotein cholesterol, 60 metabolic syndrome, 61 obesity in children, 3 obesity in adults, 1 serum uric acid, 57 type 2 diabetes mellitus, 6 liver fat accumulation, 54 and muscle fat accumulation. 54 In addition, harmful associations between dietary sugar consumption and cardiovascular outcomes were also observed, including coronary heart disease, 10 cardiovascular disease, 8 cardiovascular disease mortality, 68 71 hypertension in children and adolescents, 69 hypertension in adults, 70 myocardial infarction, 66 change in systolic blood pressure in children and adolescents, 69 and stroke. 10 Significant harmful associations between dietary sugar consumption and a higher risk of cancer were observed for breast cancer, 19 breast cancer mortality, 18 hepatocellular carcinoma, 18 prostate cancer, 18 pancreatic cancer, 72 overall cancer risk, 18 and overall cancer mortality. 18 Finally, harmful associations existed between dietary sugar consumption and all cause mortality, 76 asthma in children, 79 attention deficit/hyperactivity disorder, 80 bone mineral density, 81 dental caries, 17 dental erosion, 17 depression, 77 non-alcoholic fatty liver disease, 16 and intrahepatocellular lipids. 78

In general, no reliable evidence shows beneficial associations between dietary sugar consumption and any health outcomes, apart from glioma (sugar sweetened beverages), 18 total cholesterol (sugar sweetened beverages), 60 type 2 diabetes mellitus (sucrose), 62 and cardiovascular disease mortality (sucrose). 71 However, these favourable associations are not supported by strong evidence, and the interpretation of these results should be done with caution. For the decreased risk of glioma, evidence for this came from only two cohort studies, and no studies have shown that sugar sweetened beverage consumption is a protective factor to lower the incidence of cancer. High sugar sweetened beverage consumption was associated with lower total cholesterol concentrations. However, subgroup analysis indicated that sugar sweetened beverage consumption was associated with higher total cholesterol concentrations in studies with sugar sweetened beverage consumption >750 g/day and studies involving adolescents. Therefore, potential confounders, including region, sugar sweetened beverage dose, sample size, and sex, should be considered in explaining the association between sugar sweetened beverage consumption and total cholesterol concentrations. In terms of the protective effect of sucrose intake on type 2 diabetes mellitus and cardiovascular disease mortality, we note that sucrose tends to be found more in solid foods than in sugar sweetened beverages, including grains and grain based products, fruit and fruit products, and sweetened dairy and dairy products. 84 85 86 These main sources of sucrose have shown beneficial associations (for example, whole grain cereals, fruit, and yogurt) with type 2 diabetes mellitus and cardiovascular disease mortality. 87 88 89 90 91 92 Therefore, the protective association between sucrose intake and type 2 diabetes mellitus and cardiovascular disease mortality may reflect important contributions from these other food sources rather than sucrose. 62 71 Further large scale, prospective studies are warranted to evaluate the association of sucrose intake with type 2 diabetes mellitus and cardiovascular disease mortality and to clarify the possible underlying mechanisms.

Our umbrella review showed harmful associations between dietary sugar consumption and a range of cardiometabolic diseases, especially weight gain, ectopic fat accumulation, obesity, and cardiovascular disease, which can largely be attributed to excessive consumption of fructose containing sugars. In response to the intake of large carbohydrates, fructose could enhance hepatic lipogenic capacity by inducing hepatic master transcription factors. 93 94 95 Moreover, an animal study found that dietary fructose could be converted to microbial acetate by the gut microbiota, which may enhance hepatic lipogenesis by supplying lipogenic acetyl-CoA independently of ATP citrate lyase. 96 Intermediate products such as diacylglycerols generated during the process of lipogenesis may impair insulin signalling in the liver and peripheral tissues and then lead to insulin resistance. 97 Subsequently, it may promote ectopic fat deposition in the liver and muscle. 98 99 Dietary fructose may also inhibit fatty acid oxidation in the liver by impairing mitochondrial size and function and acetylation of the rate limiting enzyme. 100 A recent animal study showed that dietary fructose improves the survival of intestinal cells and increases the length of intestinal villus in mouse models, resulting in an expanded surface area of the gut and increased nutrient absorption and adiposity in mice. 101 Furthermore, fructose contained in sugar sweetened beverages is suggested to likely induce the onset of obesity by reducing resting energy expenditure and promoting leptin resistance. 102 103 In addition, sugar sweetened beverages are associated with less satiety compared with solid food containing the same amount of calories, which may stimulate appetite and induce excessive calorie consumption, liver fat accumulation, and insulin resistance in the long term. 104 This hypothesis is confirmed by several clinical trials conducted in healthy adults, which found that sugar sweetened beverage consumption results in more caloric intake and weight gain than artificially sweetened beverages. 105 106 107 Additionally, a recent double blind, randomised controlled trial carried out in 94 healthy men suggested that consumption of sugar sweetened beverages containing fructose might induce a significant change in the low density lipoprotein particle distribution towards smaller, more atherogenic particles, partially mediating the associations of sugar sweetened beverage consumption with dyslipidaemia and cardiovascular disease. 108

Another important mechanism to explain the associations between dietary sugar consumption and cardiometabolic diseases involves uric acid synthesis. Many studies have confirmed that excessive fructose consumption can promote uric acid synthesis by inducing degradation ATP to AMP, a substrate for uric acid production. 109 110 111 Fructose phosphorylation in the liver uses ATP to convert fructose into fructose-1-phosphate and leads to phosphate depletion, which limits the regeneration of ATP from ADP. Then, ADP is converted to AMP and consequently induces the synthesis of uric acid. 57 In addition, fructose induced hyperinsulinaemia and insulin resistance may also result in higher serum uric acid by reducing the excretion of uric acid. 110 112 113 Hyperuricaemia is a precursor to gout. 109 110 The positive associations between gout, hyperuricaemia, and other cardiometabolic diseases, such as hypertension, type 2 diabetes mellitus, and cardiovascular disease, have been proposed for a long time. 114 115 Hyperuricaemia has been shown to precede the occurrence of type 2 diabetes mellitus and obesity. 27 Mechanistically, hyperuricaemia could induce renal microvascular alteration, chronic sodium retention, reduction in nitric oxide concentrations in endothelial cells, and the activation of the renin-angiotensin system, which may account for the association between fructose containing sugar consumption and cardiovascular disease. 114 116 117 118

Until now, the evidence for the association between dietary sugar consumption and the risk of cancer has remained limited and controversial. 27 In 2018 the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) reported that evidence was limited for the associations between consumption of sugars and food containing sugars and the risk of colorectal cancer. 119 However, at the same time, this report recommended reducing or avoiding sugar sweetened beverage consumption for the prevention of breast cancer. 119 Evidence from this umbrella review supports the recommendations from the WCRF/AICR to some extent. In our study, although eight of the 25 cancer outcomes were identified as being positively associated with dietary sugar consumption (seven exposure factors were sugar sweetened beverages, and one was fructose), only evidence of hepatocellular carcinoma (sugar sweetened beverages) and pancreatic cancer (fructose) were rated as “low” quality because of the magnitude of effect or dose-response gradient, and the remaining outcomes were all rated as “very low” quality. As a result, caution is warranted when explaining the significant associations between dietary sugar consumption and some cancer risks.

The effect of dietary sugars on obesity might partly explain their association with the risk of cancer. 21 As mentioned previously, dietary sugar consumption, especially sugar sweetened beverage consumption, is convincingly associated with the risk of obesity weight gain, 1 3 53 which in turn is regarded as a strong risk factor for various cancers. 21 119 Another pathway mediating the association between dietary sugar consumption and the risk of cancer might involve a high glycaemic index or glycaemic load. The glycaemic index has been associated with the risk of type 2 diabetes mellitus, 120 which may be involved in carcinogenesis of the breast, prostate, liver, bladder, and endometrium. 120 121 Moreover, excessive fructose consumption might lead to intestinal flora disturbance and intestinal barrier deterioration, which promote the development of metabolic endotoxaemia, inflammation, and lipid accumulation, finally leading to colorectal carcinogenesis. 20 122 123 A recent animal study showed that high fructose corn syrup intake could induce intestinal tumourigenesis in mice by expediting glycolysis and de novo lipogenesis. The mice treated with the syrup had a substantially increased tumour size and tumour grade, independent of obesity and metabolic syndrome. 124 Considering the different mechanisms of site specific cancers, further prospective studies that explore the definite associations between sugar consumption and cancer risk for diverse cancer types and ethnic groups are warranted. 27

On the other hand, dietary sugar consumption has also been shown to be negatively associated with some neuropsychiatric diseases, such as depression and attention deficit/hyperactivity disorder. 77 80 Several biological mechanisms might be involved in these associations. Data from an animal study showed that a high fructose diet might alter behaviour, hypothalamic-pituitary-adrenal axis function, and the hypothalamic transcriptome in male Wistar rats, inducing anxiety-like behaviour and depressive-like behaviour. 125 Furthermore, sugar consumption has been suggested to stimulate the secretion of endogenous opioids in the nucleus accumbens and to stimulate the dopaminergic reward system. 27 Evidence of sugar dependence in an animal model indicated that similarly to addiction to morphine and cocaine, rats with intermittent sugar intake had decreased concentrations of dopamine D2 receptor mRNA in the nucleus accumbens and showed the characteristics of addictive-like behaviours called sugar addiction. 27 126

In addition, the adverse association between sugar consumption and bone mineral density might be attributed to the increased loss of urinary calcium and imbalance in calcium homoeostasis induced by high sugar intake. 127 As well as the negative effect of sugars, phosphate, acidity, and caffeine contained in sugar sweetened beverages are three other major factors that affect bone metabolism. 81 We note that for the link between sugar sweetened beverages and bone mineral density, stratification analysis by gender showed a significant harmful effect of sugar sweetened beverages on bone mineral density in females but not in males. 81 These diverse findings indicated that sugar sweetened beverage consumption had a more detrimental effect on female bone health than on male bone health because women generally have smaller bones and lower bone strength and are therefore more susceptible to osteoporosis. 128 Moreover, the high acidity of sugar sweetened beverages is also thought to be an important factor in promoting dental caries and tooth erosion. 129 130 131

Of the subgroup analyses conducted in this umbrella review, the most noteworthy is the stratification according to region, as several health outcomes showed a regional discrepancy, including overall cancer mortality, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and total cholesterol. Potential reasons for these discrepancies may include regional differences in sugar consumption and culture. According to the report conducted in 2010 for the quantification of global, regional, and national consumption of sugar sweetened beverages in 187 countries, consumption among Asian countries was lower than that among European and American countries. 33 The consumption of sugar sweetened beverages was highest in the Caribbean and lowest in East Asia and Oceania. 33 In addition, cultural factors have been shown to potentially cause different dietary quality and health inequalities by affecting food preferences or choices. 132 Regional cultural diversity in lifestyle and sociodemographic factors also plays an important role in dietary sugar consumption, which may partly explain the different relations between sugar consumption and disease risk in ethnically diverse populations. 132 133 On the other hand, subgroup analyses with adjustment for confounding factors should also be considered. High consumption of sugars, especially sugar sweetened beverages, may be a marker of an unhealthy diet and lifestyle. 9 66 People who consumed sugar sweetened beverages more frequently were likely to ingest more total and saturated fat, carbohydrate, and sodium and less fruit, fibre, dairy products, and wholegrain foods. 134 135 136 137 138 This dietary pattern was also associated with more frequent smoking and drinking, lower physical activity levels, and more time spent watching television. 137 138 Therefore, the role of these confounding factors should be taken into consideration when explaining the association between sugar consumption and burden of disease.

Strengths and weaknesses of study and in relation to other studies

This umbrella review first reported a comprehensive summary of the current evidence from previous meta-analyses of observational studies and randomised controlled trials for the association between dietary sugar consumption and all health outcomes. Given the high levels of dietary sugar consumption worldwide, this study has clinical and social significance for developing preventive strategies against excessive sugar consumption, especially for children and adolescents. This study was carried out on the basis of systematic methods in which independent literature searching, study selection, and data extraction by two authors were involved. If the data were sufficient, we reanalysed the risk ratio, odds ratio, weighted mean difference, or standardised mean difference with 95% confidence intervals through random or fixed effects models and evaluated the heterogeneity and publication bias for each included meta-analysis. Furthermore, we used three standard approaches, AMSTAR, GRADE, and evidence classification criteria, to assess the methodological quality (AMSTAR), strength (GRADE) and classification (evidence classification criteria) of evidence for each health outcome and to evaluate our confidence in the estimates. Interestingly, in our umbrella review, the GRADE rating of several health outcomes was not completely consistent with the results of evidence classification. As we know, evidence classification criteria are a completely objective classification standard, whereas the GRADE rating has a certain degree of subjectivity. 139 Therefore, both the GRADE rating and evidence classification criteria should be considered when evaluating evidence and making recommendations.

Original studies included in meta-analyses used different methods of food intake investigation, including food records, 24 hour dietary recall, food frequency questionnaires, and dietary history. All of these are associated with an unavoidable measurement bias even if validated methods are used. 3 This limitation is common to all major epidemiological studies carried out worldwide in this field. 21 In addition, most studies focused on beverages pre-sweetened before purchase. 9 For instance, in the Nurses’ Health Study, coffee with sugars was excluded from sugar sweetened beverages, which might affect the reliability of the association. 137 Similarly, another limitation of our study was that we could not evaluate sugar intake in some foods that potentially contain sugars, such as chocolate and ice cream, because of a failure to extract data on sugar consumption. Furthermore, the types of sugar sweetened beverages and dosage of their consumption varied in the original studies. In this umbrella review, most meta-analyses produced summary effects from original studies that measured exposure to dietary sugars through the number of servings a day. However, in some original studies, the number of millilitres a day, grams a day, times a day, times a week, times a month, servings a week, or servings a month were used to estimate sugar consumption, which may partly explain the origin of heterogeneity in meta-analyses. Therefore, dose-response analysis and stratification analysis by sugar sweetened beverage types were unavailable for most outcomes owing to diverse measurements of sugar sweetened beverage consumption in the original studies. Consumption of sugars in sugar sweetened beverages is generally accompanied by the ingestion of some other chemical compounds, such as 4-methylimidazole, 140 141 pesticides, 142 143 artificial sweeteners, 144 sodium benzoate, 79 and sulfites, 79 which may confuse the effect of sugars and therefore should be regarded as potential confounding factors.

We reviewed details of competing interest and funding disclosures from meta-analyses included in this umbrella review. Only two meta-analyses were funded by companies that produce sugar sweetened beverages. 65 145 Among them, the meta-analysis conducted by Wang and colleagues was selected for data extraction and is shown in summary tables. 65 Therefore, caution is warranted when explaining the non-significant association between fructose intake and postprandial triglycerides. Another meta-analysis was not selected for data extraction, 145 and the list of all meta-analyses not selected for data extraction and reanalysis are available if needed. We did not investigate the original studies included in each meta-analysis and therefore could not confirm whether these studies had a competing interest with companies associated with the sugar industry. 42

The harmful association between dietary sugar consumption and multiple health outcomes observed in our umbrella review is supported by several large scale prospective cohort studies published in recent years. The first was a large prospective cohort study conducted using the results of the French NutriNet-Santé cohort (2009-17), which included 101 257 participants with an average age of 42.2. 21 During the eight year follow-up period, a total of 2193 cases of cancer were reported, including 693 cases of breast cancer. A harmful association was found between sugar sweetened beverage consumption and the risk of overall cancer (hazard ratio 1.18, 1.10 to 1.27) and breast cancer (1.22, 1.07 to 1.39). No significant association was observed for sugar sweetened beverage consumption and the risk of prostate, colorectal, and lung cancer. 21 In this umbrella review, however, the highest versus lowest sugar sweetened beverage consumption was associated with a 17% increased risk of prostate cancer, without a dose-response gradient. Notably, the non-significant association between sugar sweetened beverage consumption and the risk of colorectal cancer observed both in this study and in our umbrella review was inconsistent with another cohort conducted in women. 20 In the Nurses’ Health Study II (1991-2015), the authors prospectively explored the association of sugar sweetened beverage consumption in adulthood and adolescence with the risk of early onset colorectal cancer among 95 464 women. A total of 109 cases of early onset colorectal cancer were confirmed during follow-up. Compared with women who consumed less than one serving a week of sugar sweetened beverages in adulthood, those who consumed two or more servings a day had a 118% higher risk of early onset colorectal cancer (risk ratio 2.18, 1.10 to 4.35). Each one serving a day increment of sugar sweetened beverage consumption was associated with a 16% (risk ratio 1.16, 1.00 to 1.36) increased risk of early onset colorectal cancer. 20 In addition, another prospective cohort study showed that excessive consumption of sugars and sugar sweetened beverage during adolescence was significantly associated with the risk of colorectal adenoma (odds ratio 1.20, 1.04 to 1.39). 146 Each one serving a day increase in sugar sweetened beverage consumption was associated with 11% (odds ratio 1.11, 1.02 to 1.20) and 30% (1.30, 1.08 to 1.55) higher risks of total colorectal adenoma and rectal adenoma, respectively. 146 Given that the association between sugar consumption and colorectal cancer risk remains controversial, further well designed, large scale prospective studies are needed to clarify it.

The positive associations between sugar sweetened beverage consumption and the risk of mortality detected in this umbrella review were supported by a prospective cohort study of 118 363 people followed for 34 years in the US, during which time 36 436 deaths were documented. 147 After adjustment for diet and lifestyle confounders, the consumption of two or more servings of sugar sweetened beverages a day was linked with a 21% (hazard ratio 1.21, 1.13 to 1.28) higher risk of total mortality, a 31% (1.31, 1.15 to 1.50) higher risk of cardiovascular disease mortality, and a 16% (1.16, 1.04 to 1.29) higher risk of cancer mortality. 147 On the other hand, a prospective cohort study of 120 343 UK participants followed for 8.4 years confirmed the harmful association of added sugar consumption with the risk of type 2 diabetes mellitus. 148 A dietary pattern high in added sugars was associated with a higher incidence of type 2 diabetes mellitus (hazard ratio 1.09, 1.06 to 1.12) after adjustment for confounders. 148 Similar to their findings, we observed a strongly significant association between consumption of sugar sweetened beverages (one of the main sources of added sugars) and the risk of type 2 diabetes mellitus.

Conclusions and recommendations

This umbrella review shows that high dietary sugar consumption, especially intake of sugars that contain fructose, is harmfully associated with large numbers of health outcomes. Evidence for the harmful associations between dietary sugar consumption and changes in body weight (sugar sweetened beverages), ectopic fat accumulation (added sugars), obesity in children (sugar sweetened beverages), coronary heart disease (sugar sweetened beverages), and depression (sugar sweetened beverages) seems to be more reliable than that for other outcomes. Evidence of the association between dietary sugar consumption and cancer remains limited but warrants further research. In combination with the WHO and WCRF/AICR recommendations and our findings, we recommend reducing the consumption of free sugars or added sugars to below 25 g/day (approximately six teaspoons a day) and limiting the consumption of sugar sweetened beverages to less than one serving a week (approximately 200-355 mL/week). 38 119 To change sugar consumption patterns, especially for children and adolescents, a combination of widespread public health education and policies worldwide is urgently needed.

What is already known on this topic

Sugar consumption could have negative effects on health, especially obesity, diabetes, cardiovascular disease, hyperuricaemia, gout, ectopic fatty accumulation, dental caries, and some cancers

Deficiencies in study design, varying measurements, inconsistent findings, and different definitions of exposure make drawing final conclusions on associations difficult

Comprehensive evaluation of the quality of existing evidence on the associations of sugar consumption with all health outcomes is needed

What this study adds

High dietary sugar consumption is generally more harmful than beneficial for health, especially in cardiometabolic disease

Evidence of the association between dietary sugar consumption and cancer remains limited but warrants further research

Existing evidence is mostly observational and of low quality, and further randomised controlled trials are needed

Ethics statements

Ethical approval.

Not needed.

Data availability statement

The list of all meta-analyses not selected for data extraction and reanalysis is available if needed.

Acknowledgments

We thank Nanxi Yan for her linguistic assistance during the preparation and revision of this manuscript.

Contributors: YH, ZYC, BC, and, JZL are joint first authors and contributed equally to this work. QW, DHC, and LRL are joint corresponding authors and contributed equally to this work. YH, ZYC, BC, and JZL conducted study selection, data extraction, and analysis and wrote the manuscript. QW, DHC, and LRL designed the study, supervised the project, and revised the manuscript. XY, JL, WW, TTD, HYC, YW, RYW, PZW, JBG, QD, and CFL assisted with detailed statistical analysis. All authors reviewed and approved the final version of the manuscript. LRL is the guarantor. The corresponding authors (QW, DHC, and LRL) attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: This study was funded by the National Natural Science Foundation of China (grant number 82000721) and Program from the Department of Science and Technology of Sichuan Province (grant number 2020YJ0054). The funders had no role in considering the study design or in the collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Natural Science Foundation of China and Program from the Department of Science and Technology of Sichuan Province for the submitted work; no financial relationship with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patients and public communities: After publication, the findings of this review will be disseminated to appropriate audiences such as academia, clinicians, policy makers, and the general public, through various channels including blogs, press releases, and social media.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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5 Important Discoveries About Sugar's Effect on the Brain

3. we love it even when we can't taste it..

Posted March 28, 2023 | Reviewed by Ekua Hagan

• What are healthy approaches to dieting?
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• Sugar is one of the most common ingredients in the modern U.S. diet.
• The more sugar a person eats, the more sweet-tolerant they become.
• The potent brain effects of sugar help explain the modern sugar obsession and frequent difficulties moderating sugar consumption.

Sugar is the Dr. Jekyll and Mr. Hyde of the nutrition world. Pleasure and poison, desire and danger, love and Lucifer—sugar somehow embodies all these qualities and more in our modern culture.

Part sweet-tasting nutrient (sugar is a source of carbohydrates, one of the three major macronutrients along with fat and protein) and part mind-altering substance, sugar began taking Western civilization by storm in the 18th century. By the 21st century, sugar's candied conquest of the U.S. was complete, appearing as an additive in two-thirds to three-fourths of all food and drinks. 1

While most recent media attention to sugar focuses on potential health harms and ways to reduce sugar intake, neuroscientific research about sugar has revealed how and why this plain white substance wields so much power in our lives. Here are five of the most compelling findings:

1. Your sweet tooth may be made (experience and exposure) rather than born (genetic).

In a March 2023 study published in Cell Metabolism , 2 researchers reported findings from a clinical trial of normal-weight adults assigned to consume either a daily high-sugar/high-fat snack or a low-sugar/low-fat snack. Over the eight weeks of the study, the researchers observed a pronounced increase in the high-sugar/high-fat group's dopamine response to the sweet snack and a pronounced decrease toward low-sugar/low-fat options.

What does this mean? A sweet tooth can be rapidly learned. With just a few weeks of regular exposure to high-sugar foods, participants' brains in this study rewired themselves to find these foods more pleasurable and dislike alternatives.

2. Sugar tolerance is a real thing.

Have you ever consumed something so sweet that it actually made you feel ill? If so, ask yourself how Americans can stomach eating, on average, over 126 grams (almost 30 teaspoons) of sugar a day.

The answer is that the more sugar we eat, the more sweet-tolerant we become. Many people don't realize that their tastebuds are dynamic. Name any primary taste—sweet, salty, sour, bitter, umami—and consider that the tastebuds detecting them change (i.e., becoming more or less sensitive) depending on how much we're exposed to that taste.

Technically called "chemosensory plasticity," if you wish to impress your friends, numerous studies show in species ranging from insects to humans that high-sugar diets rapidly increase tolerance to sweet tastes. 3 What was once too sweet to stomach now becomes just right. For the typical person, this increased sweet tolerance is clearly measurable in just a month. 4

3. We love sugar even if we can't taste it.

Mother Nature is too smart to be fooled by artificial sweeteners. She knows how to detect real sugar. In fact, she gave you not one, but two systems to make sure of it. System one is your tastebuds; the ability to detect sweet tastes is programmed right into our mouths.

Most people, however, don't know about the second system. Beyond our conscious awareness, we possess a biochemically mediated pathway connecting our digestive system to the reward circuits in our brain. This reward pathway is more strongly stimulated by sugar than by non-caloric artificial sweeteners. 5

This effect is so potent that scientists have conducted studies in insects and rodents where the genes responsible for sweet taste detection are deactivated (i.e., they can no longer taste sweets). The organisms still strongly prefer sugar-sweetened (but not artificially sweetened) water due to this secondary brain-reward system. 6

4. Sugar is a pacifier for the mind.

One of the most common reasons fueling our sugar preoccupation is the rapid soothing effect it has on our emotions. Almost from birth in the U.S., we begin pacifying ourselves with food and drink. The most effective "comfort foods" almost always contain significant amounts of natural or added sugars (e.g., pizza is often rated as the favorite comfort food in the U.S., yet even a typical slice of pizza contains five to six grams of added sugar). This is no coincidence.

Sugary foods calm us in two ways: via the hedonic properties of the food (sugar triggering the dopaminergic brain reward pathway) and by altering metabolic and neurohormonal function (e.g., lowering cortisol levels and up-regulating " happiness hormones " like serotonin). 7 In combination, these effects make sugar a potent balm for stress and predispose us to overconsumption.

5. Sugar delights the senses but dampens brain function.

Although health experts caution us about sugar consumption due to sugar's contribution to obesity and diabetes, arguably the most worrisome harm associated with sugar is its effect on brain function.

Sugar appears to interfere with healthy brain function in at least two ways. Firstly, some laboratory experiments show that sugar adversely affects genes regulating the hippocampus—an area of the brain critical to memory and learning. Surprisingly, the negative impact of sugar on hippocampal function may be as severe as the effects of early life stressors. 8

Secondly, excess sugar consumption causes dysbiotic changes in the gut microbiome (the bacteria living inside the stomach and intestines) that also disrupt the hippocampus. 9 Collectively, this research may help explain the growing scientific consensus regarding a potential causal relationship between high-sugar diets and dementia .

Sugar is a ubiquitous and pleasurable part of modern life. Yet like other two-faced companions of modernity—such as social media and smartphones—we can benefit from research that helps us balance the risks with the rewards.

Facebook image: Drazen Zigic/Shutterstock

1. Popkin BM, Hawkes C. Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses . Lancet Diabetes Endocrinol. 2016 Feb;4(2):174-86.

2. Sharmili Edwin Thanarajah, Alexandra G. DiFeliceantonio, Kerstin Albus, Bojana Kuzmanovic, Lionel Rigoux, Sandra Iglesias, Ruth Hanßen, Marc Schlamann, Oliver A. Cornely, Jens C. Brüning, Marc Tittgemeyer, Dana M. Small, Habitual daily intake of a sweet and fatty snack modulates reward processing in humans, Cell Metabolism, 2023, ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2023.02.015 .

3. May CE, Dus M. Confection Confusion: Interplay Between Diet, Taste, and Nutrition. Trends Endocrinol Metab. 2021 Feb;32(2):95-105. doi: 10.1016/j.tem.2020.11.011.

4. Wise PM, Nattress L, Flammer LJ, Beauchamp GK. Reduced dietary intake of simple sugars alters perceived sweet taste intensity but not perceived pleasantness. Am J Clin Nutr. 2016 Jan;103(1):50-60. doi: 10.3945/ajcn.115.112300.

5. Wilk K, Korytek W, Pelczyńska M, Moszak M, Bogdański P. The Effect of Artificial Sweeteners Use on Sweet Taste Perception and Weight Loss Efficacy: A Review. Nutrients. 2022 Mar 16;14(6):1261. doi: 10.3390/nu14061261.

6. High Dietary Sugar Reshapes Sweet Taste to Promote Feeding Behavior in Drosophila melanogaster. Cell Rep. 2019 May 7;27(6):1675-1685.e7. doi: 10.1016/j.celrep.2019.04.027.

7. Ulrich-Lai YM. Self-medication with sucrose. Curr Opin Behav Sci. 2016 Jun;9:78-83. doi: 10.1016/j.cobeha.2016.02.015.

8. Maniam J, Antoniadis CP, Youngson NA, Sinha JK, Morris MJ. Sugar Consumption Produces Effects Similar to Early Life Stress Exposure on Hippocampal Markers of Neurogenesis and Stress Response. Front Mol Neurosci. 2016 Jan 19;8:86. doi: 10.3389/fnmol.2015.00086.

9. Noble, E.E., Olson, C.A., Davis, E. et al. Gut microbial taxa elevated by dietary sugar disrupt memory function. Transl Psychiatry 11, 194 (2021). https://doi.org/10.1038/s41398-021-01309-7 .

Thomas Rutledge, Ph.D. , is a Professor-in-Residence in the Department of Psychiatry at UC San Diego and a staff psychologist at the VA San Diego Healthcare System.

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• Published: 09 December 2023

Sugar substitutes and taste enhancers need more science, sensitivity- and allergy-guided labeling

• D. A. Steindler   ORCID: orcid.org/0000-0002-9891-8455 1  

npj Science of Food volume  7 , Article number:  64 ( 2023 ) Cite this article

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There is new attention to food safety resulting from the second White House Conference on Hunger, Nutrition, and Health, as well as new advisories from the World Health Organization calling for more research on sugar substitutes because of possible cancer risks. Together they point to a need for rethinking how we study sugar substitutes and taste enhancers as potentially contributing to adverse health changes. In addition to the need for more research on sweeteners and taste enhancers, including the use of sensitive bioassays, and epidemiological and human clinical trial studies, there should be a call for better truth in labeling, especially including single names for such dietary elements that would afford easier recognition and potential avoidance by those with sensitivities and allergies.

On the heels of the second, some 50 years after the first, “White House Conference on Hunger, Nutrition and Health”, along with the “Biden-Harris Administration National Strategy on Hunger, Nutrition and Health”, food safety is an important area of focus. The World Health Organization cancer agency’s recent advisory on the artificial sweetener, aspartame, and its potential cancer risk, in addition to their new guideline on not using non-sugar sweeteners for body weight control, all together signal a need to revisit how to best study sugar substitutes and other food additives for their potential negative physiological actions as their presence grows in our food supply. This also follows two studies of the NutriNet-Santé population-based cohort that have linked both “artificial sweeteners” as well as “sugar consumption” itself with potentially elevated cancer risks 1 , 2 . Two more recent studies on aspartame 3 and erythritol 4 have brought additional interest in food safety and better product labeling of sweeteners (with most of the field and practitioners recognizing the availability of these sugar substitutes as being needed for those with certain health issues including obesity, diabetes, and heart disease) and flavor enhancers. Of course, sugar itself is contraindicated for these health issues, and should also be studied in all of the paradigms and models discussed here, but like sugar, enhancing the umami taste with additives can also lead to obesity, metabolic syndrome, and brain, e.g., hypothalamic, inflammation which has been described as, “…mediated by nucleotide degradation and uric acid generation…’ 5 . The 1969 White House Conference on Food, Nutrition, and Health was organized by Dr. Jean Mayer, for whom the previous institution of food and nutrition science where I was privileged to work was named. Professor Mayer also studied a controversial, umami taste-enhancing food additive, monosodium glutamate (“MSG”), in animal models 6 , and it is still controversial today. Kanarek et al.’s 6 findings on deficits in caloric restriction and juvenile-onset obesity, along with Mayer’s advocacy and similar reports from other groups, ultimately led to baby food manufacturers suspending MSG use after Congressional Hearings questioned its safety. A conclusion will be reached here that more research and thoughtful product labeling will help the cause of food safety in general, as new consumables and warnings are introduced. In a constantly changing landscape from both new product introductions and new research findings, an open mind is warranted when it comes to supporting or challenging regulation.

There are many critical questions with both the Jones et al. 3 and Witkowski et al. 4 studies, but together they provide a powerful impetus for industry and government to come together to help remove stigma over debate of adverse health effects of food additives. This is needed in the meantime until we have better modeling and studying of the distinct human omics, including metabolomics, of food sensitivities within a heterogeneous population offering better stratification of at-risk populations with sensitivities and allergies. This ultimately will lead to easier scrutiny of substances that can trigger adverse health events in certain susceptible individuals who now rely almost totally on truth in labeling, or more accurately, sensitivity- and allergy-guided labeling (since current labeling usually does include names for food components that are truthful, but because of the pervasive use of pseudonyms for many of these additives, it is not obvious or clear enough for easy recognition of any food component that may be undesirable for those with health issues, allergies or sensitivities). All of us are at risk for unrecognized dietary elements that could contribute to potentially serious allergies and sensitivities 7 . Building on the needed use of highly sensitive models and bioassays, and comparisons with carefully run patient studies to determine the actions of dietary components, this Comment hopes to expand the awareness of the significance of studies like these that aim to uncover pathophysiological changes from the consumption of certain food additives. This issue has now been brought to light again from the findings in these new studies on the dietary consumption of artificial sweeteners, aspartame, and erythritol 3 , 4 , and raises concern again about the safety of additives in our food supply, with potentially adverse health effects that range from neurological to cardiovascular changes. Of considerable concern, the aspartame study reported a transgenerational passage of molecular and physiological changes in the amygdala of a robust animal model, that led to altered neurotransmission and changes in behavior including anxiety in descendants of users 3 . Jones et al conclude their recent study of aspartame’s transgenerational transmission affecting higher function forebrain areas, with the strong suggestion that aspartame’s effect on brain gamma amino butyric acid, “GABA” and glutamate signaling, “…deserves a place on the list of environmental agents such as hormones, insecticides, and drugs of abuse whose adverse effects are not limited to the exposed individuals but manifest in multiple generations of descendants…” 3 . It is noteworthy that this study was done in a rodent model, and therefore before drawing conclusions on human aspartame use, there is a need to see if these findings translate to the human condition. This rodent aspartame study did however attempt to reconcile animal versus human exposure and dosing regimen differences, by having a drinking water dose equivalent to 8–15% of the FDA’s recommended maximum daily intake for humans.

Since aspartame is a derivatized form of the amino acid, aspartic acid, it is also reasonable to consider another widely present food additive for enhancing the savory “umami” taste - another “excitatory amino acid” 8 and glutamate derivative, monosodium glutamate (“MSG”). It is now ubiquitously present in our food supply, including its increasing presence in synthetic meats because of the need for a savory component. MSG’s potential effects on metabolic and neurologic function 5 , 6 , 9 , 10 have also been considered as a potential “threat to public health” 11 .

There is debate, triggered in part by the recent publications on aspartame and erythritol, as well as other recently challenged sweeteners and other food additives, within government, industry, and academia regarding the regulation of product labeling of dietary additives, taking into consideration the United States Food and Drug Administration adopting generally regarded as safe, “GRAS”, for many of these products 7 , 11 . A history of controversy and contentiousness in the description, discussion, and introduction of artificial sweeteners and umami taste enhancers into our food supply has resulted in confusion and to some extent, apathy, amongst scientists, industry, healthcare, and the general public. This may result in part because of a sense of security when it comes to additives that come from natural sources. Erythritol, which the body produces and which also can be found naturally in some foods, is mass-produced for consumption from yeast fermentation. Glucose, sucrose, fucose, erythritol, Stevia, Monk fruit, and other plant-derived sweeteners are different from derivatized compounds like aspartame, whose function may be altered from additive preparation protocols (e.g., adding elements to produce a methyl ester of the aspartic acid/phenylalanine dipeptide, aspartame or “NutraSweet”; or adding sodium to the native chemical structure of glutamate in the case of MSG), are all presumed to be GRAS unless the field finds further evidence of health risk. An argument that these particular additives should not affect one’s physiology any more than the consumption of such substances that the body creates or that occur naturally in certain foods (e.g., erythritol, tomatoes, and mushrooms that contain free glutamate that could have sodium groups added during digestion), needs to be considered in light of introducing boluses of the already derivatized compounds like MSG, in individuals with an extreme sensitivity to the derivatized compound but not to the natural underivatized sources. The two represent completely different processes with different physiological outcomes. In light of the recent publication from the Bhide group 3 , which presented data on altered omics responses from consumption of aspartame, including metabolomics, in studies that unfortunately do not afford direct comparisons of in vitro and in vivo mouse data with such human data, this work supports a conclusion for revisiting the safety of aspartame 12 , 13 , as well as the other excitatory amino acid derivatives including MSG. This should go beyond the scrutiny of neurological disorders to also have analyses of physiological, biochemical, and metabolic processes that include potential rodent and human cardiometabolic risk 4 , 5 , 6 , 13 . The Bhide article nonetheless challenged previous attempts at downplaying or questioning potential adverse effects of aspartame, including anxiety disorders in susceptible populations that can be transgenerational transmitted. Just as with this the artificial sweetener, aspartame, another sugar substitute, erythritol, exhibited the potential to contribute to changes in the heart and vascular systems 4 .

The Witkowski et al. study 4 initially used an untargeted metabolomics approach, combined with a patient study and using blood analysis for quantifying the presence of endogenous erythritol levels, not related to consumption that they did not test in that patient cohort. They used different in vitro and in vivo approaches that don’t necessarily lend themselves to easy comparisons of the different findings from in vitro versus in vivo studies.. They reported that, “…circulating levels of multiple polyols, especially erythritol, was associated with incident (3 years) risk for major adverse cardiovascular events…”, including heart attack and stroke, and their observed effects on thrombosis even though they did not carry out coagulation studies in subjects following erythritol consumption… “, warrant more scrutiny by science, medicine, industry and government since currently, “…The FDA does not require disclosure of erythritol content in food products, making its levels in foods as an additive is hard to track…” 4 . There are apparent methodological and concomitant interpretation shortcomings in the erythritol study because the investigators did not analyze erythritol levels and platelet function after consuming this sweetener, and it is possible that the levels they measured were from endogenous production, potentially from an elevated glucose level and it’s production of erythritol. That said, the author’s goal, as well as that of the current author, is to stimulate more science and clinical studies that are needed for erythritol and all currently used sugar substitutes. Interestingly, MSG has also been a focus of many observational and other epidemiological and experimental studies showing potential adverse effects on both cardiovascular and neurological functions 10 , 11 , 12 , 13 , 14 , and therefore it has also been considered as a potential “threat to public health” 11 .

The safety of the artificial sweetener, derivatized “excitatory amino acid” 8 aspartame, has been revisited a great deal over the last several decades 12 , 13 , ever since Olney and colleagues first introduced the concept that consuming aspartates and glutamates can have profound effects, including negative ones, on our physiology and health 8 , 9 , 10 , 14 . The new studies (e.g., 3,4) have brought this issue to light once again, this time with the rather surprising altered brain gene expression patterns and other findings on aspartame, relevant to GABA and glutamate transmission in the rodent forebrain. Changes in this GABA and glutamate neurotransmission is associated with anxiety and other affective disorders, and their findings showed that, “…aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation…and changes in gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males…” 3 . There certainly may be more than one type of sugar substitute that exhibits potentially adverse physiological effects on both the brain and heart, as presented in another recent study that questioned the toxicity of sucralose and its derivative, sucralose-6 acetate, in a cell culture system using human blood cells, and where DNA strand breaks were produced 15 . And yet another recent study, this time looking at acesulfame-K, a sugar-substitute present in many foods and especially drinks and which is not significantly biodegraded either in our bodies or in the environment as seen in e.g., wastewater analysis 16 , exhibited effects on the state of isolated human blood neutrophils – “homeostasis to priming” 17 . We still do not know all of the health effects of this artificial sweetener, but certainly, there should be freedom of choice to eat foods that contain all of the aforementioned sugar substitutes as well as taste-enhancing food additives like MSG until otherwise regulated. That said, clear and substantive information must be provided on food labels, to afford informed decisions, as well as easy scrutiny and recognition for those who would want to completely avoid them. This requires single names for food additives in such “flavor enhancing” categories, that can be prominently displayed on packaging and thus avoided by those who choose to do so.

It is well accepted that there are foods and nutrients with the ability to affect everything from heart rhythm to brain cognition, plasticity, cancer, and neurodegenerative disease onset and progression 18 . It is possible that such derivatized excitatory amino acids are involved with certain human health conditions involving the nervous or cardiovascular systems including atrial fibrillation. This may not be so surprising in light of MSG often being described by clinicians as having the ability to cause “palpitations” in certain individuals, and atrial fibrillation has also been linked to the combined use of aspartame and monosodium glutamate 14 , 19 , 20 . There have been many articles and perspectives written about sugar substitutes versus the use of their “natural” counterparts, in addition to articles about the virtues and risks associated with MSG consumption. The current Comment relied on a nearly coincidental publication of two rather visible research articles on the sugar substitutes aspartame and erythritol to, again, make a call for more truth in labeling and rigorous scientific investigation of these and other sweeteners including the “natural” ones (e.g., sucrose, fructose, and glucose). This should also therefore include flavor enhancers like MSG with similar biochemical and metabolic properties to the other derivatized excitatory amino acid taste-enhancing additives (e.g., aspartame). To date there has been little attention paid to the potential physiological and metabolic effects of derivatized excitatory amino acids (“excitatory” in this case again refers to the free forms of these particular amino acids having excitatory versus inhibitory actions on CNS neurons, with a potential to elicit tissue damaging excitotoxicity 8 , 9 , 10 ). This should include the promotion of new and robust multi-omics applications in in vitro and in vivo bioassays of any consumable in question 18 . This recently has been put to the test in a study of a “disease avatar” for use in bioassays, by looking at glial activation and the inflammation-associated hippocampal microenvironment relevant to age-related cognitive decline and Alzheimer’s disease 21 . This work, done in the author’s laboratory, is a proof of principle for this approach and focused on three widely studied, putative anti-inflammatory nutrient agents: curcumin, sulforaphane-rich broccoli sprouts, and epigallocatechin-3-gallate (EGCG) from green tea, individually and in combination. It was found that, together, they had the ability to attenuate the tissue-increased inflammatory level of chemically-stressed hippocampal neurons and microglia in cell culture 21 . Such work 18 , 21 represents a new approach for studying discrete effects of a combination phytonutrient for positively affecting human physiology and health, and is applicable to bioassays for any food or nutrient component.

In all, for the author, this story is respective and it was originally intended to be a firsthand essay in part inspired by the publication of the Bhide and Witkowski groups’ articles. A pragmatic self-understanding of the etiology of such additive sensitivities, from experiential in addition to the perspective gained from physiology, molecular medicine, and nutrition science of neurological and cardiovascular risk including arrhythmias, consumption of aspartame with subsequent unintended exposures to MSG led to attempts at preventing and mitigating, in my case, notable consequences. Carrying a list, e.g., of almost twenty commonly used names for the umami flavor enhancer and its sources, and handing it to willing food servers for their conferring with the kitchen about any foods that might contain MSG or any of its pseudonym sources, especially from prepackaged vendors rather than made in that kitchen, ultimately proved to be inadequate. With such attempted vigilance, the burden of too many names for MSG to afford scrutinization of every prepared food item label in a restaurant’s kitchen ultimately led to, at best, confusion and avoidance, or in the worst case scenario from casting fate to the wind, countless cardiac events over the years. In many ways, the derivatized glutamate, MSG, is not so different from the aspartic acid derivative, aspartame, with many previous studies including some that associated the use of aspartame and MSG with atrial fibrillation in certain people 19 . Focusing on the two articles about aspartame and erythritol 3 , 4 afforded an opportunity to bring personal experience and knowledge into the discussion of the potential that there are others, like me, who might also have just the perfect omics storm, especially genomics, and metabolomics, that can contribute to potentially extreme sensitivities to such derivatized excitatory amino acids. The sugar substitutes, as well as their natural food targets, MSG and other additives, and for that matter, any consumable, can be modeled and robustly studied in the laboratory as well as their in-human use through carefully designed clinical trials that include extensive multi-omics analyses, both from the patient as well as from their experimental “avatar” 18 , 21 .

Thus, there is a need to encourage both further research and especially dialogue amongst investigators about the need for a better understanding of the physiology and potential toxicity of flavor enhancers for particular at-risk individuals. This holds promise to help those with extreme sensitivities to even small quantities of a particular additive, to not have to deal with many confusing names for it that they may not tolerate well. There is a need for utilizing more sensitive bioassays, including controls and human subjects with health issues and food sensitivities or allergies, in a dietary-risk “avatar” model that possesses personalized risk and disease elements such as immune and relevant at-risk tissue cells, for deep interrogation that could include machine learning of the cell and molecular biology of therapeutic and potentially contraindicated foods and nutrients 18 .

The umami taste enhancer, MSG, including any of its pseudonym sources e.g., hydrolyzed vegetable protein(s) of different vegetable origins, autolyzed yeast extract, and Torula yeast, increases appetite via stimulating the savory flavor and has been implicated in metabolic syndrome, as well as potentially contributing to cardiac and central nervous system changes (5, 6, 9, 10, 11, 14). MSG is believed to stimulate the release of glucocorticoids and catecholamines from the adrenal glands 22 , 23 , that can affect the heart directly or through other systemic metabolic and inflammatory actions that can lead to changes in heart rate and/or rhythm. Similar changes in brain electrophysiology via altering glutamate and GABA neurotransmission could affect numerous connectional and molecular pathways leading to cardiovascular, behavioral, and cognitive changes. Many synthetic derivatives, along with increasing numbers of other names for sources of MSG, are appearing on food labels that make surveillance and thus avoidance difficult. It is noteworthy that previous work has suggested the possibility of cell and tissue, including both heart and brain, excitotoxicity resulting from consumption of so-called excitatory amino acids and their derivatives 8 . These compounds have been reported to reach sites in the central nervous system possessing a weak blood–brain barrier, including circumventricular organ access to the chief autonomic and neuroendocrine center of the brain, the hypothalamus 9 , 10 , 24 . Excitotoxicity also has been discussed in relation to gliomagenesis 25 and possibly other pathological conditions 26 .

Sugar substitutes, the aspartates and glutamates, or any other additive or food component in question, can be further examined in future epidemiological studies, and despite the nutritional science field acknowledging that well-controlled human and behavioral studies are difficult, the precise effects of dietary components on human physiology and behavior can be determined. As has been applied in the Jones et al study of an artificial sweetener like aspartame 3 , or as attempted in the erythritol study 4 , any consumable in question could be assayed both ex vivo and in highly controlled and carefully executed human behavioral paradigms, e.g., as shown by Brickman et al looking at cocoa flavonoid’s role in supporting human memory function 27 . It is notable that the field of oncology is paying close attention to such approaches for also studying food as medicine, e.g., supporting cancer therapies, and in silico and other screens are beginning to uncover natural product sources of oncogenic-network-mediating drugs. For example, a study of WWP1- of the human tumor suppressor gene, PTEN, has uncovered potent inhibitors of this oncogenic axis, derived from cruciferous vegetables in a mouse avatar model 28 . There is a need for reinforcing findings on dietary component contributions to normal and pathophysiological functions, via comparison with in vitro and in vivo animal modeling experiments of the same dietary components. Robust in vitro cell and tissue preparation assays, along with in vivo animal models (transgene, knockout, and at-risk cell xenografts) that focus on gene expression patterns, cell biology, physiology, and behavior that may be affected by any food component in question, can help establish generalized effects of foods and food products on human central nervous system, heart as well as other tissue and organ function 18 .

It is reasonable to suggest that following a similar protocol as presented for the screening of neuroactive, regeneration-supporting, or nutrient components 18 , food additives and other dietary elements can be directly assayed in such models for their potential contributions to sensitivities and counterproductive health effects in susceptible individuals. This can employ state-of-the-art methods including omics, cell, molecular and systems biology, where together, “…Any dietary intervention, whether for purposes of diagnosis or management of a food allergy or intolerance, should be adapted to the individual’s dietary habits… [and sensitivities to additive ‘food chemicals’]… ” 7 , and one’s individual omics and nutritional requirements, that together can help prevention and mitigation of related health challenges. At the same time, these approaches offer the potential for deep characterization and stratification of populations of people at risk for diet-associated cardiac arrhythmias, and other heart and brain disorders. These patients may be amenable to diet, lifestyle, and behavioral modifications as an adjunctive therapeutic approach to be used along with standard-of-care medicine or emerging treatments for any health malady they are also having to deal with.

With more epidemiological and modeling studies providing data on food and food additive sensitivities, it is hoped that both industry and government will respond with better documentation of potential non-IgE allergies and sensitivities. This should not affect access from the population who wants and may not have the risk for the dietary contribution in question, but rather it would allow at-risk populations the opportunity for easier scrutiny and avoidance. Ultimately, people who desire to keep particular sugar substitutes and flavor enhancers in their diet, irrespective of possible food sensitivities that could put them at risk for health challenges, should have the right to purchase and consume these products. As pointed out by Witkowski et al., 4 , their findings regarding erythritol, “… highlight the need to establish reporting requirements, safety profiles and margins of daily intake amounts given that broad consumption continues to increase. Public policy decisions need to be evidence-based and better informed…” But with regard to regulation, it is important that we remain open to emerging findings that could inform revisions or the addition of new guidelines. It is clear that the area of nutrition science that focuses on sweeteners and flavor enhancers is constantly being defined and redefined. There is a need for human clinical studies that, in addition to strategically complementing laboratory and modeling studies, examine the effects of any consumable that is purported to be neither safe nor healthy in a longer time period and randomized controlled trials, that include a greater number of subjects with food sensitivities, especially to that consumable. In addition to the need for more science, and the need to increase our knowledge of the physiological actions of different sugar substitutes and taste-enhancing additives in our diet, it behooves us to have truth in package labeling, with simple and clear names for compounds and components present in our foods, since we all possess allergies and sensitivities 7 that from ongoing advances in bioassays and data science should afford us easier scrutiny of any food component, and informed decision-making on its use.

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Acknowledgements

I would like to thank Drs. Howard Horn, James Kirshenbaum, Peter and Joan Cohn, David Iansmith, Jamie Conti, Michael Jantz, Vilma Torres, Sonja Solomon, Paul Zei and Adrienne Samuels, and MGH’s Debbie Krivitsky, and finally J.U. Steindler for their help and support.

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Steindler, D.A. Sugar substitutes and taste enhancers need more science, sensitivity- and allergy-guided labeling. npj Sci Food 7 , 64 (2023). https://doi.org/10.1038/s41538-023-00240-z

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• Cancers (Basel)

Understanding the Link between Sugar and Cancer: An Examination of the Preclinical and Clinical Evidence

Margeaux epner.

1 Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA

Peiying Yang

2 Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA

Richard W. Wagner

Lorenzo cohen, associated data.

Not applicable.

Simple Summary

The average consumption of sugar in the US is significantly higher than the World Health Organization’s, the American Cancer Society’s, and the American Heart Association’s recommendations for daily sugar consumption. This review summarizes the research on the link between added sugar and cancer and the plausible mechanisms for a causal association. Evidence from epidemiologic and preclinical studies demonstrates that excess sugar consumption can lead to development of cancer and progression of disease for those with cancer independent of the association between sugar and obesity. The mechanistic preclinical studies in multiple cancers show that high-sucrose or high-fructose diets activate several mechanistic pathways, including inflammation, glucose, and lipid metabolic pathways.

Per capita sugar consumption has increased in the United States to over 45 kg per year. The average person in the US currently consumes significantly more added sugar in their diet than the World Health Organization’s, the American Cancer Society’s, and the American Heart Association’s recommendations for daily sugar consumption. Evidence from epidemiologic and preclinical studies demonstrates that excess sugar consumption can lead to development of cancer and progression of disease for those with cancer independent of the association between sugar and obesity. Human epidemiologic studies and mechanistic preclinical studies in multiple cancers support a causal link between excess sugar and cancer. Preclinical studies show that high-sucrose or high-fructose diets activate several mechanistic pathways, including inflammation, glucose, and lipid metabolic pathways. Although human studies are limited, compelling human and primate studies have explored the link between added sugar and metabolic syndrome (MetS), a risk factor for cancer. Substantial evidence suggests a causal link between MetS and added sugar, indicating important implications in the association between excess sugar consumption and cancer. Human clinical trials are needed to determine whether sugar increases cancer development and progression independently of its established role in causing obesity as well as for further exploration of the mechanisms involved.

1. Introduction

Historically, the highest cancer rates were in high-income countries, yet cancer is now ravaging low- and middle-income countries [ 1 ]. This is especially true for what are considered lifestyle- and obesity-related cancers, such as breast, prostate, colon and rectal, kidney, liver, pancreas, uterine, ovarian, and others. The “Westernization” of diets with increased consumption of highly processed foods and added sugars is viewed by many as the culprit [ 2 ]. The average United States resident consumes over 350 calories (approximately 21 tsp) of added sugar daily, which is significantly higher than the American Cancer Society’s, the World Health Organization’s (WHO), and the American Heart Association’s (AHA) recommendations for sugar consumption [ 3 , 4 , 5 , 6 ].

The Dietary Guidelines for Americans 2020–2025 [ 7 ], the ACS [ 4 ], and the WHO [ 8 ] recommend limiting added sugars to no more than 10% of total calories. For a 2000-calorie diet, that means about 200 calories from added sugars. The WHO has a further conditional recommendation to reduce added sugar consumption to less than 5% of calories, about 100 calories. This is more in line with the AHA recommendations of no more than 100 calories for women and 150 calories for men [ 6 ]. However, as can be seen in Figure 1 , the US population consumption far exceeds even the more “generous” recommendations, consuming more than 350 calories from added sugars on average. Between the 1970s and the 1990s, there was a precipitous decrease in the consumption of refined cane and beet sugars, yet a sharp increase in high fructose corn syrup (HFCS). In the late 1990s, consumer and organizational pressures against using HFCS led to a reduction in HFCS consumption. Unfortunately, that reduction in HFCS consumption paralleled an increase in cane and beet sugars with the promise that being “natural” would be less harmful ( Figure 1 ). Although total added sugar intake is down from 2000, total calorie intake increased from 2000 calories in 1970 to 2500 calories in 2010 (subsequent data not available). Furthermore, other calorie sources from high-glycemic-load, refined, fast-digesting carbohydrate foods (e.g., white flour, corn flower, and corn starch, etc.) have also increased, and, combined with added sugars, account for nearly 900 calories a day [ 5 ].

Average daily per capita calories from added sugars in the United States from 1970 through 2016. Food Availability (Per Capita) Data System; Loss-Adjusted Food Availability [ 5 , 8 ].

Sugary foods are perceived to be harmful primarily because they can cause weight gain. However, weight is not the only determinant of health: 20% of obese people have a normal metabolism, and 40% of people with normal body mass indices (BMIs) develop diabetes, hypertension, heart disease, and non-alcoholic fatty liver disease [ 9 ]. New research suggests that sugar plays a major role in the etiology of cancer and cancer progression [ 9 ]. Breast [ 10 ], colorectal [ 11 ], pancreatic [ 12 , 13 ], and other cancers [ 14 , 15 ] may be linked to added sugar, and in most cases independent of obesity and weight gain. Preclinical studies using mouse models show increased tumor burden [ 16 ], earlier onset [ 17 ], and a greater prevalence [ 18 ] of various cancers in mice fed high-sucrose or high-fructose diets compared with isocaloric starch diets. While no human clinical trials have explored the relationships between sucrose, fructose, and cancer, epidemiological studies and preclinical research in mice have found a strong association between excess sugar consumption and cancer. In addition, the literature from primate and human studies in the field of metabolic syndrome (MetS) indicates a need for further sugar-related research [ 19 ].

The role of added sugar in cancer development and progression is controversial. This paper aims to: (1) provide an overview on the evolution of sugar consumption and cancer incidence worldwide; (2) review current research linking dietary added sugars and cancer risk, prevalence, progression, and illness burden; and (3) explore plausible mechanisms linking added sugars to cancer.

1.1. Sugar and Cancer: The Past and Present

1.1.1. what, exactly, are we eating.

The per capita consumption of processed sugar in the US has surged to over 45 kg/year [ 20 ]. The increased consumption of added sugars, particularly sugar-sweetened beverages (SSB), is a pivotal contributor to worldwide epidemics of obesity, diabetes, heart disease, and cancer. Now that sodas in the US are sweetened mainly with HFCS, consumption of HFCS has increased more than 1000% between 1970 and 1990 [ 21 ], representing the greatest change in consumption of any food or food group in the United States. HFCS currently represents more than 40% of caloric sweeteners added to foods and beverages in the US [ 21 ], with some consuming as many as 316 daily kcal from HFCS alone, contributing to the worldwide obesity epidemic [ 21 ].

Sucrose, or table sugar, is a disaccharide comprising equal parts fructose and glucose. Glucose, a monosaccharide, is found in all carbohydrates and starchy foods and serves as the key source of energy for all animals, including humans, during cellular metabolism. Fructose, also a monosaccharide, is naturally found in fruit but has since been harnessed as a prominent added caloric sweetener in many foods.

Fructose is digested, absorbed, and metabolized differently from glucose. Unlike with glucose, hepatic metabolism of fructose favors de novo lipogenesis [ 21 ]. In addition, fructose found in HFCS, sugar, and certain foods does not stimulate production of insulin or leptin, both of which regulate food intake by increasing satiety and inhibiting hunger [ 18 ]. Thus, excess fructose in food likely contributes substantially to the current weight gain and obesity epidemic worldwide [ 21 ]. Therefore, added sugars containing fructose must be studied further to determine whether their impact on chronic diseases, especially cancer, is due mainly to their propensity to cause obesity or to a separate, more specific mechanism.

1.1.2. The Westernization of Diet and Cancer Rates

Cancer was previously considered a disease of the affluent. However, low- and middle-income countries (LMIC) now make up 57% of cancer cases worldwide. The World Health Organization (WHO) estimates that, in only two decades, the rates will reach 22 million new cancer cases and 13 million cancer deaths annually [ 1 ], an estimated 57% increase in annual new cancer cases and a 65% increase in annual cancer deaths [ 22 ]. Countries such as Brazil, India, and China, which previously reported low rates of breast, prostate, and colon cancer, are now seeing significant increases in the incidence and mortality of these cancers [ 23 , 24 ]. A case-control study examining breast cancer incidence among women of Chinese, Japanese, and Filipino ethnicity in California and Hawaii found that those born in the United States had a 60% higher risk of breast cancer than those born in Asia [ 23 ]. Furthermore, Asian American women born in the United States with all four grandparents born in Asia had incidence rates similar to those of white women living in the same geographic area [ 23 ]. Breast cancer has now surpassed cervical cancer as the leading cause of cancer death among women in LMICs [ 22 ]. In Brazil, breast cancer mortality rates are also increasing steadily, with the highest average rates in the more urban southern and southeastern regions where São Paulo and Rio de Janeiro are located [ 25 ]. In 1998, prostate cancer accounted for 32% of cancer cases in men in the US but for less than 1% of all male cancers in men in Shanghai [ 26 ]. Prostate cancer mortality rates in the US have steadily declined by more than 40% between 1999 and 2017 [ 27 ]. In contrast, prostate cancer mortality rates in China increased by 5.5% annually between 2000 and 2011 [ 27 ]. In India, cancer incidence increased 1.1 to 2.0 percent per year between 2010 and 2019 [ 28 ], with breast cancer being the most common cancer in women and lung cancer for men [ 24 ]. India and China also have the highest incidence and number of people living with diabetes [ 29 ], a known risk factor for many cancers [ 30 ]. By 2040, global cancer cases will increase by over 40%, and it is estimated that two-thirds will occur in LMICs [ 31 ]. Changing diets, including consumption of fast-foods, highly processed foods, and excess sugar consumption, are hypothesized as a causative factor in the increasing incidence of cancer in LMICs.

According to food consumption trends in 2010, diets worldwide are undergoing Westernization, becoming more energy-dense and sugary than ever before [ 2 ]. LMICs, especially in Asia, Latin America, and Africa, have seen astonishing spikes in sugar consumption in recent years [ 2 ]. In 2002, the average Brazilian consumed 50.2 g of sugar per day, a number that has continued to grow each year [ 32 ]. The annual increase in sugar consumption in China between 2000 to 2007 was 2.2%, and is expected to double to 4.4% annually over the next few decades [ 33 ]. In addition, inhabitants of these LMICs received 54% to 70% of their daily calories in cereals alone [ 2 ]. The ubiquity of American fast- and processed foods and the overall Westernization of diets around the world has been hypothesized as the cause for the increased incidence of non-communicable diseases [ 34 , 35 ].

1.1.3. Changing Perceptions and Guidelines about Sugar

Research on the relationship of added sugar and non-communicable diseases dates back over 50 years. During the 1960s and 1970s, physiologist John Yudkin identified sugar as a key cause of coronary heart disease (CHD) [ 36 , 37 ]. Fearing the impact of such results on the sugar industry, the Sugar Research Foundation paid two scientists at the Harvard University School of Public Health Nutrition Department to write a literature review, later published in the New England Journal of Medicine in 1967 [ 36 ]. The review questioned the validity of any study in which the research implicated sucrose in worsening CHD and instead blamed food high in saturated fats and cholesterol [ 36 ].

The resulting 1980 Dietary Guidelines for Americans recommended lowering saturated fat and cholesterol intake to prevent CHD [ 36 ]. With these guidelines came an era of low-fat diets and low-fat/fat-free processed foods. Soon, much of the fat in processed food was replaced with sugar, and sugar became nearly unavoidable in the American diet. The sugar industry continues to fund research on CHD and other chronic diseases, indirectly influencing decades of American policy and health [ 36 ]. In 2003, when the WHO halved its sugar intake recommendation, the US Sugar Association pressured the US government to cut funding for the WHO if the recommendations were not changed [ 38 ]. While the AHA has since changed its recommendations to reflect the current knowledge that sucrose directly causes heart disease [ 39 ], other chronic disease institutions are lagging behind [ 40 ]. The current AHA guidelines recommend a daily limit of six teaspoons (30 g, or 120 calories) of added sugar for women and nine teaspoons (45 g, or 180 calories) for men [ 6 ]. The WHO also recommends dietary sugar intake less than 10% of daily energy intake (50 g per 2000 daily calories) and conditionally recommends that less than 5% of daily energy intake consist of added sugar.

Despite studies showing the potential harms of added sugar and the important etiologic role it plays for many diseases, the current cancer dietary guidelines do not reflect this knowledge [ 9 , 41 , 42 , 43 , 44 ]. The American Institute for Cancer Research states, “There is no strong evidence that directly links sugar to increased cancer risk” [ 41 ] and recommends generally reducing sugar intake to avoid weight gain, but no specific guidelines are provided [ 41 ]. Additionally, none of the leading institutions in cancer research have substantial educational material or dietary guidelines on their websites regarding dietary sucrose. They either omit any mention of sugar completely or state that sugar and cancer may be linked only indirectly through weight gain [ 42 , 43 , 45 ].

The WHO issued a press release in February 2014 calling for quick and effective cancer prevention measures, entailing adequate legislation, taxation, and regulation of various carcinogenic agents, including SSB [ 1 ]. Additionally, the WHO strongly recommended dietary sugar intake less than 10% of daily energy intake (50 g per 2000 daily calories) and conditionally recommended that less than 5% of daily energy intake consist of added sugar [ 3 ]. Dietary cancer guidelines and federal and state policies also need to incorporate the knowledge that added sugar can be directly harmful.

2. Materials and Methods

Search strategy and selection criteria.

References for this review were identified through searches of Ovid MEDLINE and PubMed with the search terms “sugar”, “sucrose”, “fructose”, “sweets”, “dessert”, “cancer”, “tumor”, “neoplasm”, carcinogenesis”, “breast neoplasm”, “neoplastic processes”, “neoplasm metastases”, “arachidonate 12 lipoxygenase”, “peroxisome proliferator-activated receptor”, “metabolic syndrome”, “insulin like growth factor 1”, “inflammation”, “immune system” from 1946 until present. Articles were also identified through searches of the authors’ own files and examining references sections of each article selected for review. Only papers published in English were reviewed. The final reference list was generated based on originality and relevance to the broad scope of this review.

3.1. Epidemiologic Studies Linking Sugar to Cancer

The following sections review epidemiological studies examining the association between added sugars and cancer risk and/or mortality. In the tables where the “Main Findings” are reported, we present the outcomes from the final models, controlling for multiple covariates. Importantly, 22 of 24 studies controlled for BMI (in some cases before and after diagnosis) and various other factors associated with cancer (e.g., smoking history, age, physical activity, and other dietary factors). The final statistical model of most studies described below found an association between sugar consumption and cancer outcomes independent of these other factors, suggesting unique risks associated with excess sugar consumption independent of other lifestyle factors, including BMI.

3.1.1. Breast Cancer

Numerous epidemiologic studies have shown an association between sugar and breast cancer ( Table 1 ) [ 46 , 47 ]. Additionally, sucrose intake during adolescence [ 48 ] was significantly correlated with higher percentage of dense breast volume [ 49 ], a known risk factor for breast cancer [ 50 ].

In a case-control study in the United States, women under age 45 who consumed sweets 9.8 times per week or more experienced significantly higher breast cancer risk than those who consumed sweets less than 2.8 times per week [ 51 ]. The study found no significant association between risk of breast cancer and calorie intake, macronutrients, or types of fat, showing a sugar-specific association [ 51 ]. Similarly, a case-control study conducted in Italy found that women with the highest intake of desserts and sugars had multivariate odds ratios (OR)s of 1.19 (95% confidence interval (CI) 1.02–1.39) and 1.19 (95% CI 1.02–1.38), respectively, for breast cancer [ 47 ]. A French study found that sugary drinks were significantly associated with increased risk of breast cancer, with a hazard ratio (HR) of 1.22 (95% CI 1.07–1.39) [ 52 ].

While most research in this field has been conducted in high-income countries, one case-control study in Malaysia also found a significant two-fold increase in breast cancer risk with high sugar intake among both premenopausal (OR = 1.93, 95% CI 1.53–2.61) and postmenopausal participants (OR = 1.87, 95% CI 1.03–2.61) [ 10 ]. Taken together, findings in high- and LMICs show a consistent association between sugar consumption and increased risk of breast cancer.

Sugar intake is also associated with increased risk of cancer-specific and all-cause mortality after a diagnosis of breast cancer. Consuming sugar-sweetened soda ≥5 times weekly vs. never/rarely was associated with total (HR = 1.62; 95% CI, 1.16–2.26; P trend < 0.01) breast cancer mortality (HR = 1.85; 95% CI, 1.16–2.94; P trend < 0.01) among women diagnosed with invasive breast cancer [ 53 ]. Similarly, Farvid at al. [ 46 ] examined 8863 women with stage I to III breast cancer who were part of the Nurses’ Health Study and found that women who had SSB consumption after diagnosis greater than zero to one serving per week had higher breast-cancer-specific mortality (>1 to 3 servings per week: HR = 1.31 [95% CI, 1.09–1.58]; >3 servings per week: HR = 1.35 [95% CI, 1.12–1.62]; P trend = 0.001) and all-cause mortality (>1 to 3 servings per week: HR = 1.21 [95% CI, 1.07–1.37]; >3 servings per week: HR = 1.28 [95% CI, 1.13–1.45]; P trend = 0.0001). In addition, replacing SSBs with coffee (18%) or tea (15%) reduced breast-cancer-specific mortality, and coffee (19%), tea (17%), or water (9%) lowered all-cause mortality risk [ 46 ].

Added sugar intake and risk of developing breast cancer and mortality.

* Outcomes reported are from the final regression models that controlled for body mass index, as well as other factors associated with breast cancer. ASB = artificially sweetened beverages; CI = confidence interval; HR = hazard ratio; OR = odds ratio; SSB = sugar-sweetened beverages.

3.1.2. Colorectal Cancer

Sugar may also play a role in the development and progression of colon cancer ( Table 2 ). In a prospective cohort study of colon cancer patients, consuming two or more servings of SSB daily significantly increased risk of recurrence by 75% and risk of mortality compared to those who consumed less than two servings of SSB daily (95% CI 1.04–2.68) [ 11 ]. When further adjusted for dietary glycemic load in the multivariate model, the results remained nearly unchanged, suggesting a strong role for sugar [ 11 ].

One case-control study found total sucrose intake positively associated with a more than two-fold increase in risk of colorectal cancer and a significant dose–response gradient (OR 2.18, 95% CI 1.35–3.51) [ 54 ]. Contrary results in a pooled analysis of prospective cohort studies found no significant increase in colon cancer risk due to sugar-sweetened carbonated beverage intake (95% CI 0.66–1.32) [ 55 ], suggesting that more research is needed to better understand the role of added sugar in colon cancer development.

Added sugar intake and risk of developing colorectal cancer and mortality.

* Outcomes reported are from the final regression models that controlled for body mass index (except where indicated), as well as other factors associated with colorectal cancer. BMI = body mass index; CI = confidence interval; HR = hazard ratio; OR = odds ratio; SSB = sugar-sweetened beverages.

3.1.3. Pancreatic Cancer

A strong body of evidence suggests that a sucrose- and/or fructose-filled diet is associated with increased risk of pancreatic cancer, but other studies reported a weak association between added sugar intake and risk of pancreatic cancer ( Table 3 ). A systematic review and meta-analysis of 10 cohort studies [ 56 ] found significant associations between fructose consumption and pancreatic cancer risk (relative risk (RR) = 1.22, 95% CI 1.08–1.37) [ 56 ]. One study showed a non-significant 53% increase in pancreatic cancer with high carbohydrate and sucrose intake [ 12 ], and, more specifically, found that high glycemic load and fructose intake were strongly associated with pancreatic cancer in overweight women [ 12 ]. Additionally, a prospective study demonstrated that higher consumption of sugar, soft drinks, and sweetened fruit soups or stewed fruit was associated with significant increases in pancreatic cancer risk of 69%, 93%, and 51%, respectively [ 57 ]. A multiethnic cohort study in Hawaii and Los Angeles documented a similar association between high fructose intake and pancreatic cancer [ 13 ]. In contrast, one study found that juice and soft drink consumption was not associated with risk of pancreatic cancer, and another study found that juice or nectar consumption was associated with a decrease in pancreatic cancer risk [ 58 , 59 ]. However, the authors suggest the results should be interpreted with caution as juices and nectars are usually rich in added sugars and fructose, which could potentially increase pancreatic cancer risk. It is important to note that, in all these studies, they controlled for BMI. More research is needed to improve understanding of the role of added sugar in the risk of pancreatic cancer.

Added sugar intake and risk of developing pancreatic cancer and mortality.

* Outcomes reported are from the final regression models that controlled for body mass index, as well as other factors associated with pancreatic cancer. ASB = artificially sweetened beverage; CI = confidence interval; HR = hazard ratio; RR = relative risk; SSB = sugar-sweetened beverages.

3.1.4. Miscellaneous Cancers

Studies of other cancer types also find sugar intake as a risk factor for cancer ( Table 4 ). All but one study [ 15 ] controlled for weight and/or BMI, suggesting that the associations were independent of the harms of weight and weight gain. A large longitudinal and observational study found that daily consumption of only 100 mL of sugary drinks, including fruit juices, significantly increases the risk of overall cancer by 18% [ 52 ]. One review of 15 epidemiologic studies examining sugar intake and cancer [ 60 ] found positive associations between added simple-sugar and pancreatic, prostate, and liver cancer; hepatocellular carcinoma, lymphoma, and leukemia; cancer of the colon, breast, and small intestine; and cancer in general [ 60 ]. In a large prospective study of 435,674 participants, added sugars were significantly associated with an increased risk of esophageal adenocarcinoma, added fructose was significantly associated with a greater risk of small intestine cancer, and all sugars (total, sucrose, fructose, added sugars) were associated with an increased risk of pleural cancer [ 14 ]. Conversely, all the sugars were inversely correlated with ovarian cancer risk in women, and no association was found between any dietary sugars and risk of any other major cancer [ 14 ].

The Framingham Offspring Cohort (1991–2013) prospective study analyzed dietary-questionnaire data and cancer incidence and found no significant associations between sucrose, fructose, sugary foods, or sugary beverages with any site-specific cancers [ 61 ]. However, a 58% increased risk of prostate cancer was associated with higher consumption of fruit juices (>7 servings/week) [ 61 ]. Additionally, Jackson et al. found that a diet high in carbohydrates, including SSB, was positively associated with increased risk of prostate cancer [ 62 ]. Another case-control study found that sucrose consumption was positively associated with an increased risk of lung cancer [ 15 ]. A 70,000-person prospective study found that both men and women experienced significantly increased risk for extrahepatic biliary tract cancer and gallbladder cancer with high consumption of sugar-sweetened and artificially sweetened beverages [ 63 ]. Stepien et al. found that people who consumed more than six soft drinks per day had a significantly increased risk of developing hepatocellular carcinoma compared with non-consumers (HR = 1.83, 95% CI 1.11–3.02) [ 64 ]. Finally, a population-based case-control study found that excess sugar consumption was associated with shorter survival time among patients with esophageal cancer (HR for fourth vs. first quartile: 1.88; 95% CI 1.29–2.72) [ 65 ].

More recently, McCullough et al. [ 66 ] reported that, in a cohort of almost 1 million individuals with consumption of ≥2 SSB drinks/day vs. never, SSBs were associated with increased mortality from colorectal (HR = 1.09; 95% CI, 1.02–1.17; P trend = 0.011) and kidney (HR = 1.17; 95% CI, 1.03–1.34; P trend = 0.056) cancers, even after controlling for BMI. SSB consumption was also associated with mortality from obesity-related cancers, but the effect disappeared when controlling for obesity.

Added sugar intake and risk of developing cancers and mortality (mixed cancers).

* Outcomes reported are from the final regression models that controlled for body mass index (except where indicted), as well as other factors associated with developing cancers. ASB = artificially sweetened beverages; BMI = body mass index; CI = confidence interval; HR = hazard ratio; mL/d = milliliters per day; OR = odds ratio; SSB = sugar-sweetened beverages.

3.2. Preclinical Animal Studies

Preclinical studies have examined the effects of sucrose consumption on cancer outcomes and purported biological pathways driving disease processes. A study exploring the effects of high-sucrose diets compared with a starch diet in an APC Min mouse model that spontaneously develops adenomas in the small intestine and colon showed a significant increase in the prevalence of colonic papillary tumors (32 of 54 mice vs. 19 of 63 mice) [ 18 ]. High-sucrose diets also increased the number of tumors in the proximal intestine (21.9 ± 1.4) compared to the control group (13.1 ± 1.6) [ 18 ].

Similarly, a study examining the effects of glucose and sucrose diets on hepatocarcinogenesis in rats that were exposed to the carcinogen diethylnitrosamine prior to being placed on the high sucrose diet found that the sucrose diet resulted in significantly heavier livers and two-fold more gamma-glutamyltranspeptidase-positive foci in the liver [ 67 ]. Another study using diethylnitrosamine to induce hepatocellular carcinoma found that mice receiving the carcinogen at 2 weeks of age and then fed high-sugar diets starting at 6 weeks of age through 32 weeks had significantly higher liver tumor burden, and numbers of tumors were significantly higher in mice fed high-sugar diets than in mice fed low-sugar diets irrespective of fat content [ 16 ]. Mice who consumed high-sugar diets had low adiposity but had significantly higher tumor burden compared to mice with high adiposity who consumed high-fat diets [ 16 ]. Importantly, overall body weights were not significantly different between groups [ 16 ]. The lack of an association between adiposity and liver tumor burden calls into question the theory that sugar increases cancer incidence via increased obesity [ 16 , 43 ].

The faulty reasoning linking sucrose with cancer only through obesity is corroborated by research from our laboratory [ 17 ]. Three breast cancer mouse models were used, with mice given an isocaloric non-sugar starch control diet or diets enriched with sucrose, fructose, or fructose plus glucose. Overall, the mice on the sucrose, fructose, and fructose-plus-glucose diets provided after tumor cell inoculation all exhibited significantly more widespread metastases to the lungs compared with those on the non-sugar control diets in the mice bearing mouse mammary carcinoma 4T1 orthotopic model [ 17 ]. Mice fed a high sucrose diet starting one day after injection of MDA-MB-231 cells also had increased tumor growth in the human breast cancer mouse orthotopic model. The third model used MMTV/neu mice that spontaneously develop mammary tumors and found that the mice fed the sucrose diet also developed significantly larger tumors and more rapid onset of breast cancer than did the control group [ 17 ]. Some argue that sugar’s harmful effects are due only to the unrealistically high amounts of sugar used in these types of preclinical studies. However, the sucrose-enriched diet used in our study was similar to the average sugar intake consumed in a Western diet. Furthermore, there was no statistically significant weight gain or difference in weights between any of the diet groups in all three tumor models, suggesting that sucrose, and especially fructose, plays an independent role in breast cancer risk and progression independent from body weight gain [ 17 ].

Although studies have indicated that glycemic load and its effects on the insulin pathway serve as the primary link between sugar and cancer, there are other potential mechanisms ( Figure 2 ) [ 18 , 68 , 69 , 70 , 71 , 72 ]. Chronic inflammatory states with overexpression of cyclooxygenase or lipoxygenases have been associated with numerous cancer types and chronic diseases. More specifically, studies have found a strong association between 12-lipoxygenase (12-LOX) and its metabolites, 12-hydroxyeicostatetraenoic acid (12-HETE), and a variety of cancers [ 17 , 73 , 74 ]. Our study found that 12-HETE levels in breast tumors of mice fed sucrose-, fructose-, and fructose-plus-glucose-enriched diets were all significantly higher than those in mice fed a starch control diet [ 17 ]. This spike in 12-LOX/12-HETE levels due to the sugar-enriched diets suggests that inflammation, independent of weight gain or metabolism, is a novel causal mechanism in the association between sugar and cancer. Finally, a four-arm randomized controlled trial examining SSB consumption reported that fructose and sucrose (median basal hepatic fractional secretion rates (FSR)%/day: fructose 19.7 ( p = 0.013); sucrose 20.8 ( p = 0.0015); control 9.1) but not glucose increased liver lipid production, creating conditions for future adverse health outcomes [ 75 ].

Proposed model whereby dietary sugar influences multiple cancer-specific pathways, including energy metabolism, lipid metabolism, inflammation, and immune function.

A 2019 study published in Science demonstrated that HFCS enhanced intestinal tumor growth independently of weight gain [ 76 ]. When transgenic mice with APC deletion (APC −/− ) were given 400 μL of 25% HFCS solution via oral gavage, providing calories from HFCS similar to human consumption of less than 355 g of SSB, for 8 weeks, the number of large adenomas (>3 mm in diameter) and high-grade tumors significantly increased in the HFCS group compared to a control group. Interestingly, chronic exposure to modest amounts of HFCS did not lead to obesity or metabolic dysfunction in the APC −/− mice. This study also found that HFCS accelerated glycolysis by upregulating ketohexokinase and increasing de novo activation of the lipogenic pathway. Interestingly, the levels of 12-HETE in colon tumor tissues of HFCS-treated APC −/− were significantly elevated compared with those of control mice, consistent with the results from Jiang et al. [ 17 ].

Other preclinical research published in Cell supports specific carbohydrate metabolic pathways linking fructose and liver metastases [ 77 ]. A study examining the effects of fructose on colon cancer liver metastases found that aldolase B (ALDOB), an enzyme that is involved in fructose metabolism, was upregulated in liver metastases compared with a normal colon and a primary colorectal cancer tumor [ 77 ]. Mice inoculated with human colorectal cancer cells and subsequently fed high-fructose diets had consistently increased liver metastases and shortened survival compared with control mice and with mice fed low-fructose diets [ 77 ]. In addition, mice with ALDOB knockdown had increased survival compared with the control group, suggesting that ALDOB is a potential target for fructose-induced liver metastases [ 77 ]. These are provocative findings given that cancer metastasis is the most common cause of cancer-related death and that liver metastases are common for almost every type of cancer. A greater understanding of the potential dangers of dietary fructose and sucrose regarding risk of cancer overall is critically important.

3.3. Human and Primate Studies of Sugar and Metabolic Syndrome

To experimentally test the effects of sucrose and fructose on the risk of cancer in humans, we would need to manipulate diets. Because cancer is complex and usually would take decades to manifest, human subjects research in this field is currently non-existent and is of ethical concern. However, compelling human and primate studies have explored the link between added sugar and metabolic syndrome (MetS). MetS is a cluster of medical risk factors that include high triglycerides, low high-density lipoprotein, high blood pressure, high fasting glucose, and central obesity. MetS is diagnosed when a patient has three of the five factors [ 78 ]. MetS is associated with an increased risk for cardiovascular diseases, diabetes, cognitive disorders, and other health conditions [ 79 ], including an increased risk for a number of common cancers, including breast, liver, pancreatic, colorectal, endometrial, and more [ 80 ]. The connections between MetS and cancer or between MetS and added sugar do not necessarily translate to a connection between cancer and added sugar. Nevertheless, substantial evidence suggests a causal link between MetS and added sugar [ 81 ], indicating important implications for our review.

In a rhesus monkey model, researchers found that 100% of monkeys fed a high-fructose diet had insulin resistance and other features of MetS [ 19 ]. Within 6–12 months, the high-fructose diet in monkeys produced central obesity, insulin resistance, inflammation (increased serum levels of C-reactive protein and monocyte chemoattractant protein-1), and dyslipidemia [ 19 ]. These results suggest that this rhesus monkey model of diet-induced obesity, insulin resistance, and dyslipidemia is directly translatable to MetS in humans [ 19 ].

Schwarz et al. explored the effects of fructose restriction in obese children [ 44 ]. Forty-one children aged 8–18 years with obesity and MetS whose normal diets consisted of large amounts of added sugars (fructose intake >50 g/day) were provided sugar-restrictive meals for 9 days that swapped sucrose and fructose for a calorically neutral and macronutrient-equivalent amount of starch [ 44 ]. Over that period, liver fat decreased from 7.2% to 3.8% [ 44 ]. In addition, fractional de novo lipogenesis decreased significantly in 37 of 40 participants (68% to 26%), including in those who did not lose weight, and insulin sensitivity increased significantly [ 44 ]. These results suggest that a reduction in sucrose was responsible for significantly lowered liver fat, visceral fat, and fractional de novo lipogenesis independent of weight loss [ 44 ]. Another study by Schwarz et al. used a similar design but with eight healthy men. This nine-day study explored the effects of a high-fructose diet compared with an equivalent macronutrient breakdown, with complex carbohydrates replacing the fructose [ 82 ]. Even though all the subjects maintained weight stability, those who consumed a high-fructose diet had significantly higher de novo lipogenesis and liver fat [ 82 ].

Other research has examined fructose-sweetened beverage versus glucose-sweetened beverage consumption in overweight or obese adult men and women and found that those who consumed fructose-sweetened beverages had significantly increased de novo lipogenesis, higher accumulation of intra-abdominal fat, a more atherogenic lipid profile, and reduced insulin sensitivity [ 83 ]. A follow-up study found that those who consumed the fructose-sweetened beverages had significantly decreased net postprandial fat oxidation and significantly increased net postprandial carbohydrate oxidation [ 84 ]. In addition, resting energy expenditure significantly decreased compared with baseline values in the fructose-consuming group [ 84 ].

The consistency in results across both primates and humans (children and adults) shows strong evidence of a direct causal link between fructose and MetS. Emerging data suggest a strong association between MetS and cancer risk [ 80 , 85 , 86 , 87 , 88 ], progression of disease [ 89 ], and mortality [ 85 , 89 ], although more research is needed to better understand the mechanisms. While the links between MetS, cancer, and added sugar remain unclear, the evidence connecting them is strong enough to warrant further research.

4. Discussion

The current review revealed evidence linking added sugar consumption to increased cancer incidence and mortality. The epidemiologic evidence was strongest for breast cancer [ 49 , 51 , 53 ], and we also identified studies examining and finding a connection between added sugar and colon cancer [ 11 , 55 ]. Research on the association between added sugar consumption and pancreatic cancer was mixed [ 12 , 13 , 57 , 58 , 59 ], yet the preponderance of the evidence suggests an association. Although some of the observational studies were prospective with large sample sizes [ 14 , 57 , 64 , 65 ], others had less robust designs with smaller samples [ 15 , 62 , 75 ]. Overall, the majority of the studies found an association between excess sugar consumption and cancer.

A critical question is whether the link between sugar and cancer is solely mediated by weight gain and obesity. Population-based studies on added sugar, especially SSB, and cancer risk and outcomes are equivocal on whether the association is driven by obesity or is also independent of obesity and weight gain. Some studies implicate a role for obesity [ 11 , 12 , 13 , 16 ], others show the enhanced risks independent of BMI and other lifestyle factors [ 44 , 90 ], and some suggest that the association may be cancer-specific [ 66 , 91 ]. However, as is the case with all observational studies, association does not mean causation, and further mechanistic and human clinical trials are needed.

In contrast, most preclinical research demonstrates that the effects of excess added sugar on cancer development and progression are independent of body weight gain [ 17 , 77 ]. Extensive research now supports the role for multiple mechanisms whereby sugar modifies cancer risk, independent of obesity, including inflammation, glucose/fructose metabolism, lipid metabolic pathways, and immune modulation ( Figure 2 ) [ 17 , 76 , 77 , 92 ]. This suggests that obesity may have more of a bystander effect. Our review of the preclinical research revealed that high-sucrose or high-fructose diets activate several mechanistic pathways, including inflammation, glucose, and lipid metabolic pathways. Although human prospective studies linking sugar and cancer are limited, compelling human and primate studies have explored the link between added sugar and metabolic syndrome (MetS), a risk factor for cancer. Substantial evidence suggests a causal link between MetS and added sugar [ 19 , 44 ], supporting the association between excess sugar consumption and cancer. Therefore, it is the increased underlying inflammatory processes or alteration of metabolic pathways that may be driving the sugar–cancer link. Given the importance of inflammation in driving sugar-induced tumorigenesis and progression, it is logical for future research to investigate the role of the immune system in these processes. Overall, exploring the association between added sugar and cancer, in addition to other dietary constituents and patterns, independent of obesity, should be prioritized [ 43 ].

Perhaps the largest knowledge-gap comes from the lack of clinical trials research on humans. Such studies are not only near non-existent but also ethically challenging and would face time restrictions, as well as limited funding. Although animal studies show links between sugar and cancer that are independent of obesity [ 17 , 18 ], these models are not always translatable to humans. Both human and animal studies are needed to clarify sugar’s role in cancer and further explore the mechanisms of such effects. In the meantime, perhaps more caution is needed in how our population, and cancer patients in particular, are counseled in this area.

The current nutritional guidelines for cancer prevention and people with cancer remain silent on the harms of sugar and fructose consumption outside the context of weight gain, and perhaps a more precautionary message is needed [ 4 ]. Normal weight individuals may inappropriately believe the harms of sugar do not apply to them. As added sugar intake is increasing globally and added sugar consumption in the US far exceeds the ACS, AHA, and WHO recommendations for maximum intake, there is cause for concern that this modifiable risk factor is not being adequately addressed. Outside the context of cancer, excess sugar intake is linked with diabetes [ 93 , 94 ], cardiovascular disease [ 95 ], and Alzheimer’s disease and other forms of dementia [ 96 ] and is linked with other cause-specific deaths [ 97 ], and these associations are independent of obesity [ 93 , 94 , 95 , 97 ]. The underlying mechanisms are likely similar to those of cancer risk.

Without appropriate guidelines and regulatory changes, the general population will continue to experience sugar-induced health problems, including preventable cancers. As there is no research showing the benefits of consuming any amount of added sugar, and, given that added sugar is devoid of nutritional value, the recommended daily guidelines must reflect the health risks of sugar consumption independent of weight gain. It is also important that, as a society, we start to actually follow the guidelines established by the AHA, the ACS, and the WHO. This includes ensuring that food manufactures also reduce added sugars in their products. By using a system-wide approach to lowering sugar consumption, millions of premature deaths could be averted annually [ 98 ]. The general population and cancer survivors are entitled to and deserve appropriate counseling based on this evidence.

There are several limitations with the current review. The study did not set out to be a formal systematic review, and, as such, no specific search criteria were used to select research examining the link between sugar and cancer. Because of the dearth of research in the field of sugar consumption and cancer, we did not use specific selection criteria when choosing research studies to include. However, we tried to locate and highlight the most relevant and well-designed research that has been published to date. While we have cited epidemiologic, preclinical, and clinical studies that show a potential link between added sugar and cancer and those that do not, as well as explored plausible mechanisms, we understand that these findings are far from definitive.

5. Conclusions

In conclusion, research suggests a direct link between sugar and cancer. Preclinical studies and studies of people with MetS show that high-sucrose or high-fructose diets activate several mechanistic pathways, including inflammation, glucose, and lipid metabolic pathways, suggesting a causal link between excess sugar consumption and cancer development and progression that is independent of weight gain. Dietary guidelines and US policy need to reflect this new knowledge. Concerted action is needed to lower sugar intake in the US and other countries, better inform the public of the risks of excess sugar intake, and conduct more robust research in the field of added sugar and cancer.

Acknowledgments

We thank Greg Pratt for library support and database searches.

Funding Statement

This project was supported in part by the Richard E. Haynes Distinguished Professorship for Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center, and NIH/NCI P30CA016672.

Author Contributions

Conceptualization, M.E., P.Y. and L.C.; methodology, M.E., P.Y. and L.C.; data curation, M.E., P.Y., L.C. and R.W.W.; writing—original draft preparation, M.E., P.Y., L.C. and R.W.W.; writing—review and editing, M.E., P.Y., L.C. and R.W.W. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Study Suggests Possible Link Between Sugar Substitute and Heart Issues. Experts Say, Don’t Panic.

Recent findings underscore the need for more research into artificial sweeteners.

By Dani Blum

In a study published in the journal Nature Medicine on Monday , researchers reported links between the popular zero-calorie sugar substitute erythritol and an increased risk of cardiovascular events, including heart attack and stroke. The sweetener, which is often added to many low- or zero-calorie foods and drinks, is just one of many sugar substitutes researchers have called into question in terms of their long-term safety risks.

“People are trying to do something healthy for themselves but inadvertently may be doing harm,” said Dr. Stanley Hazen, a cardiologist at the Cleveland Clinic and an author of the study.

In the study, researchers looked at the levels of erythritol in the blood of around 4,000 people from the United States and Europe and found that those with the highest blood concentration of the sugar substitute were more likely to have a stroke or heart attack. The participants, who mostly were over the age of 60, either already had or were at high risk for cardiovascular diseases because of conditions like diabetes and hypertension.

The researchers also found that when they fed mice erythritol, that promoted blood clot formation. Erythritol appeared to induce clotting in human blood and plasma as well. Among eight people who consumed erythritol at levels typical in a pint of keto ice cream or a can of an artificially sweetened beverage, the sugar alcohol lingered in their blood for longer than two days.

“Every way we looked at it, it kept showing the same signal,” Dr. Hazen said.

“This compound isn’t innocuous,” said Dr. Dariush Mozaffarian, a cardiologist and professor of nutrition at the Friedman School of Nutrition Science and Policy at Tufts University who was not involved with the study. And there haven’t been enough studies to determine the long-term health effects of sugar substitutes in humans, he said. “That’s the problem. Regardless of this study, there’s just not been enough evidence that they’re really safe.”

There were, however, key limitations to the study, Dr. Mozaffarian said. First, the majority of participants either had cardiovascular disease or had multiple risk factors for cardiovascular issues, which potentially skewed the data.

And while the study found an association between erythritol and elevated cardiovascular risk, it did not prove that the compound itself caused strokes and heart attacks. The study includes observational research that requires further validation, said Dr. Priya M. Freaney, a cardiologist at Northwestern University who was not involved with the study. But, she added, “it’s concerning enough that it certainly deserves more investigation.”

Scientists have tried to examine the health effects of sugar substitutes as they have become increasingly popular over the last 10 years. There’s a vast amount of research on artificial sweeteners in general, often with conflicting conclusions, said Marion Nestle, a professor emerita of nutrition, food studies and public health at New York University who was not involved with the study.

Some past studies that examine the potential links between artificial sweeteners and cancer as well as with cardiovascular diseases have concluded that these chemicals may increase the risk of these conditions, although not by much, Dr. Nestle said. They invariably conclude that more research is needed, she added.

Previous reviews have found that erythritol may be a good replacement for sugar, although much of that research has been performed in animals, said Joanne Slavin, a professor of food science and nutrition at the University of Minnesota-Twin Cities who was not involved with the new research.

“There are going to be studies that show that it’s good, bad or indifferent,” Dr. Nestle said. People have been consuming artificial sweeteners for years, she added, “it’s really hard to put your finger on any specific problem.”

And it’s especially challenging to examine the health effects of sugar substitutes and alternative sweeteners when they are consumed as part of a larger diet, Dr. Slavin said.

Dr. Slavin noted that the people who consume high amounts of artificial sweeteners may already be at risk for cardiovascular issues. If they have conditions like diabetes or obesity, they may be using artificial sweeteners to try to cut back on sugar, she said. “That’s the really important thing, for people to not say, ‘Hey, this stuff is terrible, it’s giving us heart attacks,’” Dr. Slavin said. “No. This is another data point that says, ‘Hey, we have to look into this.’”

For some people, sugar substitutes like erythritol can be an important tool for those who are trying to lower the amount of added sugars they’re consuming, Dr. Slavin said, which can help with weight management and blood glucose control. But there are alternative options to lower our overall sugar consumption, Dr. Hazen noted. While the research on the health risks of erythritol is still evolving, people may want to avoid large amounts of artificial sweeteners, Dr. Freaney said, especially if they already have heart disease or are at risk for heart attacks or strokes. That can start with small changes, she suggested — if you consume five artificially sweetened beverages a day, for example, try replacing two of those with water. But it doesn’t need to be all or nothing, she said.

“You take in erythritol, you will not die on the spot,” Dr. Nestle said. “You will not.”

Dani Blum is a reporter for Well. More about Dani Blum

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“When my son was diagnosed [with Type 1], I knew nothing about diabetes. I changed my research focus, thinking, as any parent would, ‘What am I going to do about this?’” says Douglas Melton.

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Breakthrough within reach for diabetes scientist and patients nearest to his heart

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100 years after discovery of insulin, replacement therapy represents ‘a new kind of medicine,’ says Stem Cell Institute co-director Douglas Melton, whose children inspired his research

When Vertex Pharmaceuticals announced last month that its investigational stem-cell-derived replacement therapy was, in conjunction with immunosuppressive therapy, helping the first patient in a Phase 1/2 clinical trial robustly reproduce his or her own fully differentiated pancreatic islet cells, the cells that produce insulin, the news was hailed as a potential breakthrough for the treatment of Type 1 diabetes. For Harvard Stem Cell Institute Co-Director and Xander University Professor Douglas Melton, whose lab pioneered the science behind the therapy, the trial marked the most recent turning point in a decades-long effort to understand and treat the disease. In a conversation with the Gazette, Melton discussed the science behind the advance, the challenges ahead, and the personal side of his research. The interview was edited for clarity and length.

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

MELTON: The first major change in the treatment of Type 1 diabetes was probably the discovery of insulin in 1920. Now it’s 100 years later and if this works, it’s going to change the medical treatment for people with diabetes. Instead of injecting insulin, patients will get cells that will be their own insulin factories. It’s a new kind of medicine.

GAZETTE: Would you walk us through the approach?

MELTON: Nearly two decades ago we had the idea that we could use embryonic stem cells to make functional pancreatic islets for diabetics. When we first started, we had to try to figure out how the islets in a person’s pancreas replenished. Blood, for example, is replenished routinely by a blood stem cell. So, if you go give blood at a blood drive, your body makes more blood. But we showed in mice that that is not true for the pancreatic islets. Once they’re removed or killed, the adult body has no capacity to make new ones.

So the first important “a-ha” moment was to demonstrate that there was no capacity in an adult to make new islets. That moved us to another source of new material: stem cells. The next important thing, after we overcame the political issues surrounding the use of embryonic stem cells, was to ask: Can we direct the differentiation of stem cells and make them become beta cells? That problem took much longer than I expected — I told my wife it would take five years, but it took closer to 15. The project benefited enormously from undergraduates, graduate students, and postdocs. None of them were here for 15 years of course, but they all worked on different steps.

GAZETTE: What role did the Harvard Stem Cell Institute play?

MELTON: This work absolutely could not have been done using conventional support from the National Institutes of Health. First of all, NIH grants came with severe restrictions and secondly, a long-term project like this doesn’t easily map to the initial grant support they give for a one- to three-year project. I am forever grateful and feel fortunate to have been at a private institution where philanthropy, through the HSCI, wasn’t just helpful, it made all the difference.

I am exceptionally grateful as well to former Harvard President Larry Summers and Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, who supported the creation of the HSCI, which was formed specifically with the idea to explore the potential of pluripotency stem cells for discovering questions about how development works, how cells are made in our body, and hopefully for finding new treatments or cures for disease. This may be one of the first examples where it’s come to fruition. At the time, the use of embryonic stem cells was quite controversial, and Steve and Larry said that this was precisely the kind of science they wanted to support.

GAZETTE: You were fundamental in starting the Department of Stem Cell and Regenerative Biology. Can you tell us about that?

MELTON: David Scadden and I helped start the department, which lives in two Schools: Harvard Medical School and the Faculty of Arts and Science. This speaks to the unusual formation and intention of the department. I’ve talked a lot about diabetes and islets, but think about all the other tissues and diseases that people suffer from. There are faculty and students in the department working on the heart, nerves, muscle, brain, and other tissues — on all aspects of how the development of a cell and a tissue affects who we are and the course of disease. The department is an exciting one because it’s exploring experimental questions such as: How do you regenerate a limb? The department was founded with the idea that not only should you ask and answer questions about nature, but that one can do so with the intention that the results lead to new treatments for disease. It is a kind of applied biology department.

GAZETTE: This pancreatic islet work was patented by Harvard and then licensed to your biotech company, Semma, which was acquired by Vertex. Can you explain how this reflects your personal connection to the research?

MELTON: Semma is named for my two children, Sam and Emma. Both are now adults, and both have Type 1 diabetes. My son was 6 months old when he was diagnosed. And that’s when I changed my research plan. And my daughter, who’s four years older than my son, became diabetic about 10 years later, when she was 14.

When my son was diagnosed, I knew nothing about diabetes and had been working on how frogs develop. I changed my research focus, thinking, as any parent would, “What am I going to do about this?” Again, I come back to the flexibility of Harvard. Nobody said, “Why are you changing your research plan?”

GAZETTE: What’s next?

MELTON: The stem-cell-derived replacement therapy cells that have been put into this first patient were provided with a class of drugs called immunosuppressants, which depress the patient’s immune system. They have to do this because these cells were not taken from that patient, and so they are not recognized as “self.” Without immunosuppressants, they would be rejected. We want to find a way to make cells by genetic engineering that are not recognized as foreign.

I think this is a solvable problem. Why? When a woman has a baby, that baby has two sets of genes. It has genes from the egg, from the mother, which would be recognized as “self,” but it also has genes from the father, which would be “non-self.” Why does the mother’s body not reject the fetus? If we can figure that out, it will help inform our thinking about what genes to change in our stem cell-derived islets so that they could go into any person. This would be relevant not just to diabetes, but to any cells you wanted to transplant for liver or even heart transplants. It could mean no longer having to worry about immunosuppression.

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New cause of diabetes discovered, offering potential target for new classes of drugs to treat the disease

Researchers at Case Western Reserve University and University Hospitals have identified an enzyme that blocks insulin produced in the body -- a discovery that could provide a new target to treat diabetes.

Their study, published Dec. 5 in the journal Cell, focuses on nitric oxide, a compound that dilates blood vessels, improves memory, fights infection and stimulates the release of hormones, among other functions. How nitric oxide performs these activities had long been a mystery.

The researchers discovered a novel "carrier" enzyme (called SNO-CoA-assisted nitrosylase, or SCAN) that attaches nitric oxide to proteins, including the receptor for insulin action.

They found that the SCAN enzyme was essential for normal insulin action, but also discovered heightened SCAN activity in diabetic patients and mice with diabetes. Mouse models without the SCAN enzyme appeared to be shielded from diabetes, suggesting that too much nitric oxide on proteins may be a cause of such diseases.

"We show that blocking this enzyme protects from diabetes, but the implications extend to many diseases likely caused by novel enzymes that add nitric oxide," said the study's lead researcher Jonathan Stamler, the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation at the Case Western Reserve School of Medicine and president of Harrington Discovery Institute at University Hospitals. "Blocking this enzyme may offer a new treatment."

Given the discovery, next steps could be to develop medications against the enzyme, he said.

The research team included Hualin Zhou and Richard Premont, both from Case Western Reserve School of Medicine and University Hospitals, and students Zack Grimmett and Nicholas Venetos from the university's Medical Science Training Program.

Many human diseases, including Alzheimer's, cancer, heart failure and diabetes, are thought to be caused or accelerated by nitric oxide binding excessively to key proteins. With this discovery, Stamler said, enzymes that attach the nitric oxide become a focus.

With diabetes, the body often stops responding normally to insulin. The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems. Individuals with diabetes, the Centers for Disease Control reports, are more likely to suffer such conditions as heart disease, vision loss and kidney disease.

But the reason that insulin stops working isn't well understood.

Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can't be targeted specifically, Stamler said.

"This paper shows that dedicated enzymes mediate the many effects of nitric oxide," he said. "Here, we discover an enzyme that puts nitric oxide on the insulin receptor to control insulin. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases."

• Diseases and Conditions
• Hormone Disorders
• Chronic Illness
• Alzheimer's
• Huntington's Disease
• Disorders and Syndromes
• Nitrous oxide
• Diabetes mellitus type 1
• Diabetes mellitus type 2
• Drug discovery
• Nitrogen oxide

Story Source:

Materials provided by Case Western Reserve University . Note: Content may be edited for style and length.

Journal Reference :

• Hua-Lin Zhou, Zachary W. Grimmett, Nicholas M. Venetos, Colin T. Stomberski, Zhaoxia Qian, Precious J. McLaughlin, Puneet K. Bansal, Rongli Zhang, James D. Reynolds, Richard T. Premont, Jonathan S. Stamler. An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling . Cell , 2023; DOI: 10.1016/j.cell.2023.11.009

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Cancer is Adaptive and Can Switch Sugar for Fatty Acids to Spread Around the Body

A ll cells need glucose, aka sugar, to survive – including cancer cells, right? That's what scientists used to think, that is until they took a deep dive into how cancer cells really spread throughout the body so easily. Our understanding of cancer biology and its ability to spread within the human body has now taken a significant leap forward, thanks to this groundbreaking research. This new study reveals how cancer cells can adapt and even switch their preferred energy source to facilitate their spread. This discovery challenges traditional thinking about cancer and its growth mechanisms, opening up new avenues for research and potential treatment strategies.

How Cancer Spreads: The New Research

Recent research has uncovered a crucial change in cancer cells that allows them to spread around the body. Contrary to conventional wisdom, which suggests that cancer cells solely rely on sugar (glucose) as their primary fuel source, scientists have discovered that these adaptive cells can switch to fatty acids to fuel their growth. This metabolic flexibility empowers cancer cells to establish themselves in newly invaded sites where resources such as glucose may be limited. The study, published in Nature Communications and funded by Breast Cancer Now, sheds light on the molecular mechanisms underlying cancer adaptability and spread. ( 1 )

"Cancer cells have to work hard to take root and form a tumor. When tumor cells head on the move to other parts of the body, a process called metastasis, they have to work even harder to adapt to the energy and nutrient sources available to them wherever they find themselves, as well as surviving the journey," explained Professor Clare Isacke, Professor of Molecular Cell Biology in the Breast Cancer Now Toby Robins Research Centre at the ICR. "Our study has shown the importance of cancer cell learning how to use different nutrients and energy sources in order to survive." ( 2 )

Read More:  Video Time-Lapse Shows How Dark Patch of Skin Turns Into Melanoma Cancer

How the Study Was Conducted

Underpinning this remarkable finding is the identification of a protein called AKR1B10, which plays a pivotal role in enabling cancer cells to adapt and thrive in diverse environments. The research team at The Institute of Cancer Research, London, conducted a comprehensive analysis and found that high levels of AKR1B10 reduce cancer cells' dependency on sugar while enhancing their ability to utilize fatty acids as an alternative energy source. This metabolic adaptability was further correlated with the cells' ability to establish themselves in new locations within the body.

What This Means for the Future of Cancer and Cancer Treatment

Night owls tend to die sooner. but it's not late bedtimes killing them..

The implications of these findings are significant for the future of cancer research and treatment. The identification of AKR1B10 and the understanding of its role in fostering cancer cell adaptability offer a potential pathway for screening breast cancer patients for increased levels of this protein. Such screening may aid in identifying patients at higher risk of metastatic relapse, thus enabling tailored treatment strategies. Furthermore, the study opens doors for the development of novel treatment options that focus on disrupting cancer cells' ability to utilize fatty acids, potentially reducing relapse rates, as evidenced in experiments on mice.

"This research significantly improves our understanding of cancer cell metabolism and metastatic relapse and could lead to new avenues of exploration for new therapies and treatments for patients with metastatic breast cancer." said Professor Isacke.

Read More:  Is Decaf Coffee Safe to Drink? Advocacy Groups Highlights Additive Linked to Cancer

What This Means for You

For individuals and the broader community, this research could hold profound implications for cancer prevention strategies. The discovery of cancer cells' ability to switch their metabolic preferences signifies a need for a reevaluation of existing prevention and detection approaches. It underscores the need for a holistic understanding of cancer biology, potentially leading to the development of more targeted and effective preventive measures, as well as new cancer screening and detection methods. Moreover, this research contributes to the collective knowledge that can guide personalized treatment approaches and improve patient outcomes in the future.

The Bottom Line

The recent breakthrough in cancer research, revealing the adaptive nature of cancer cells and their ability to switch energy sources, marks a significant milestone in our understanding of cancer biology. This discovery not only sheds light on the intricate survival mechanisms of cancer cells but also presents new opportunities for the development of advanced screening methods and targeted treatment strategies. As we continue to unravel the complexities of cancer spread and adaptability, these insights hold tremendous promise for reshaping future cancer research and treatment paradigms.

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• " Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation ." Nature . Antoinette van Weverwijk, et al. June 2019
• " Cancer Cells Switch Sugar for Fatty Acids to Spread Around the Body ." Technelogy Networks . July 19, 2019

The post Cancer is Adaptive and Can Switch Sugar for Fatty Acids to Spread Around the Body appeared first on The Hearty Soul .

The Type Of Cheese That Has More Protein Than Cooked Meat And Fish

Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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New Research Sheds Light on Cause of Type 2 Diabetes

St. Petersburg, Fla. – September 12, 2023 – Scientists at Johns Hopkins All Children’s Hospital, along with an international team of researchers, are shedding new light on the causes of Type 2 diabetes. The new research, published in the journal Nature Communications , offers a potential strategy for developing new therapies that could restore dysfunctional pancreatic beta-cells or, perhaps, even prevent Type 2 diabetes from developing.

The new study shows that the beta-cells of Type 2 diabetes patients are deficient in a cell trafficking protein called “phosphatidylinositol transfer protein alpha” (or PITPNA), which can promote the formation of “little packages,” or intracellular granules containing insulin. These structures facilitate processing and maturation of insulin “cargo.” By restoring PITPNA in the Type 2 deficient beta-cells, production of insulin granule is restored and this reverses many of the deficiencies associated with beta-cell failure and Type 2 diabetes.

Researchers say it’s important to understand how specific genes regulate pancreatic beta-cell function, including those that mediate insulin granule production and maturation like PITPNA to provide therapeutic options for people.

Matthew Poy, Ph.D. , an associate professor of Medicine and Biological Chemistry in the Johns Hopkins University School of Medicine and leader of the Johns Hopkins All Children’s team within the  Institute for Fundamental Biomedical Research , was lead researcher on the study. He adds that follow-up work is now focused on whether PITPNA can enhance the functionality of stem-cell-derived pancreatic beta-cells. Since stem cell-based therapies are still in their relatively early stages of clinical development, it appears a great deal of the potential of this approach remains untapped. Poy believes that increasing levels of PITPNA in stem cell-derived beta-cells is an approach that could enhance the ability to produce and release mature insulin prior to transplantation in diabetic subjects.

“Our dream is that increasing PITPNA could improve the efficacy and potency of beta-like stem cells,” Poy says. “This is where our research is heading, but we have to discover whether the capacity of these undifferentiated stem cells that can be converted into many different cell types can be optimized — and to what level — to be converted into healthy insulin producing beta-cells. The goal would be to find a cure for type 2 diabetes.”

Read more about this groundbreaking research.

This study was funded through grants from the  Johns Hopkins All Children’s Foundation , the  National Institute of Health, the Robert A. Welch Foundation, the Helmholtz Gemeinschaft , the European Foundation for the Study of Diabetes, the  Swedish Science Council , the  NovoNordisk Foundation  and the  Deutsche Forschungsgemeinschaft .     About Johns Hopkins All Children’s Hospital Johns Hopkins All Children’s Hospital in St. Petersburg is a leader in children’s health care, combining a legacy of compassionate care focused solely on children since 1926 with the innovation and experience of one of the world’s leading health care systems. The 259-bed teaching hospital, stands at the forefront of discovery, leading innovative research to cure and prevent childhood diseases while training the next generation of pediatric experts. With a network of Johns Hopkins All Children’s Outpatient Care centers and collaborative care provided by All Children’s Specialty Physicians at regional hospitals, Johns Hopkins All Children’s brings care closer to home. Johns Hopkins All Children’s Hospital consistently keeps the patient and family at the center of care while continuing to expand its mission in treatment, research, education and advocacy. For more information, visit HopkinsAllChildrens.org .

Spate of new research points to the potential harms of artificial sweeteners

New research adds to mounting evidence that artificial sweeteners may be harmful to your health.

A study published Wednesday in the BMJ, which involved more than 100,000 adults in France, found a potential link between consumption of artificial sweeteners and heart disease.

The results showed that participants who consumed large amounts of aspartame — found in the tabletop sweeteners Equal and NutraSweet as well as cereals, yogurt, candy and diet soda — had a higher risk of stroke than people who didn’t consume the sweetener.

Similarly, people who consumed high quantities of sucralose — found in Splenda as well as baked goods, ice cream, canned fruit, flavored yogurt and syrups — and acesulfame potassium, often used in "sugar-free" soda, had a higher risk of coronary heart disease.

"Artificial sweeteners may not be a safe alternative to sugar," said Mathilde Touvier, the study’s author and a research director at the French National Institute for Health and Medical Research.

Last month, a smaller study found that consuming non-nutritive sweetener — sugar substitutes that contain few calories or nutrients — could alter a person's gut microbes and potentially elevate blood sugar levels. High blood sugar can increase one's risk of diabetes, heart disease or stroke.

Prior to that, a June lab study found that artificial sweeteners prompted gut bacteria to invade cells in the intestine wall, which could ultimately raise one's risk of infection or organ failure.

Other previous research has linked artificial sweeteners to obesity , high blood pressure, diabetes and increased cancer risk as well.

"The more data that comes out showing these adverse health effects, the less we're going to want to encourage people to switch from added sugars to non-nutritive sweeteners," said Dr. Katie Page, an associate professor of medicine at the University of Southern California.

But the healthiest course of action, Page said, isn't to opt for regular sugar instead.

"We really need to encourage people to eat sugar in more moderation and try to decrease sugar consumption," she said. "And the way to do that isn’t to consume more non-nutritive sweeteners."

Some sweeteners thought of as natural aren't preferable either, Page said.

"I definitely would not switch to agave," she said. "I know people think that’s healthy, but it actually has a very high fructose content."

An emerging link between sweeteners and heart disease

As a category, artificial sweeteners are low- or no-calorie additives often found in soft drinks and other highly processed foods like yogurt, granola bars, cereal or microwaveable meals. They're also sold as tabletop sweeteners like Equal, Splenda, Sweet ‘N Low and Truvia.

The sweeteners were originally billed as a healthier replacement for sugar, which is known to promote obesity and diabetes and can increase one's risk of heart disease if consumed in excess.

Touvier said her study is the first to directly assess how overall dietary consumption of artificial sweeteners impacts one’s risk of heart disease. Previous studies mostly looked at how artificially sweetened beverages impact heart disease risk.

Her team defined a large amount of sweetener as around 77 milligrams per day, on average, which is a little less than two packets of tabletop sweetener.

More than half of the participants' artificial sweetener consumption came from soft drinks, while 30% came from tabletop sweeteners. Another 8% came from sweetened dairy products like yogurt or cottage cheese with fruit topping.

Sucralose is the most commonly consumed artificial sweetener worldwide, Page said, whereas "aspartame has kind of gotten out of favor, so people aren’t consuming it as much."

She said sodas are the biggest source of artificial sweeteners in our food supply, though "a lot of the non-nutritive sweeteners people are consuming are coming from foods that you might think of as healthy."

Two prime examples: flavored yogurts and sports drinks.

The best alternative to sugary food, Page said, is naturally sweet fruit. If water isn't a satisfying substitute for soft drinks or juice, she suggested carbonated water without artificial sweeteners.

Sweeteners could disrupt your metabolism and elevate blood sugar

A growing body of research suggests that artificial sweetener may disrupt the body's ability to properly metabolize glucose, which can be a risk factor for diabetes and cardiovascular health issues. 

For the study published last month, Israeli researchers asked 120 people to consume four artificial sweeteners — aspartame, saccharin, stevia and sucralose — for two weeks. Participants consumed six sachets of sweetener per day, which is within the Food and Drug Administration’s acceptable intake.

The researchers observed changes in the makeup and function of participants' gut microbes, which help break down food and ward off disease-causing bacteria. The changes were not seen in people who did not consume artificial sweeteners.

"All four sweeteners changed the microbiome, each in their unique way," said Eran Elinav, the study's author and a microbiome researcher at the Weizmann Institute of Science.

Two sweeteners in particular, sucralose and saccharin (found in Sweet ‘N Low), altered some people's ability to process glucose.

"It changed the way the bugs in their gut are functioning and that, in turn, led to increases in their glucose levels, which is of course not a good thing," Page said.

The researchers even transferred samples of gut microbes from the study participants with significant metabolism changes into mice. The mice, too, developed blood sugar alterations, Elinav said.

"That's pretty good evidence suggesting that [artificial sweeteners] have some type of effect on metabolism and on the gut microbiome," Page said.

Page said her team is now studying how artificial sweeteners affect children's risk of metabolic conditions like diabetes.

"There's been very, very few studies in children and there's data showing that the increases in non-nutritive sweetener consumption are even higher among children and adolescents," she said.

Aria Bendix is the breaking health reporter for NBC News Digital.

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Obesity and High Blood Sugar Play Ever Growing Role in Ill-Health, Study Shows

FILE PHOTO: People sit near a banner advertising the Brussels West Obesity Clinic during a 2-day event marking World Obesity Day, at CHIREC Sainte Anne Saint Remi Clinic in Brussels, Belgium March 6, 2024. REUTERS/Yves Herman/File Photo

By Jennifer Rigby

LONDON (Reuters) - Obesity, high blood sugar and high blood pressure among other metabolic issues now lead to almost 50% more years of healthy life lost to either disease or premature death than in 2000, a major international study showed on Thursday.

Over the same period, the number of years lost due to factors associated with undernutrition for mothers and children, such as stunting or wasting, dropped by 71.5%.

The Global Burden of Diseases, Injuries and Risk Factors Study 2021, published on Thursday in The Lancet, used data from 204 countries and territories to identify the leading causes worldwide of illness and early death. These are measured in disability-adjusted life years, or "DALYs".

The data shows a clear shift in global health challenges as populations age and lifestyles change, the authors said, although air pollution was the biggest risk factor in both the 2000 and 2021 data.

They also pointed out that the results were not uniform. Undernutrition remained a major risk factor in sub-Saharan Africa, for example.

Ill-health among 15- to 49-year-olds worldwide was increasingly attributable to a high body-mass index (BMI) and high blood sugar - two risk factors in the development of diabetes, the authors said.

"Future trends may be quite different than past trends because of factors such as climate change and increasing obesity and addiction," said Liane Ong, lead research scientist at the Institute for Health Metrics and Evaluation at the University of Washington, which led the study.

An accompanying study from the Global Burden of Diseases team predicted that life expectancy is expected to rise by 4.5 years by 2050, from 73.6 years to 78.1 years.

The biggest increases are likely in countries where the existing estimates are lower, meaning life-expectancies are starting to converge around the world.

However, while people will live longer, they are likely to experience more years spent in poor health, the study forecast.

(Reporting by Jennifer Rigby; Editing by Hugh Lawson)

Copyright 2024 Thomson Reuters .

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Sugar Is Definitely Toxic, a New Study Says

• Alice Park @aliceparkny

That’s what scientists have concluded from a first-of-its-kind diet study involving overweight kids

Fat was the food villain these past few decades but sugar is quickly muscling in to take its place. As rates of sugar-related disorders such as diabetes, obesity and heart disease climb, many experts believe that when Americans rid themselves of fat, they simply replaced it with sugar in all its forms.

But proving that the rise of the chronic diseases was actually linked to higher sugar consumption is a challenge. Dr. Robert Lustig, from the department of pediatrics at the University of California, San Francisco, who has made a name for himself publishing books and research addressing the question of sugar’s effects on the body, wanted clearer answers. Now, in a paper published Tuesday, he and his colleagues believe they have come up with the definitive evidence that sugar, as Lustig says, “is toxic.”

In most lab studies, the doses of sugar that scientists test are quite high; they want to see what the effect is quickly and, depending on the research, they may not have time to wait to study the more gradual effects that might emerge. And in studies where people reduce the amount of sugar they eat, for instance, those people end up eating fewer calories overall, so it’s difficult to know whether any changes are due to the removal of sugar or to the drop in calories.

Lustig and his colleagues think they’ve produced the “hard and fast data that sugar is toxic irrespective of its calories and irrespective of weight.”

MORE: FDA Wants Nutrition Labels to Include More Detail on Added Sugars

Lustig’s confidence comes from the unique study, described in Obesity , of 43 Hispanic or African-American children aged eight to 18 years old. He collected detailed food questionnaires from each of the adolescents to get an idea of the average amount of calories they ate per day, then designed a special menu for each of them for nine days that matched the total numbers of calories they would normally eat. The only difference in the nine-day diet was that most of the sugar the children ate was replaced by starch — the overall number of calories remained the same. The children weighed themselves daily, and if they were losing weight, they were told to eat more of the provided food in order to keep their weight the same throughout the study.

“Everything got better,” says Lustig. Some of the children went from being insulin resistant, a precursor state to developing diabetes, in which the body’s insulin levels can no longer keep up with the pace of breaking down sugar that’s coming in from the diet, to insulin sensitive.

MORE: Artificial Sweeteners Aren’t the Answer to Obesity: Here’s Why

“We took chicken teriyaki out, and put turkey hot dogs in. We took sweetened yogurt out, and put baked potato chips in. We took pastries out and put bagels in,” says Lustig. “So there was no change in [the children’s] weight and no change in calories.”

After nine days of having their total dietary sugar reduced to 10% of their daily calories, however, they showed improvements in all of these measures. Overall, their fasting blood sugar levels dropped by 53%, along with the amount of insulin their bodies produced since insulin is normally needed to break down carbohydrates and sugars. Their triglyceride and LDL levels also declined and, most importantly, they showed less fat in their liver.

MORE: 7 Amazing Things That Happen to Your Body When You Give Up Soda

Because some of the children lost weight, to convince themselves that the effects weren’t due to the small amount of weight that some of the children lost, Lustig and his team compared those who lost weight to those who didn’t during the study, and found similar improvements in both groups.

“Up until now, there have been a lot of correlation studies linking sugar and metabolic syndrome,” says Lustig. “This is causation.”

The diet he provided the children isn’t considered ideal from a health perspective — starches are still a considerable source of calories and can contribute to weight gain. But Lustig relied on the starches to prove a point in a scientific study — that the effect sugar has on the body goes beyond anything connected to its calories and to weight. “I’m not suggesting in any way, shape or form that we gave them healthy food,” he says. “We gave them crappy food, shitty food, processed food — and they still got better. Imagine how much even better they would have gotten if we didn’t substitute and took the sugar out. Then they would have gotten even better yet. That’s the point.”

MORE: The Trouble With Sugar Free Kids

Not everyone is convinced that the results definitely prove sugar, and not weight loss, is the culprit, however. Susan Roberts, professor of Nutrition, USDA Nutrition Center at Tufts University notes that because some of the children lost weight, it’s still possible that shedding the pounds helped their metabolic measures to improve. She also points out that the children self-reported their initial diet, which can often be inaccurate. “We know that a healthy diet and weight loss cause good metabolic changes, and although this study tries to attribute its effects to low fructose, in fact it is impossible to do that because of the study design.”

Some experts are concerned for other reasons. They’re worried that the findings may shift attention away from what they consider to be the more fundamental issue — that overall, we’re eating too much. “Too much calorie intake is still the biggest problem,” says Dr. Mark Corkins, professor of pediatrics at University of Tennessee Health Science Center and member of the American Academy of Pediatrics committee on nutrition. He notes that the study involved children who were obese already and consuming too many calories. “It’s an important study, and the facts coming out of it are very important. It means we need to look at sugars, and at the type of sugars and sugar intake. But I worry that people are going to hang everything on this when we still need to reduce consumption.”

Lustig hopes that won’t happen as more data emerges that details how sugar is altering the body in unhealthy ways outside of its caloric contribution. That wasn’t the subject of the current paper, but he promises follow up studies based on this work that will address that. This study does hint however, at what might be happening. While there has been a lot of attention on the presence of belly fat and its connection to metabolic syndrome, the fact that the children saw improvements in the amount of fat in their liver suggests that might be an important way that sugar is contributing to chronic disease. Obese children and those with diabetes often suffer from fatty liver, a condition normally associated with alcohol abuse but increasingly common among non-drinkers who gain excessive amounts of weight.

This new view of sugar could change the advice that doctors and government health officials give about eating the sweet stuff. Lustig’s hope is that the information is considered as the U.S. Department of Agriculture finalizes its latest Dietary Guidelines, expected by the end of the year, which delineate recommendations for what, and how much of different types of foods and nutrients Americans should eat.

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Recent Advances

ADA-funded researchers use the money from their awards to conduct critical diabetes research. In time, they publish their findings in order to inform fellow scientists of their results, which ensures that others will build upon their work. Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards!

Identification of a new player in type 1 diabetes risk

Type 1 diabetes is caused by an autoimmune attack of insulin-producing beta-cells. While genetics and the environment are known to play important roles, the underlying factors explaining why the immune system mistakenly recognize beta-cells as foreign is not known. Now, Dr. Delong has discovered a potential explanation. He found that proteins called Hybrid Insulin Peptides (HIPs) are found on beta-cells of people with type 1 diabetes and are recognized as foreign by their immune cells. Even after diabetes onset, immune cells are still present in the blood that attack these HIPs.

Next, Dr. Delong wants to determine if HIPs can serve as a biomarker or possibly even targeted to prevent or treat type 1 diabetes. Baker, R. L., Rihanek, M., Hohenstein, A. C., Nakayama, M., Michels, A., Gottlieb, P. A., Haskins, K., & Delong, T. (2019). Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes , 68 (9), 1830–1840.

Understanding the biology of body-weight regulation in children

Determining the biological mechanisms regulating body-weight is important for preventing type 2 diabetes. The rise in childhood obesity has made this even more urgent. Behavioral studies have demonstrated that responses to food consumption are altered in children with obesity, but the underlying biological mechanisms are unknown. This year, Dr. Schur tested changes in brain and hormonal responses to a meal in normal-weight and obese children. Results from her study show that hormonal responses in obese children are normal following a meal, but responses within the brain are reduced. The lack of response within the brain may predispose them to overconsumption of food or difficulty with weight-loss.

With this information at hand, Dr. Schur wants to investigate how this information can be used to treat obesity in children and reduce diabetes.

Roth, C. L., Melhorn, S. J., Elfers, C. T., Scholz, K., De Leon, M. R. B., Rowland, M., Kearns, S., Aylward, E., Grabowski, T. J., Saelens, B. E., & Schur, E. A. (2019). Central Nervous System and Peripheral Hormone Responses to a Meal in Children. The Journal of Clinical Endocrinology and Metabolism , 104 (5), 1471–1483.

A novel molecule to improve continuous glucose monitoring

To create a fully automated artificial pancreas, it is critical to be able to quantify blood glucose in an accurate and stable manner. Current ways of continuously monitoring glucose are dependent on the activity of an enzyme which can change over time, meaning the potential for inaccurate readings and need for frequent replacement or calibration. Dr. Wang has developed a novel molecule that uses a different, non-enzymatic approach to continuously monitor glucose levels in the blood. This new molecule is stable over long periods of time and can be easily integrated into miniaturized systems.

Now, Dr. Wang is in the process of patenting his invention and intends to continue research on this new molecule so that it can eventually benefit people living with diabetes.

Wang, B. , Chou, K.-H., Queenan, B. N., Pennathur, S., & Bazan, G. C. (2019). Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose. Angewandte Chemie (International Ed. in English) , 58 (31), 10612–10615.

Addressing the legacy effect of diabetes

Several large clinical trials have demonstrated the importance of tight glucose control for reducing diabetes complications. However, few studies to date have tested this in the real-world, outside of a controlled clinical setting. In a study published this year, Dr. Laiteerapong found that indeed in a real-world setting, people with lower hemoglobin A1C levels after diagnosis had significantly lower vascular complications later on, a phenomenon known as the ‘legacy effect’ of glucose control. Her research noted the importance of early intervention for the best outcomes, as those with the low A1C levels just one-year after diagnosis had significantly lower vascular disease risk compared to people with higher A1C levels.

With these findings in hand, physicians and policymakers will have more material to debate and determine the best course of action for improving outcomes in people newly diagnosed with diabetes.

Laiteerapong, N. , Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care , 42 (3), 416–426.

A new way to prevent immune cells from attacking insulin-producing beta-cells

Replacing insulin-producing beta-cells that have been lost in people with type 1 diabetes is a promising strategy to restore control of glucose levels. However, because the autoimmune disease is a continuous process, replacing beta-cells results in another immune attack if immunosorbent drugs are not used, which carry significant side-effects. This year, Dr. Song reported on the potential of an immunotherapy he developed that prevents immune cells from attacking beta-cells and reduces inflammatory processes. This immunotherapy offers several potential benefits, including eliminating the need for immunosuppression, long-lasting effects, and the ability to customize the treatment to each patient.

The ability to suppress autoimmunity has implications for both prevention of type 1 diabetes and improving success rates of islet transplantation.

Haque, M., Lei, F., Xiong, X., Das, J. K., Ren, X., Fang, D., Salek-Ardakani, S., Yang, J.-M., & Song, J . (2019). Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight , 4 (7).

A new target to improve insulin sensitivity

The hormone insulin normally acts like a ‘key’, traveling through the blood and opening the cellular ‘lock’ to enable the entry of glucose into muscle and fat cells. However, in people with type 2 diabetes, the lock on the cellular door has, in effect, been changed, meaning insulin isn’t as effective. This phenomenon is called insulin resistance. Scientists have long sought to understand what causes insulin resistance and develop therapies to enable insulin to work correctly again. This year, Dr. Summers determined an essential role for a molecule called ceramides as a driver of insulin resistance in mice. He also presented a new therapeutic strategy for lowering ceramides and reversing insulin resistance. His findings were published in one of the most prestigious scientific journals, Science .

Soon, Dr. Summers and his team will attempt to validate these findings in humans, with the ultimate goal of developing a new medication to help improve outcomes in people with diabetes.

Chaurasia, B., Tippetts, T. S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., … Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science (New York, N.Y.) , 365 (6451), 386–392.

Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A. , Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society , 3 (3), 643–654.

Investigating the loss of postmenopausal protection from cardiovascular disease in women with type 1 diabetes

On average, women have a lower risk of developing heart disease compared to men. However, research has shown that this protection is lost in women with type 1 diabetes. The process of menopause increases rates of heart disease in women, but it is not known how menopause affects women with type 1 diabetes in regard to risk for developing heart disease. In a study published this year, Dr. Snell-Bergeon found that menopause increased risk markers for heart disease in women with type 1 diabetes more than women without diabetes.

Research has led to improved treatments and significant gains in life expectancy for people with diabetes and, as a result, many more women are reaching the age of menopause. Future research is needed to address prevention and treatment options.

Keshawarz, A., Pyle, L., Alman, A., Sassano, C., Westfeldt, E., Sippl, R., & Snell-Bergeon, J. (2019). Type 1 Diabetes Accelerates Progression of Coronary Artery Calcium Over the Menopausal Transition: The CACTI Study. Diabetes Care , 42 (12), 2315–2321.

Identification of a potential therapy for diabetic neuropathy related to type 1 and type 2 diabetes

Diabetic neuropathy is a type of nerve damage that is one of the most common complications affecting people with diabetes. For some, neuropathy can be mild, but for others, it can be painful and debilitating. Additionally, neuropathy can affect the spinal cord and the brain. Effective clinical treatments for neuropathy are currently lacking. Recently, Dr. Calcutt reported results of a new potential therapy that could bring hope to the millions of people living with diabetic neuropathy. His study found that a molecule currently in clinical trials for the treatment of depression may be valuable for diabetic neuropathy, particularly the type affecting the brain.

Because the molecule is already in clinical trials, there is the potential that it can benefit patients sooner than later.

Jolivalt, C. G., Marquez, A., Quach, D., Navarro Diaz, M. C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D. R., Fernyhough, P., Johe, K., & Calcutt, N. A. (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes , 68 (11), 2143–2154.

ADA-funded researcher studying link between ageing and type 2 diabetes

One of the most important risk factors for developing type 2 diabetes is age. As a person gets older, their risk for developing type 2 diabetes increases. Scientists want to better understand the relationship between ageing and diabetes in order to determine out how to best prevent and treat type 2 diabetes. ADA-funded researcher Rafael Arrojo e Drigo, PhD, from the Salk Institute for Biological Studies, is one of those scientists working hard to solve this puzzle.

Recently, Dr. Arrojo e Drigo published results from his research in the journal Cell Metabolism . The goal of this specific study was to use high-powered microscopes and novel cellular imaging tools to determine the ‘age’ of different cells that reside in organs that control glucose levels, including the brain, liver and pancreas. He found that, in mice, the cells that make insulin in the pancreas – called beta-cells – were a mosaic of both old and young cells. Some beta-cells appeared to be as old as the animal itself, and some were determined to be much younger, indicating they recently underwent cell division.

Insufficient insulin production by beta-cells is known to be a cause of type 2 diabetes. One reason for this is thought to be fewer numbers of functional beta-cells. Dr. Arrojo e Drigo believes that people with or at risk for diabetes may have fewer ‘young’ beta-cells, which are likely to function better than old ones. Alternatively, if we can figure out how to induce the production of younger, high-functioning beta-cells in the pancreas, it could be a potential treatment for people with diabetes.

In the near future, Dr. Arrojo e Drigo’s wants to figure out how to apply this research to humans. “The next step is to look for molecular or morphological features that would allow us to distinguish a young cell from and old cell,” Dr. Arrojo e Drigo said.

The results from this research are expected to provide a unique insight into the life-cycle of beta-cells and pave the way to novel therapeutic avenues for type 2 diabetes.

Watch a video of Dr. Arrojo e Drigo explaining his research!

Arrojo E Drigo, R. , Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., … Hetzer, M. W. (2019). Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism , 30 (2), 343-351.e3.

Researcher identifies potential underlying cause of type 1 diabetes

Type 1 diabetes occurs when the immune system mistakenly recognizes insulin-producing beta-cells as foreign and attacks them. The result is insulin deficiency due to the destruction of the beta-cells. Thankfully, this previously life-threatening condition can be managed through glucose monitoring and insulin administration. Still, therapies designed to address the underlying immunological cause of type 1 diabetes remain unavailable.

Conventional approaches have focused on suppressing the immune system, which has serious side effects and has been mostly unsuccessful. The American Diabetes Association recently awarded a grant to Dr. Kenneth Brayman, who proposed to take a different approach. What if instead of suppressing the whole immune system, we boost regulatory aspects that already exist in the system, thereby reigning in inappropriate immune cell activation and preventing beta-cell destruction? His idea focused on a molecule called immunoglobulin M (IgM), which is responsible for limiting inflammation and regulating immune cell development.

In a paper published in the journal Diabetes , Dr. Brayman and a team of researchers reported exciting findings related to this approach. They found that supplementing IgM obtained from healthy mice into mice with type 1 diabetes selectively reduced the amount of autoreactive immune cells known to target beta-cells for destruction. Amazingly, this resulted in reversal of new-onset diabetes. Importantly, the authors of the study determined this therapy is translatable to humans. IgM isolated from healthy human donors also prevented the development of type 1 diabetes in a humanized mouse model of type 1 diabetes.

The scientists tweaked the original experiment by isolating IgM from mice prone to developing type 1 diabetes, but before it actually occurred. When mice with newly onset diabetes were supplemented with this IgM, their diabetes was not reversed. This finding suggests that in type 1 diabetes, IgM loses its capacity to serve as a regulator of immune cells, which may be contribute to the underlying cause of the disease.

Future studies will determine exactly how IgM changes its regulatory properties to enable diabetes development. Identification of the most biologically optimal IgM will facilitate transition to clinical applications of IgM as a potential therapeutic for people with type 1 diabetes.    Wilson, C. S., Chhabra, P., Marshall, A. F., Morr, C. V., Stocks, B. T., Hoopes, E. M., Bonami, R.H., Poffenberger, G., Brayman, K.L. , Moore, D. J. (2018). Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice. Diabetes .

ADA-funded researcher designs community program to help all people tackle diabetes

Diabetes self-management and support programs are important adjuncts to traditional physician directed treatment. These community-based programs aim to give people with diabetes the knowledge and skills necessary to effectively self-manage their condition. While several clinical trials have demonstrated the value of diabetes self-management programs in terms of improving glucose control and reducing health-care costs, whether this also occurs in implemented programs outside a controlled setting is unclear, particularly in socially and economically disadvantaged groups.

Lack of infrastructure and manpower are often cited as barriers to implementation of these programs in socioeconomically disadvantaged communities. ADA-funded researcher Dr. Briana Mezuk addressed this challenge in a study recently published in The Diabetes Educator . Dr. Mezuk partnered with the YMCA to evaluate the impact of the Diabetes Control Program in Richmond, Virginia. This community-academic partnership enabled both implementation and evaluation of the Diabetes Control Program in socially disadvantaged communities, who are at higher risk for developing diabetes and the complications that accompany it.

Dr. Mezuk had two primary research questions: (1) What is the geographic and demographic reach of the program? and (2) Is the program effective at improving diabetes management and health outcomes in participants? Over a 12-week study period, Dr. Mezuk found that there was broad geographic and demographic participation in the program. The program had participants from urban, suburban and rural areas, most of which came from lower-income zip codes. HbA1C, mental health and self-management behaviors all improved in people taking part in the Greater Richmond Diabetes Control Program. Results from this study demonstrate the value of diabetes self-management programs and their potential to broadly improve health outcomes in socioeconomically diverse communities. Potential exists for community-based programs to address the widespread issue of outcome disparities related to diabetes.  Mezuk, B. , Thornton, W., Sealy-Jefferson, S., Montgomery, J., Smith, J., Lexima, E., … Concha, J. B. (2018). Successfully Managing Diabetes in a Community Setting: Evidence from the YMCA of Greater Richmond Diabetes Control Program. The Diabetes Educator , 44 (4), 383–394.

Using incentives to stimulate behavior changes in youth at risk for developing diabetes

Once referred to as ‘adult-onset diabetes’, incidence of type 2 diabetes is now rapidly increasing in America’s youth. Unfortunately, children often do not have the ability to understand how everyday choices impact their health. Could there be a way to change a child’s eating behaviors? Davene Wright, PhD, of Seattle Children’s Hospital was granted an Innovative Clinical or Translational Science award to determine whether using incentives, directed by parents, can improve behaviors related to diabetes risk. A study published this year in Preventive Medicine Reports outlined what incentives were most desirable and feasible to implement. A key finding was that incentives should be tied to behavior changes and not to changes in body-weight.

With this information in hand, Dr. Wright now wants to see if incentives do indeed change a child’s eating habits and risk for developing type 2 diabetes. She is also planning to test whether an incentive program can improve behavior related to diabetes management in youth with type 1 diabetes. Jacob-Files, E., Powell, J., & Wright, D. R. (2018). Exploring parent attitudes around using incentives to promote engagement in family-based weight management programs. Preventive Medicine Reports , 10 , 278–284.

Determining the genetic risk for gestational diabetes

Research has identified more than 100 genetic variants linked to risk for developing type 2 diabetes in humans. However, the extent to which these same genetic variants might affect a woman’s probability for getting gestational diabetes has not been investigated.

Pathway to Stop Diabetes ® Accelerator awardee Marie-France Hivert, MD, of Harvard University set out to answer this critical question. Dr. Hivert found that indeed genetic determinants of type 2 diabetes outside of pregnancy are also strong risk factors for gestational diabetes. This study was published in the journal Diabetes .

The implications? Because of this finding, doctors in the clinic may soon be able to identify women at risk for getting gestational diabetes and take proactive steps to prevent it. Powe, C. E., Nodzenski, M., Talbot, O., Allard, C., Briggs, C., Leya, M. V., … Hivert, M.-F. (2018). Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus. Diabetes , 67 (12), 2703–2709.

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• About Healthy Growth and Weight
• Water and Healthier Drinks
• Healthy Eating for a Healthy Weight
• Steps for Losing Weight
• Tips for Physical Activity and Your Weight
• Tips for Parents and Caregivers
• External Resources
• Be Sugar Smart
• Rethink Your Drink

What to know

Sugary drinks are the leading source of added sugars in the American diet. People who often drink sugary drinks are more likely to experience health problems. These problems include weight gain, obesity, type 2 diabetes, heart disease, cavities, and gout, a type of arthritis. Learn how to rethink your drink.

Sugar and calories in common drinks

The next time you go grocery shopping, read the nutrition labels on the items in your cart to see which ones have the most added sugars. You may be surprised to see the amount of added sugars in some drinks. Sugary drinks are the leading source of added sugars in the American diet.

Sugary drinks include regular sodas, fruit drinks, sports drinks, energy drinks, and sweetened waters. The flavored coffees we grab on the way to work and sweet drinks we order when eating out are also sugary drinks. Adding sugar and flavored creamer to coffee and tea at home counts too.

Drink (12-ounce serving)

Teaspoons of Sugar

Total Drink Calories

Plain Water

Unsweetened Tea

Lemonade, podwer, prepared with water

Sports Drinks

Brewed Sweet Tea

Energy Drink

Regular Soda

Fruit Juice Drink

Regular Orange Soda

Sugar content is derived from US Department of Agriculture FoodData Central .

Why should I be concerned?

People who often drink sugary drinks are more likely to experience health problems. These problems include weight gain, obesity, type 2 diabetes, heart disease, cavities, and gout, a type of arthritis 1 2 .

How much added sugar is too much?

The Dietary Guidelines for Americans recommends that children younger than 2 do not have any added sugar. The recommendation for people 2 and older is to limit added sugars to less than 10% of total daily calories. That means if you eat 2,000 calories in a day, no more than 200 of those calories should come from added sugars.

200 calories is equal to about 12 teaspoons of added sugar. A 12-ounce regular soda has more than 10 teaspoons of added sugar. That's more than 150 calories from sugar.

CDC research found about 30% of Americans 2 and older eat and drink high amounts of added sugar (more than 15% of daily calories from added sugar) each day. Cutting out two regular sodas per day would reduce total calories by 2,100 in a week and help reduce sugar intake.

Aim for less than 50 grams a day, 0 grams for children under 2‎

Try to limit added sugars as much as possible. Aim for less (or much less!) than 50 grams a day if your recommended calories are 2,000 a day. This differs by age, sex, and physical activity level. Children under 2 should have 0 grams of added sugars.

Tricks to Rethink Your Drink

Choose water instead of sugary drinks. This can be tap water or unsweetened, bottled, or sparkling water.

Need more flavor? Add berries or slices of lime, lemon, or cucumber to water.

If water just won't do , reach for drinks that contain important nutrients. Nutrient-dense drinks include:

• Low or fat-free milk.
• Unsweetened, fortified milk alternatives.
• 100% juice.

Missing fizzy drinks? Add a splash of 100% juice to plain sparkling water for a refreshing, low-calorie drink.

Need help breaking the habit? Don't stock up on sugary drinks. Instead, keep a jug or resuable bottles of cold water in the fridge.

At the coffee shop? Skip the flavored syrups and whipped cream. Ask for a drink with low or fat-free milk or unsweetened milk alternatives such as soy or almond. Or, you can get back to basics with black coffee.

At the store? Read the Nutrition Facts label to choose drinks that are low in calories, added sugars, and saturated fat.

On the go? Carry a reusable water bottle with you and refill it throughout the day.

Still thirsty? Learn how to drink more water .

Remember that you can be a role model for your friends and family by choosing water and other healthy, low-calorie beverages.

A note about energy drinks

Energy drinks are often marketed as products that increase energy. In addition to added sugar, these products may also contain large amounts of caffeine and other legal stimulants. Concerns have been raised about the potential health risks of these products, especially for young people 1 3 . If you're looking for a quick pick-me-up, alternatives to energy drinks include:

Plain or unsweetened flavored water . Dehydration is often a reason for low energy. 4

Unsweetened tea. Many tea flavors are available in naturally caffeinated varieties that can be enjoyed hot or cold.

Hot or iced coffee , unsweetened of course!

100% fruit or vegetable juice . There are many types of juices and juice combinations. Find one you enjoy!

Whole fruit. Sometimes a snack can give you as much of a boost as a drink.

See more about energy drinks and children and adolescents.

Other names for added sugars

Added sugars are those added during food processing, foods packaged as sweeteners, sugars from syrups and honey, and sugars from concentrated fruit or vegetable juices. Added sugars do not include naturally occurring sugars in milk, fruits, and vegetables. 5

If any of these are in your beverage, you are drinking a sugar-sweetened beverage:

• Fruit juice concentrates
• Fruit nectars (such as agave nectar)
• High fructose corn syrup
• Maple syrup and syrup

Get the Facts: Added Sugars

Get the Facts: Sugar-Sweetened Beverages and Consumption

Water and Consumption

Healthy Weight and Diabetes

Make Better Beverage Choices

• US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025 . 9th Edition. Accessed December 27, 2023
• Ebrahimpour-Koujan S, Saneei P, Larijani B, Esmaillzadeh A. Consumption of sugar sweetened beverages and dietary fructose in relation to risk of gout and hyperuricemia: a systematic review and meta-analysis . Crit Rev Food Sci Nutr . 2020;60(1):1–10.
• Committee on Nutrition and the Council on Sports Medicine and Fitness. Sports drinks and energy drinks for children and adolescents: are they appropriate? Pediatrics . 2011;127(6):1182–1189.
• Energy Drinks . National Institutes of Health. Updated July 2018. Accessed December 27, 2023. https://www.nccih.nih.gov/health/energy-drinks.
• Added Sugars on the New Nutrition Facts Label . US Food and Drug Administration. Updated September 27, 2023. Accessed December 27, 2023. https://www.fda.gov/food/nutrition-facts-label/added-sugars-nutrition-facts-label.

Healthy Weight and Growth

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May 17, 2024

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Study reveals how a sugar-sensing protein acts as a 'machine' to switch plant growth—and oil production—on and off

by Brookhaven National Laboratory

Proteins are molecular machines, with flexible pieces and moving parts. Understanding how these parts move helps scientists unravel the function a protein plays in living things—and potentially how to change its effects. Biochemists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory and colleagues at DOE's Pacific Northwest National Laboratory (PNNL) have published a new example of how one such molecular machine works.

Their paper in the journal Science Advances describes how the moving parts of a particular plant protein control whether plants can grow and make energy-intensive products such as oil—or instead put in place a series of steps to conserve precious resources. The study focuses specifically on how the molecular machinery is regulated by a molecule that rises and falls with the level of sugar—plants' main energy source.

"This paper reveals the detailed mechanism that tells plant cells, 'we have lots of sugar,' and then how that signaling affects the biochemical pathways that trigger processes like plant growth and oil production," said Brookhaven Lab biochemist Jantana Blanford, the study's lead author.

The study builds on earlier work by the Brookhaven team that uncovered molecular links between sugar levels and oil production in plants. One potential goal of this research is to identify specific proteins—and parts of proteins—scientists can engineer to make plants that produce more oil for use as biofuels or other oil-based products.

"Identifying exactly how these molecules and proteins interact, as this new study does, brings us closer to identifying how we might engineer these proteins to increase plant oil production," said John Shanklin, chair of Brookhaven Lab's Biology Department and leader of the research team.

Unraveling molecular interactions

The team used a combination of laboratory experiments and computational modeling to zero in on how the molecule that serves as a sugar proxy binds to a "sensor kinase" known as KIN10.

KIN10 is the protein that contains the moving parts that determine which biochemical pathways are on or off. The scientists already knew that KIN10 acts as both a sugar sensor and a switch: When sugar levels are low, KIN10 interacts with another protein to set off a cascade of reactions that ultimately shut down oil production and break down energy-rich molecules like oil and starch to make energy that powers the cell.

But when sugar levels are high, KIN10's shut-down function is shut off—meaning plants can grow and make lots of oil and other products with the abundant energy.

But how does the sugar proxy binding to KIN10 flip the switch?

To find out, Blanford started with the adage of "opposites attract." She identified three positively charged parts of KIN10 that might be attracted to abundant negative charges on the sugar proxy molecule. A laboratory-based process of elimination that involved making variations of KIN10 with modifications to these sites identified the one true binding site.

Then the Brookhaven team turned to computational colleagues at PNNL.

Marcel Baer and Simone Raugei at PNNL examined at the atomic level how the sugar proxy and KIN10 fit together.

"By using multiscale modeling we observed that the protein can exist in multiple conformations but only one of them can effectively bind the sugar proxy," Baer said.

The PNNL simulations identified key amino acids within the protein that control the binding of the sugar. These computational insights were then confirmed experimentally.

The combined body of experimental and computational information helped the scientists understand how interaction with the sugar proxy directly affects the downstream action of KIN10.

Flipping the switch

"Additional analyses showed that the entire KIN10 molecule is rigid except for one long flexible loop," Shanklin said. The models also showed that the loop's flexibility is what allows KIN10 to interact with an activator protein to trigger the cascade of reactions that ultimately shut down oil production and plant growth.

When sugar levels are low, and little sugar proxy molecule is present, the loop remains flexible, and the shutdown mechanism can operate to reduce plant growth and oil production . That makes sense to conserve precious resources, Shanklin said.

But when sugar levels are high, the sugar proxy binds tightly to KIN10.

"The calculations show how this small molecule blocks the loop from swinging around and prevents it from triggering the shutdown cascade," Blanford said.

Again, this makes sense since abundant sugar is available for plants to make oil.

Now that the scientists have this detailed information, how might they put it to use?

"We could potentially use our new knowledge to design KIN10 with altered binding strength for the sugar proxy to change the set point at which plants make things like oil and break things down," Shanklin said.

Journal information: Science Advances

Provided by Brookhaven National Laboratory

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The Two-Way

50 years ago, sugar industry quietly paid scientists to point blame at fat.

Camila Domonoske

A newly discovered cache of internal documents reveals that the sugar industry downplayed the risks of sugar in the 1960s. Luis Ascui/Getty Images hide caption

A newly discovered cache of internal documents reveals that the sugar industry downplayed the risks of sugar in the 1960s.

In the 1960s, the sugar industry funded research that downplayed the risks of sugar and highlighted the hazards of fat, according to a newly published article in JAMA Internal Medicine.

The article draws on internal documents to show that an industry group called the Sugar Research Foundation wanted to "refute" concerns about sugar's possible role in heart disease. The SRF then sponsored research by Harvard scientists that did just that. The result was published in the New England Journal of Medicine in 1967, with no disclosure of the sugar industry funding.

Sugar Shocked? The Rest Of Food Industry Pays For Lots Of Research, Too

The sugar-funded project in question was a literature review, examining a variety of studies and experiments. It suggested there were major problems with all the studies that implicated sugar, and concluded that cutting fat out of American diets was the best way to address coronary heart disease.

The authors of the new article say that for the past five decades, the sugar industry has been attempting to influence the scientific debate over the relative risks of sugar and fat.

"It was a very smart thing the sugar industry did, because review papers, especially if you get them published in a very prominent journal, tend to shape the overall scientific discussion," co-author Stanton Glantz told The New York Times .

Money on the line

How The Food Industry Manipulates Taste Buds With 'Salt Sugar Fat'

In the article, published Monday, authors Glantz, Cristin Kearns and Laura Schmidt aren't trying make the case for a link between sugar and coronary heart disease. Their interest is in the process. They say the documents reveal the sugar industry attempting to influence scientific inquiry and debate.

The researchers note that they worked under some limitations — "We could not interview key actors involved in this historical episode because they have died," they write. Other organizations were also advocating concerns about fat, they note.

There's no evidence that the SRF directly edited the manuscript published by the Harvard scientists in 1967, but there is "circumstantial" evidence that the interests of the sugar lobby shaped the conclusions of the review, the researchers say.

For one thing, there's motivation and intent. In 1954, the researchers note, the president of the SRF gave a speech describing a great business opportunity.

If Americans could be persuaded to eat a lower-fat diet — for the sake of their health — they would need to replace that fat with something else. America's per capita sugar consumption could go up by a third .

In 'Soda Politics,' Big Soda At Crossroads Of Profit And Public Health

But in the '60s, the SRF became aware of "flowing reports that sugar is a less desirable dietary source of calories than other carbohydrates," as John Hickson, SRF vice president and director of research, put it in one document.

He recommended that the industry fund its own studies — "Then we can publish the data and refute our detractors."

The next year, after several scientific articles were published suggesting a link between sucrose and coronary heart disease, the SRF approved the literature-review project. It wound up paying approximately $50,000 in today's dollars for the research.

One of the researchers was the chairman of Harvard's Public Health Nutrition Department — and an ad hoc member of SRF's board.

"A different standard" for different studies

Glantz, Kearns and Schmidt say many of the articles examined in the review were hand-selected by SRF, and it was implied that the sugar industry would expect them to be critiqued.

13.7: Cosmos And Culture

Obesity and the toxic-sugar wars.

In a letter, SRF's Hickson said that the organization's "particular interest" was in evaluating studies focused on "carbohydrates in the form of sucrose."

"We are well aware," one of the scientists replied, "and will cover this as well as we can."

The project wound up taking longer than expected, because more and more studies were being released that suggested sugar might be linked to coronary heart disease. But it was finally published in 1967.

Hickson was certainly happy with the result: "Let me assure you this is quite what we had in mind and we look forward to its appearance in print," he told one of the scientists.

The review minimized the significance of research that suggested sugar could play a role in coronary heart disease. In some cases the scientists alleged investigator incompetence or flawed methodology.

"It is always appropriate to question the validity of individual studies," Kearns told Bloomberg via email. But, she says, "the authors applied a different standard" to different studies — looking very critically at research that implicated sugar, and ignoring problems with studies that found dangers in fat.

Epidemiological studies of sugar consumption — which look at patterns of health and disease in the real world — were dismissed for having too many possible factors getting in the way. Experimental studies were dismissed for being too dissimilar to real life.

One study that found a health benefit when people ate less sugar and more vegetables was dismissed because that dietary change was not feasible.

Another study, in which rats were given a diet low in fat and high in sugar, was rejected because "such diets are rarely consumed by man."

The Harvard researchers then turned to studies that examined risks of fat — which included the same kind of epidemiological studies they had dismissed when it came to sugar.

Citing "few study characteristics and no quantitative results," as Kearns, Glantz and Schmidt put it, they concluded that cutting out fat was "no doubt" the best dietary intervention to prevent coronary heart disease.

Sugar lobby: "Transparency standards were not the norm"

In a statement, the Sugar Association — which evolved out of the SRF — said it is challenging to comment on events from so long ago.

"We acknowledge that the Sugar Research Foundation should have exercised greater transparency in all of its research activities, however, when the studies in question were published funding disclosures and transparency standards were not the norm they are today," the association said.

"Generally speaking, it is not only unfortunate but a disservice that industry-funded research is branded as tainted," the statement continues. "What is often missing from the dialogue is that industry-funded research has been informative in addressing key issues."

The documents in question are five decades old, but the larger issue is of the moment, as Marion Nestle notes in a commentary in the same issue of JAMA Internal Medicine:

"Is it really true that food companies deliberately set out to manipulate research in their favor? Yes, it is, and the practice continues. In 2015, the New York Times obtained emails revealing Coca-Cola's cozy relationships with sponsored researchers who were conducting studies aimed at minimizing the effects of sugary drinks on obesity. Even more recently, the Associated Press obtained emails showing how a candy trade association funded and influenced studies to show that children who eat sweets have healthier body weights than those who do not."

As for the article authors who dug into the documents around this funding, they offer two suggestions for the future.

"Policymaking committees should consider giving less weight to food industry-funded studies," they write.

They also call for new research into any ties between added sugars and coronary heart disease.

• heart disease

• International edition
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‘Sugar is brown!’: there’s more to the sweet stuff than its pure white version

Sugar’s texture and taste can be as individualistic as coffee beans or wine grapes grown in specific regions, but most of us don’t know that

O ne night, I was preparing steak for dinner and mistakenly reached for the wrong white granulated substance. Instead of salting my steak to create a brown crust by searing, I created a brown crust with notes of caramel.

Ethan Frisch, co-founder of Burlap & Barrel, an artisanal spice company that works with small producers worldwide, laughed wryly when he heard this story over Zoom. “This is the first time in history anyone could make that mistake. Refined, white-bleached sugar is a very modern development in the centuries-old sugar industry. Sugar is brown! It’s only white when you do a lot of work to remove the brownness.”

His co-founder, Ori Zohar, elaborated: “The whole sugar industry is focused on this pure white chemical that is so far away from being a plant: a shelf-stable, consistent, interchangeable ingredient. None of those qualities make for good food,” though it makes an item that can be traded around the world for similar base prices.

Many of us only know white, granulated sugar that comes packaged with no information about its sugarcane or beet origins – much less its geographical origins – on its package. But sugar is diverse. White, processed sugar makes up the largest segment of the global market, but sugar also comes in liquid and brown forms. About 80% of the world’s production comes from sugarcane, but some comes from beets. Even sugarcane itself is not a monolith; though most sugar is derived from the Saccharum officinarum species and its hybrids, there are hundreds of varieties which have adapted (or been adapted through human intervention) to their specific ecosystems.

Zohar and Frisch are on a mission to “do to sugar what has been done to salt” in the last few years. You can now buy specialty salts from specific places and have specific characteristics: a black Himalayan salt that has a sulphurous funk or Burlap and Barrel’s Pearl salt from Tanzania’s Swahili coast, with its surprisingly spherical crystals.

Saltverk, which sells hand-harvested salt from Iceland, has been riding this wave. Founder Björn Steinar Jónsson said, “People want to know where the products they’re buying are from. We’ve seen this as a gradual growth in the salt industry, and really, we’re only at the beginning stages of where people understand what’s going into their salts. As a staple ingredient used by most of the world, sugar could follow a similar path.”

This is not just marketing. A sugar’s texture and taste can be as individual as coffee beans from a corner of Ethiopia or wine grapes grown on a chilly slope in the Pacific north-west.

Brown sugar from Okinawa in Japan is a favorite of pastry chef Salvatore Martone of Le Jardinier in New York. He said: “Okinawa brown sugar (kokuto) is produced on eight remote Japanese islands. Each island produces sugar that has a slightly different taste. The sugar is sold in small irregular lumps, and the flavor is rich minerally smokiness with an earthy undertone and a hint of bitterness.” He uses it for ice-cream.

Burlap & Barrel’s founders want to introduce consumers to sugars connected to a specific place and that have a distinctive flavor born of the environment that produced them. The company’s work expands the market for traceable sugar, focusing on sourcing from communities using traditional processing methods.

It’s introduced panela, a traditionally unrefined cane sugar from Boyacá, Colombia. In June, the company is launching two other single-origin sugars, jaggery from Satara district, India, and a granulated sugar from Portvale, Barbados. When the company uses the term “single-origin”, it doesn’t merely refer to a country of origin, but a single farm or producer.

Had I reached for their sand-textured panela in making my steak, I could not have mistaken it for salt. Its soft, irregular granules are the color of milk caramel, with which it shares similar aromas. A spoonful is like sucking on sweet cinnamon toffee. It melts on the tongue, leaving a trace of floral spice, as if I took a shot of ginger juice.

The jaggery has the varied, irregular texture and look of crushed peanuts, and opening it fills my apartment with the scent of fresh squeezed sugarcane. It comes from Dr Shashikant Salunkhe, who has grown turmeric for Burlap & Barrel as part of a regenerative agricultural system. A local refiner filters the raw sugarcane juice with wild okra, whose gel collects any floating impurities. The jaggery is granulated and then stone ground, ancient methods that are worlds away from industrial filtration and mechanized refinement.

The Barbadian sugar’s crystals are startlingly angular and crunch loudly between one’s teeth .

“Barbadian sugar has to de-commoditize if they’re going to compete globally,” said Frisch. This means that the country’s producers need to embrace their sugar as a specialty product and divert it from being blended with other sugars before it reaches supermarket shelves where it will be simply labeled “cane sugar”. Frisch wants people to understand what makes Barbadian sugar so good – the terroir of its coral island, flavors enhanced by molasses, cane fed by rainwater and not irrigation like in most industrial practices, and its history.

Sugar production has an ugly past. About 5 million slaves were brought to the Caribbean, most to toil on sugar plantations starting in the mid-1500s. The slave trade reached its height in the 1700s, and Barbados, known as Sugar Island, was its crown jewel. Abolitionists in Europe and the US waged boycotts of sugar, a slave-derived good that represented abhorrent working conditions.

Centuries later, Frisch and Zohar want consumers to demand sugars that retain their individual, nuanced flavors. “Home cooks and chefs have huge buying power,” said Zohar, which could advance more sustainable and equitable production. Sugarcane farms are responsible for massive deforestation. Added to innumerable food products, sugar drives the global obesity epidemic. Sugar from the Dominican Republic’s Central Romana corporation, which is often supplied to and sold as Domino brand, has been banned from the US since November 2023 due to allegations about exploitative work conditions and forced labor among its largely Haitian migrant workforce.

But as of the moment, it’s difficult to know exactly where your sugar comes from. Non-alcoholic beverage company Everleaf goes to extraordinary lengths to source botanicals. Founder Paul Mathew is a conservation biologist, and his company has tracked down “cherry blossoms, hand-picked in the Shizuoka region of Japan between May and August” and gum acacia, used for mouthfeel, from the Sahel region of Africa.

That wasn’t possible with sugar, which Mathew said is all being “hoovered up into a commodity-based industrial system”. The UK-based company is currently switching from fair-trade sugar derived from sugarcane to beet sugar from the UK, prioritizing a lesser carbon footprint.

One way for a company to know where its sugar comes from is for that business to grow it themself. This is what Copalli Rum in Belize chooses to do. The majority of rum is made from molasses, produced when sugarcane juice is boiled multiple times in sugar’s refining process and sucrose is removed. But new agricole-style rums, which are made from fermenting fresh sugarcane juice, like Copalli, are emerging from former commodity sugar plantation fields, from Hawaii to Belize. Copalli uses red and black cane instead of yellow cane engineered over many years to produce commercial sugar in Belize.

Wil Maheia, the philanthropy services advisor for Copalli, has tended to this area his entire life. His great-grandparents worked the land when it was a sugarcane plantation and he helped organize Belize’s first debt-for-nature swap (a transaction where a country’s debt is exchanged for environmental conservation commitments).

He’s proud to say: “We have never cut any rainforest to plant cane.” To the contrary – Copalli is cultivating 220 acres of sugarcane on old citrus orchards rather than reaching into 12,000 acres of rainforest. As the largest employer in southern Belize, it’s creating jobs that do not rely on the logging industry and deforestation.

Most viewed

Research shows that a sugar tax would be very effective and lucrative

A tax on candy and other products containing excessive amounts of sugar would be "very effective" and could prove quite lucrative, according to a study by Ecorys. The organization carried out research on behalf of the Ministries of Finance and Health, with a goal of learing more about the impact of a theoretical wide-ranging sugar tax. If a sugar tax were implemented improperly, it could lead to multiple lawsuits, the study found.

A tax on products with more than six percent sugar could theoretically lower the risk of diabetes. The tax would effectively increase the number of healthy years for the families who eat the most sugar per person. Specifically, this would impact those whose sugar consumption is higher than 80 percent of all families in the Netherlands.

In addition, hundreds of millions of euros will be saved on healthcare costs related to sugar consumption. The tax would also mean that people would live longer on average, which would result in more money being spent on elderly care. On the other hand, productivity gains would result from fewer sick calls and medically unfit work declarations due to a healthier lifestyle.

The researchers added that the tax would provide around a billion euros to government coffers. They believe that supermarkets will earn less due to the tax as people choose other options. According to calculations, they would lose around 26 to 29 million euros.

The researcher's proposal is to gradually tax products containing six percent sugar or more. The tax would increase when the product contains more sugar. According to the study, the sugar tax is legally sustainable as a consumption tax. This does not apply to an increased value added tax rate.

It is essential to clearly define which products are subject to additional tax and which are not. The limit is "broadly based on the Wheel of Five," a specific guideline from the Nutrition Center. The tax should be limited to "products that require a nutrition label" to prevent fruit from being taxed.

The ministers who sent the report to the Tweede Kamer, the lower house of Dutch parliament, said that a political decision should be made by the next Cabinet. The Tweede Kamer also agreed with this.

Reporting by ANP