recent type 2 diabetes research

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Large-scale study reveals new genetic details of diabetes

By wynne parry weill cornell medicine.

In experiments of unprecedented scale, investigators at Weill Cornell Medicine and the National Institutes of Health have revealed new aspects of the complex genetics behind Type 2 diabetes. Through these discoveries, and by providing a template for future studies, this research furthers efforts to better understand and ultimately treat this common metabolic disease.

Previous studies have generally examined the influence of individual genes. In research described Oct. 18 in Cell Metabolism, senior co-author Shuibing Chen , the Kilts Family Professor of Surgery at Weill Cornell Medicine, working alongside senior co-author Dr. Francis Collins , a senior investigator at the Center for Precision Health Research within the National Human Genome Research Institute of the U.S. National Institutes of Health, took a more comprehensive approach. Together, they looked at the contribution of 20 genes in a single effort.

“It’s very difficult to believe all these diabetes-related genes act independently of each other,” Chen said. By using a combination of technologies, the team examined the effects of shutting each down. By comparing the consequences for cell behavior and genetics, she said, “we found some common themes.”

As with other types of diabetes, Type 2 diabetes occurs when sugar levels in the blood are too high. In Type 2 diabetes, this happens in part because specialized cells in the pancreas, known as β-cells, don’t produce enough insulin, a hormone that tells cells to take sugar out of the blood for use as an energy source. Over time, high levels of blood sugar damage tissues and cause other problems, such as heart and kidney disease. According to the United States Centers for Disease Control and Prevention, nearly 9% of adults in the United States have been diagnosed with Type 2 diabetes. 

Both genetic and environmental factors, such as obesity and chronic stress, can increase risk for it. Yet evaluating the role of the genetic contributors alone is a massive project. So far, researchers have identified more than 290 locations within the genome where changes to DNA can raise the likelihood of developing the disease. Some of these locations fall within known genes, but most are found in regions that regulate the expression of nearby genes.

For the new research, the team focused on 20 genes clearly identified as contributors. They began their investigation by using the gene editing system CRISPR-Cas9 to shut down these genes, one at a time, within 20 sets of identical stem cells. 

These stem cells had the potential to generate any kind of mature cell, but the researchers coaxed them into becoming insulin-producing β-cells. They then examined the effects of losing each gene on five traits related to insulin production and the health of β-cells. They also documented the accompanying changes in gene expression and the accessibility of DNA for expression.

To make sense of the massive amount of data they collected, the team developed their own computational models to analyze it, leading to several discoveries: By comparing the effects of all 20 mutations on β-cells, they identified four additional genes, each representing a newly discovered pathway that contributes to insulin production. They also found that, of the original 20 genes, only one, called HNF4A, contributed to all five traits, apparently by acting as a master controller that regulates the activity of other genes. In one specific example, they explained how a small variation, located in a space between genes, contributes to the risk of diabetes by interfering with HNF4A’s ability to regulate nearby genes.

Ultimately, this study and others like it hold the promise of benefiting patients, Collins said. “We need to understand all the genetic and environmental factors involved so we can do a better job of preventing diabetes, and to develop new ideas about how to effectively treat it.”

Collins and Chen note that their approach may have relevance beyond diabetes, to other common diseases, such as Alzheimer’s, Parkinson’s and Crohn’s disease, that involve many genetic factors.

The work reported in this newsroom story was supported in part by the United States’ National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and the American Diabetes Association.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see the profile for Shuibing Chen .

Wynne Parry is a freelance writer for Weill Cornell Medicine.

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New Aspects of Diabetes Research and Therapeutic Development

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans.

Significance Statement

Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

I. Introduction

Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020 ). Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing pancreatic beta cells. The much more prevalent T2D arises in conjunction with peripheral tissue insulin resistance and beta cell failure and is estimated to increase to 21%–33% of the US population by the year 2050 (Boyle et al., 2010 ). To combat this growing health threat and its cardiac, renal, and neurologic comorbidities, new and more effective diabetes drugs and treatments are essential. As the last several years have seen many new developments in the field of diabetes pharmacology and therapy, we determined that a new and up to date review of these advances was in order. Our aim is to provide a careful evaluation of both old and new therapies ( Fig. 1 ) in a manner that we hope will be of interest to both clinical and bench diabetologists. Instead of the usual encyclopedic approach to this topic, we provide here a targeted and selective consideration of the underlying issues, promising new treatments, and a re-examination of more traditional approaches. Thus, we do not discuss less frequently used diabetes agents, such as alpha-glucosidase inhibitors; these were discussed in other recent reviews (Hedrington and Davis, 2019 ; Lebovitz, 2019 ).

Pharmacologic targeting of numerous organ systems for the treatment of diabetes. Treatment of diabetes involves targeting of various organ systems, including the kidney by SGLT2 inhibitors; the liver, gut, and adipose tissue by metformin; and direct actions upon the pancreatic beta cell. Beta cell compounds aim to increase secretion or mass and/or to protect from autoimmunity destruction. Ultimately, insulin therapy remains the final line of diabetes treatment with new technologies under development to more tightly regulate blood glucose levels similar to healthy beta cells. hESC, human embryonic stem cell.

II. Diabetes Therapies

A. metformin.

Metformin is a biguanide originally based on the natural product galegine, which was extracted from the French lilac (Bailey, 1992 ; Rojas and Gomes, 2013 ; Witters, 2001 ). A closely related biguanide, phenformin, was also used initially for its hypoglycemic actions. Based on its successful track record as a safe, effective, and inexpensive oral medication, metformin has become the most widely prescribed oral agent in the world in treating T2D (Rojas and Gomes, 2013 ; He and Wondisford, 2015 ; Witters, 2001 ), whereas phenformin has been largely bypassed due to its unacceptably high association with lactic acidosis (Misbin, 2004 ). Unlike sulfonylureas, metformin lowers blood glucose without provoking hypoglycemia and improves insulin sensitivity (Bailey, 1992 ). Despite these well known beneficial metabolic actions, metformin’s mechanism of action and even its main target organ remain controversial. In fact, metformin has multiple mechanisms of action at the organ as well as the cellular level, which has hindered our understanding of its most important molecular effects on glucose metabolism (Witters, 2001 ). Adding to this, a specific receptor for metformin has never been identified. Metformin has actions on several tissues, although the primary foci of most studies have been the liver, skeletal muscle, and the intestine (Foretz et al., 2014 ; Rena et al., 2017 ). Metformin and phenformin clearly suppress hepatic glucose production and gluconeogenesis, and they improve insulin sensitivity in the liver and elsewhere (Bailey, 1992 ). The hepatic actions of metformin have been the most exhaustively studied to date, and there is little doubt that these actions are of some importance. However, several of the studies remain highly controversial, and there are still open questions.

One of the first reported specific molecular targets of metformin was mitochondrial complex I of the electron transport chain. Inhibition of this complex results in reduced oxidative phosphorylation and consequently decreased hepatic ATP production (El-Mir et al., 2008 ; Evans et al., 2005 ; Owen et al., 2000 ). As is the case in many other studies of metformin, however, high concentrations of the drug were found to be necessary to depress metabolism at this site (El-Mir et al., 2000 ; He and Wondisford, 2015 ; Owen et al., 2000 ). Also controversial is whether metformin works by activating 5′ AMP-activated protein kinase (AMPK), a molecular energy sensor that is known to be a major metabolic sensor in cells, or if not AMPK directly, then one of its upstream regulators such as liver kinase B2 (Zhou et al., 2001 ). Although metformin was shown to activate AMPK in several excellent studies, other studies directly contradicted the AMPK hypothesis. Most dramatic were studies showing that metformin’s actions to suppress hepatic gluconeogenesis persisted despite genetic deletion of the AMPK’s catalytic domain (Foretz et al., 2010 ). More recent studies identified additional or alternative targets, such as cAMP signaling in the liver (Miller et al., 2013 ) or glycogen synthase kinase-3 (Link, 2003 ). Other work showed that the phosphorylation of acetyl-CoA carboxylase and acetyl-CoA carboxylase 2 are involved in regulating lipid homeostasis and improving insulin sensitivity after exposure to metformin (Fullerton et al., 2013 ).

Although there are strong data to support each of these pathways, it is not entirely clear which signaling pathway(s) is most essential to the actions of metformin in hepatocytes. Metformin clearly inhibits complex I and concomitantly decreases ATP and increases AMP. The latter results in AMPK activation, reduced fatty acid synthesis, and improved insulin receptor activation, and increased AMP has been shown to inhibit adenylate cyclase to reduce cAMP and thus protein kinase A activation. Downstream, this reduces the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase via decreased cAMP response element-binding protein, the cAMP-sensitive transcription factor. Decreased PKA also promotes ATP-dependent 6-phosphofructokinase, liver type activity via fructose 2,6-bisphosphate and reduces gluconeogenesis, as fructose-bisphosphatase 1 is inhibited by fructose 2,6-bisphosphate, along with other mechanisms (Rena et al., 2017 ; Pernicova and Korbonits, 2014 ).

More recent work has shown that metformin at pharmacological rather than suprapharmacological doses increases mitochondrial respiration and complex 1 activity and also increases mitochondrial fission, now thought to be critical for maintaining proper mitochondrial density in hepatocytes and other cells. This improvement in respiratory activity occurs via AMPK activation (Wang et al., 2019 ).

Although the liver has historically been the major suspected site of metformin action, recent studies have suggested that the gut instead of the liver is a major target, a concept supported by the increased efficacy of extended-release formulations of metformin that reside for a longer duration in the gut after their administration (Buse et al., 2016 ). An older, but in our view an important observation, is that the intravenous administration of metformin has little or no effect on blood glucose, whereas, in contrast, orally administered metformin is much more effective (Bonora et al., 1984 ). Recent imaging studies using labeled glucose have shown directly that metformin stimulates glucose uptake by the gut in patients with T2D to reduce plasma glucose concentrations (Koffert et al., 2017 ; Massollo et al., 2013 ). Additionally, it is possible that metformin may exert its effect in the gut by inducing intestinal glucagon-like peptide-1 (GLP-1) release (Mulherin et al., 2011 ; Preiss et al., 2017) to potentiate beta cell insulin secretion and by stimulating the central nervous system (CNS) to exert control over both blood glucose and liver function. Indeed, CNS effects produced by metformin have been proposed to occur via the local release of GLP-1 to activate intestinal nerve endings of ascending nerve pathways that are involved in CNS glucose regulation (Duca et al., 2015 ). Lastly, several papers have now implicated that metformin may act by altering the gut microbiome, suggesting that changes in gut flora may be critical for metformin’s actions (McCreight et al., 2016 ; Wu et al., 2017 ; Devaraj et al., 2016 ). A new study proposed that activation of the intestinal farnesoid X receptor may be the means by which microbiota alter hyperglycemia (Sun et al., 2018 ). However, these studies will require more mechanistic detail and confirmation before they can be fully accepted by the field. In addition to the action of metformin on gut flora, the production of imidazole propionate by gut microbes in turn has been shown to interfere with metformin action through a p38-dependent mechanism and AMPK inhibition. Levels of imidazole propionate are especially higher in patients with T2D who are treated with metformin (Koh et al., 2020 ).

In summary, the combined contribution of these various effects of metformin on multiple cellular targets residing in many tissues may be key to the benefits of metformin treatment on lowering blood glucose in patients with type 2 diabetes (Foretz et al., 2019 ). In contrast, exciting new work showing metformin leads to weight loss by increasing circulating levels of the peptide hormone growth differentiation factor 15 and activation of brainstem glial cell-derived neurotropic factor family receptor alpha like receptors to reduce food intake and energy expenditure works independently of metformin’s glucose-lowering effect (Coll et al., 2020 ).

B. Sulfonylureas and Beta Cell Burnout

The class of compounds known as sulfonylureas includes one of the oldest oral antidiabetic drugs in the pharmacopoeia: tolbutamide. Tolbutamide is a “first generation” oral sulfonylurea secretagogue whose clinical usefulness is due to its prompt stimulation of insulin release from pancreatic beta cells. “Second generation” sulfonylureas include drugs such as glyburide, gliclazide, and glipizide. Sulfonylureas act by binding to a high affinity sulfonylurea binding site, the sulfonylurea receptor 1 subunit of the K(ATP) channel, which closes the channel. These drugs mimic the physiologic effects of glucose, which closes the K(ATP) channel by raising cytosolic ATP/ADP. This in turn provokes beta cell depolarization, resulting in increased Ca 2+ influx into the beta cell (Ozanne et al., 1995 ; Ashcroft and Rorsman, 1989 ; Nichols, 2006 ). Importantly, sulfonylureas, and all drugs that directly increase insulin secretion, are associated with hypoglycemia, which can be severe, and which limits their widespread use in the clinic (Yu et al., 2018 ). Meglitinides are another class of oral insulin secretagogues that, like the sulfonylureas, bind to sulfonylurea receptor 1 and inhibit K(ATP) channel activity (although at a different site of action). The rapid kinetics of the meglitinides enable them to effectively blunt the postprandial glycemic excursions that are a hallmark (along with elevated fasting glucose) of T2D (Rosenstock et al., 2004). However, the need for their frequent dosing (e.g., administration before each meal) has limited their appeal to patients.

The efficacy of sulfonylureas is known to decrease over time, leading to failure of the class for effective long-term treatment of T2D (Harrower, 1991 ). More broadly, it is now widely accepted that the number of functional beta cells in humans declines during the progression of T2D. Thus, one would expect that due to this decline, all manner of oral agents intended to target the beta cell and increase its cell function (and especially insulin secretion) will fail over time (RISE Consortium, 2019 ), a process referred to as “beta cell failure” (Prentki and Nolan, 2006 ). Currently, treatments that can expand beta cell mass or improve beta cell function or survival over time are not yet available for use in the clinic. As a result, treatments that may be able to help patients cope with beta cell burnout such as islet cell transplantation, insulin pumps, or stem cell therapy are alternatives that will be discussed below.

C. Ca 2+ Channel Blockers and Type 1 Diabetes

Strategies to treat and prevent T1D have historically focused on ameliorating the toxic consequences of immune dysregulation resulting in autoimmune destruction of pancreatic beta cells. More recently, a concerted focus on alleviating the intrinsic beta cell defects (Sims et al., 2020 ; Soleimanpour and Stoffers, 2013 ) that also contribute to T1D pathogenesis have been gaining traction at both the bench and the bedside. Several recent preclinical studies suggest that Ca 2+ -induced metabolic overload induces beta cell failure (Osipovich et al., 2020 ; Stancill et al., 2017 ; Xu et al., 2012 ), with the potential that excitotoxicity contributes to beta cell demise in both T1D and T2D, similar to the well known connection between excitotoxicity and, concomitantly, increased Ca 2+ loading of the cells and neuronal dysfunction. Indeed, the use of the phenylalkylamine Ca 2+ channel blocker verapamil has been successful in ameliorating beta cell dysfunction in preclinical models of both T1D and T2D (Stancill et al., 2017 ; Xu et al., 2012 ). Verapamil is a well known blocker of L-type Ca 2+ channels, and, in normally activated beta cells, it limits Ca 2+ entry into the beta cell (Ohnishi and Endo, 1981 ; Vasseur et al., 1987 ). This would be expected to, in turn, alter the expression of many Ca 2+ influx–dependent beta cell genes (Stancill et al., 2017 ), and the evidence to date suggests it is likely that verapamil preserves beta cell function in diabetes models by repressing thioredoxin-interacting protein (TXNIP) expression and thus protecting the beta cell. This is somewhat surprising given the physiologic role of Ca 2+ is to acutely trigger insulin secretion; this process would be expected to be inhibited by L-type Ca 2+ channel blockers (Ashcroft and Rorsman, 1989 ; Satin et al., 1995 ).

Hyperglycemia is a well known inducer of TXNIP expression, and a lack of TXNIP has been shown to protect against beta cell apoptosis after inflammatory stress (Chen et al., 2008a ; Shalev et al., 2002 ; Chen et al., 2008b ). Excitingly, the use of verapamil in patients with recent-onset T1D improved beta cell function and improved glycemic control for up to 12 months after the initiation of therapy, suggesting there is indeed promise for targeting calcium and TXNIP activation in T1D. Use of verapamil for a repurposed indication in the preservation of beta cell function in T1D is attractive due its well known safety profile as well as its cardiac benefits (Chen et al., 2009 ). Although the long-term efficacy of verapamil to maintain beta cell function in vivo is unclear, a recently described TXNIP inhibitor may also show promise in suppressing the hyperglucagonemia that also contributes to glucose intolerance in T2D (Thielen et al., 2020 ). As there is a clear need for increased Ca 2+ influx into the beta cell to trigger and maintain glucose-dependent insulin secretion (Ashcroft and Rorsman, 1990 ; Satin et al., 1995 ), it remains to be seen how well regulated insulin secretion is preserved in the presence of L-type Ca 2+ channel blockers like verapamil in the system. One might speculate that reducing but not fully eliminating beta cell Ca 2+ influx might reduce TXNIP levels while preserving enough influx to maintain glucose-stimulated insulin release. Alternatively, these two phenomena may operate on entirely different time scales. At present, these issues clearly will require further investigation.

D. GLP-1 and the Incretins

Studies dating back to the 1960s revealed that administering glucose in equal amounts via the peripheral circulation versus the gastrointestinal tract led to dramatically different amounts of glucose-induced insulin secretion (Elrick et al., 1964 ; McIntyre et al., 1964 ; Perley and Kipnis, 1967 ). Gastrointestinal glucose administration greatly increased insulin secretion versus intravenous glucose, and this came to be known as the “incretin effect” (Nauck et al., 1986a ; Nauck et al., 1986b ). Subsequent work showed that release of the gut hormone GLP-1 mediated this effect such that food ingestion induced intestinal cell hormone secretion. GLP-1 so released would then circulate to the pancreas via the blood to prime beta cells to secrete more insulin when glucose became elevated because these hormones stimulated beta cell cAMP formation (Drucker et al., 1987 ). The discovery that a natural peptide corresponding to GLP-1 could be found in the saliva of the Gila monster, a desert lizard, hastened progress in the field, and ample in vitro studies subsequently confirmed that GLP-1 potentiated insulin secretion in a glucose-dependent manner. GLP-1 has little or no significant action on insulin secretion in the absence of elevated glucose (such as might typically correspond to the postprandial case or during fasting), thus minimizing the likelihood of hypoglycemia provoked by GLP-1 in treated patients (Kreymann et al., 1987 ). Although not completely understood, the glucose dependence of GLP-1 likely reflects the requirement for adenine nucleotides to close glucose-inhibited K(ATP) channels and thus subsequently activate Ca 2+ influx–dependent insulin exocytosis. Besides potentiating GSIS at the level of the beta cell, glucagon-like peptide-1 receptor (GLP-1R) agonists also decrease glucagon secretion from pancreatic islet alpha cells, reduce gastric emptying, and may also increase beta cell proliferation, among other cellular actions (reviewed in Drucker, 2018 ; Muller et al., 2019).

Intense interest in the incretins by basic scientists, clinicians, and the pharma community led to the rapid development of new drugs for treating primarily T2D. These drugs include a range of GLP-1R agonists and inhibitors of the incretin hormone degrading enzyme dipeptidyl peptidase 4 (DPP4), whose targeting increases the half-lives of GLP-1 and gastric inhibitory polypeptide (GIP) and thereby increases protein hormone levels in plasma. GLP-1R agonists have been associated with not only a lowering of plasma glucose but also weight loss, decreased appetite, reduced risk of cardiovascular events, and other favorable outcomes (Gerstein et al., 2019; Hernandez et al., 2018; Husain et al., 2019; Marso et al., 2016a; Marso et al., 2016b ; Buse et al., 2004). Regarding their untoward actions, although hypoglycemia is not a major concern, there have been reports of pancreatitis and pancreatic cancer from use of GLP-1R agonists. However, a recent meta-analysis covering four large-scale clinical trials and over 33,000 participants noted no significantly increased risk for pancreatitis/pancreatic cancer in patients using GLP-1R agonists (Bethel et al., 2018).

Ongoing and future developments in the use of proglucagon-derived peptides such as GLP-1 and glucagon include the use of combined GLP-1/GIP, glucagon/GLP-1, and agents targeting all three peptides in combination (reviewed in Alexiadou and Tan, 2020 ). Although short-term infusions of GLP-1 with GIP failed to yield metabolic benefits beyond those seen with GLP-1 alone (Bergmann et al., 2019 ), several GLP-1/GIP dual agonists are currently in development and have shown promising metabolic results in clinical trials (Frias et al., 2017 ; Frias et al., 2020 ; Frias et al., 2018 ). At the level of the pancreatic islet, beneficial effects of dual GLP-1/GIP agonists may be related to imbalanced and biased preferences of these agonists for the gastric inhibitory polypeptide receptor over the GLP-1R (Willard et al., 2020 ) and possibly were not simply to dual hormone agonism in parallel. Dual glucagon/GLP-1 agonist therapy has also been shown to have promising metabolic effects in humans (Ambery et al., 2018 ; Tillner et al., 2019 ). Oxyntomodulin is a natural dual glucagon/GLP-1 receptor agonist and proglucagon cleavage product that is also secreted from intestinal enteroendocrine cells, which has beneficial effects on insulin secretion, appetite regulation, and body weight in both humans and rodents (Cohen et al., 2003 ; Dakin et al., 2001 ; Dakin et al., 2002 ; Shankar et al., 2018 ; Wynne et al., 2005 ). Interestingly, alpha cell crosstalk to beta cells through the combined effects of glucagon and GLP-1 is necessary to obtain optimal glycemic control, suggesting a potential pathway for therapeutic dual glucagon/GLP-1 agonism within the islets of patients with T2D (Capozzi et al., 2019a ; Capozzi et al., 2019b ). Although the early results appear promising, more studies will be necessary to better understand the mechanistic and clinical impacts of these multiagonist agents.

E. DPP4 Inhibitors

Inhibition of DPP4, the incretin hormone degrading enzyme, is one of the most common T2D treatments to increase GLP-1 and GIP plasma hormone levels. These DPP4 inhibitors or “gliptins” are generally used in conjunction with other T2D drugs such as metformin or sulfonylureas to obtain the positive benefits discussed above (Lambeir et al., 2008 ). DPP4 is a primarily membrane-bound peptidase belonging to the serine peptidase/prolyl oligopeptidase gene family, which cleaves a large number of substrates in addition to the incretin hormones (Makrilakis, 2019 ). DPP4 inhibitors provide glucose-lowering benefits while being generally well tolerated, and the variety of available drugs (including sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin) with slightly different dosing frequency, half-life, and mode of excretion/metabolism allows for use in multiple patient populations (Makrilakis, 2019 ). This includes the elderly and individuals with renal or hepatic insufficiency (Makrilakis, 2019 ).

Although hypoglycemia is not a concern for DPP4 inhibitor use, other considerations should be made. DPP4 inhibitors tend to be more expensive than metformin or other second-line oral drugs in addition to having more modest glycemic effects than GLP-1R agonists (Munir and Lamos, 2017 ). Finally, meta-analysis of randomized and observational studies concluded that heart failure in patients with T2D was not associated with use of DPP4 inhibitors; however, this study was limited by the short follow-up and lack of high-quality data (Li et al., 2016 ). Thus, the US Food and Drug Administration (FDA) did recommend assessing risk of heart failure hospitalization in patients with pre-existing cardiovascular disease, prior heart failure, and chronic kidney disease when using saxagliptin and alogliptin (Munir and Lamos, 2017 ).

F. Sodium Glucose Cotransporter 2 Inhibitors

A recent development in the field of T2D drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have an interesting and very different mechanism of action. Within the proximal tubule of the nephron, SGLT2 transports ingested glucose into the lumen of the proximal tubule between the epithelial layers, thereby reclaiming glucose by this reabsorption process (reviewed in Vallon, 2015 ). SGLT2 inhibitors target this transporter and increase glucose in the tubular fluid and ultimately increase it in the urine. In patients with diabetes, SGLT2 inhibition results in a lowering of plasma glucose with urine glucose content rising substantially (Adachi et al., 2000 ; Vallon, 2015 ). These drugs, although they are relatively new, have become an area of great interest for not only patients with T2D (Grempler et al., 2012 ; Imamura et al., 2012 ; Meng et al., 2008 ; Nomura et al., 2010 ) but also for patients with T1D (Luippold et al., 2012 ; Mudaliar et al., 2012 ). Part of their appeal also rests on reports that their use can lead to a statistically significant decline in cardiac events that are known to occur secondarily to diabetes, possibly independently of plasma glucose regulation (reviewed in Kurosaki and Ogasawara, 2013 ). Although the long-term consequences of their clinical use cannot yet be determined, raising the glucose content of the urogenital tract leads to an increased risk of urinary tract infections and other related infections in some patients (Kurosaki and Ogasawara, 2013 ).

Another recent concern about the use of SGLT2 inhibitors has been the development of normoglycemic diabetic ketoacidosis (DKA). Despite the efficacy of SGLT2 inhibitors, observations of hyperglucagonemia in patients with euglycemic DKA has led to a number of recent studies focused on SGLT2 actions on pancreatic islets. Initial studies of isolated human islets treated with small interfering RNA directed against SGLT2 and/or SGLT2 inhibitors demonstrated increased glucagon release. These studies were complemented by the finding of elevations in glucagon release in mice that were administered SGLT2 inhibitors in vivo (Bonner et al., 2015 ). Insights into the possible mechanistic links between SGLT2 inhibition, DKA frequency, and glucagon secretion in humans may relate to the observation of heterogeneity in SGLT2 expression, as SGLT2 expression appears to have a high frequency of interdonor and intradonor variability (Saponaro et al., 2020 ). More recently, both insulin and GLP-1 have been demonstrated to modulate SGLT2-dependent glucagon release through effects on somatostatin release from delta cells (Vergari et al., 2019 ; Saponaro et al., 2019 ), suggesting potentially complex paracrine effects that may affect the efficacy of these compounds.

On the other hand, several recent studies question that the development of euglycemic DKA after SGLT2 inhibitor therapy may be through alpha cell–dependent mechanisms. Three recent studies found no effect of SGLT2 inhibitors to promote glucagon secretion in mouse and/or rat models and could not detect SGLT2 expression in human alpha cells (Chae et al., 2020 ; Kuhre et al., 2019 ; Suga et al., 2019 ). A fourth study demonstrated only a brief transient effect of SGLT2 inhibition to raise circulating glucagon concentrations in immunodeficient mice transplanted with human islets, which returned to baseline levels after longer exposures to SGLT2 inhibitors (Dai et al., 2020 ). Furthermore, SGLT2 protein levels were again undetectable in human islets (Dai et al., 2020 ). These results could suggest alternative islet-independent mechanisms by which patients develop DKA, including alterations in ketone generation and/or clearance, which underscore the additional need for further studies both in molecular models and at the bedside. Nevertheless, SGLT2 inhibitors continue to hold promise as a valuable therapy for T2D, especially in the large segment of patients who also have superimposed cardiovascular risk (McMurray et al., 2019; Wiviott et al., 2019; Zinman et al., 2015).

G. Thiazolidinediones

Once among the most commonly used oral agents in the armamentarium to treat T2D, thiazolidinediones (TZDs) were clinically popular in their utilization to act specifically as insulin sensitizers. TZDs improve peripheral insulin sensitivity through their action as peroxisome proliferator-activated receptor (PPAR) γ agonists, but their clinical use fell sharply after studies suggested a connection between cardiovascular toxicity with rosiglitazone and bladder cancer risk with pioglitazone (Lebovitz, 2019 ). Importantly, an FDA panel eventually removed restrictions related to cardiovascular risk with rosiglitazone in 2013 (Hiatt et al., 2013 ). Similarly, concerns regarding use of bladder cancer risk with pioglitazone were later abated after a series of large clinical studies found that pioglitazone did not increase bladder cancer (Lewis et al., 2015 ; Schwartz et al., 2015 ). However, usage of TZDs had already substantially decreased and has not since recovered.

Although concerns regarding edema, congestive heart failure, and fractures persist with TZD use, there have been several studies suggesting that TZDs protect beta cell function. In the ADOPT study, use of rosiglitazone monotherapy in patients newly diagnosed with T2D led to improved glycemic control compared with metformin or sulfonylureas (Kahn et al., 2006). Later analyses revealed that TZD-treated subjects had a slower deterioration of beta cell function than metformin- or sulfonylurea-treated subjects (Kahn et al., 2011). Furthermore, pioglitazone use improved beta cell function in the prevention of T2D in the ACT NOW study (Defronzo et al., 2013; Kahn et al., 2011). Mechanistically, it is unclear if TZDs lead to beneficial beta cell function through direct effects or through indirect effects of reduced beta cell demand due to enhanced peripheral insulin sensitivity. Indeed, a beta cell–specific knockout of PPAR γ did not impair glucose homeostasis, nor did it impair the antidiabetic effects of TZD use in mice (Rosen et al., 2003 ). However, other reports demonstrated PPAR-responsive elements within the promoters of both glucose transporter 2 and glucokinase that enhance beta cell glucose sensing and function, which could explain beta cell–specific benefits for TZDs (Kim et al., 2002 ; Kim et al., 2000 ). Furthermore, TZDs have been shown to improve beta cell function by upregulating cholesterol transport (Brunham et al., 2007 ; Sturek et al., 2010 ). Additionally, use of TZDs in the nonobese diabetic (NOD) mouse model of T1D augmented the beta cell unfolded protein response and prevented beta cell death, suggesting potential benefits for TZDs in both T1D and T2D (Evans-Molina et al., 2009 ; Maganti et al., 2016 ). With a now refined knowledge of demographics in which to avoid TZD treatment due to adverse effects, together with genetic approaches to identify candidates more likely to respond effectively to TZD therapy (Hu et al., 2019 ; Soccio et al., 2015 ), it remains to be seen if TZD therapy will return to more prominent use in the treatment of diabetes.

H. Insulin and Beyond: The Use of “Smart” Insulin and Closed Loop Systems in Diabetes Treatment

Due to recombinant DNA technology, numerous insulin analogs are now available in various forms ranging from fast acting crystalline insulin to insulin glargine; all of these analogs exhibit equally effective insulin receptor binding. Most are generated by altering amino acids in the B26–B30 region of the molecule (Kurtzhals et al., 2000 ). The American Diabetes Association delineates these insulins by their 1) onset or time before insulin reaches the blood stream, 2) peak time or duration of maximum blood glucose–lowering efficacy, and 3) the duration of blood glucose–lowering time. Insulin administration is independent of the residuum of surviving and/or functioning beta cells in the patient and remains the principal pharmacological treatment of both T1D and T2D. The availability of multiple types of delivery methods, i.e., insulin pens, syringes, pumps, and inhalants, provides clinicians with a solid and varied tool kit with which to treat diabetes. The downsides, however, are that 1) hypoglycemia is a constant threat, 2) proper insulin doses are not trivial to calculate, 3) compliance can vary especially in children and young adults, and 4) there can be side effects of a variety of types. Nonetheless, insulin therapy remains a mainstay treatment of diabetes.

To eliminate the downsides of insulin therapy, research in the past several decades has worked toward generating glucose-sensitive or “smart” insulin molecules. These molecules change insulin bioavailability and become active only upon high blood glucose using glucose-binding proteins such as concanavalin A, glucose oxidase to alter pH sensitivity, and phenylboronic acid (PBA), which forms reversible ester linkages with diol-containing molecules including glucose itself (reviewed in Rege et al., 2017 ). Indeed, promising recent studies included various PBA moieties covalently bonded to an acylated insulin analog (insulin detemir, which contains myristic acid coupled to Lys B29 ). The detemir allows for binding to serum albumin to prolong insulin’s half-life in the circulation, and PBA provided reversible glucose binding (Chou et al., 2015 ). The most promising of the PBA-modified conjugates showed higher potency and responsiveness in lowering blood glucose levels compared with native insulin in diabetic mouse models and decreased hypoglycemia in healthy mice, although the molecular mechanisms have not yet been determined (Chou et al., 2015 ).

An additional active area of research includes structurally defining the interaction between insulin and the insulin receptor ectodomain. Importantly, a major conformational change was discovered that may be exploited to impair insulin receptor binding under hypoglycemic conditions (Menting et al., 2013 ; Rege et al., 2017 ). Challenges in the design, testing, and execution of glucose-responsive insulins may be overcome by the adaptation of novel modeling approaches (Yang et al., 2020 ), which may allow for more rapid screening of candidate compounds.

Technologies have also progressed in the field of artificial pancreas design and development. Currently two “closed loop” systems are now available: Minimed 670G from Medtronic and Control-IQ from Tandem Diabetes Care. Both systems use a continuous glucose monitor, insulin pump, and computer algorithm to predict correct insulin doses and administer them in real time. Such algorithm systems also take into account insulin potency, the rate of blood glucose increase, and the patient’s heart rate and temperature to adjust insulin delivery levels during exercise and after a meal. In addition, so-called “artificial pancreas” systems have also been clinically tested, which use both insulin and glucagon and as such result in fewer reports of hypoglycemic episodes (El-Khatib et al., 2017 ). These types of systems will continue to become more popular as the development of room temperature–stable glucagon analogs continue, such as GVOKE by Xeris Pharmaceuticals (currently available in an injectable syringe) and Baqsimi, a nasally administered glucagon from Eli Lilly.

I. Present and Future Therapies: Beta Cell Transplantation, Replication, and Immune Protection

1. islet transplantation.

The idea to use pancreatic allo/xenografts to treat diabetes remarkably dates back to the late 1800s (Minkowski, 1892 ; Pybus, 1924 ; Williams, 1894 ). Before proceeding to the discovery of insulin (together with Best, MacLeod, and Collip), Frederick Banting also postulated the potential for transplantation of pancreatic tissue emulsions to treat diabetes in dog models in a notebook entry in 1921 (Bliss, 1982 ). Decades later, Paul Lacy, David Scharp, and colleagues successfully isolated intact functional pancreatic islets and transplanted them into rodent models (Kemp et al., 1973 ). These studies led to the initial proof of concept studies for humans, with the first successful islet transplant in a patient with T1D occurring in 1977 (Sutherland et al., 1978 ). A rapid expansion of islet transplantation, inspired by these original studies led to key observations of successfully prolonged islet engraftment by the “Edmonton protocol” whereby corticosteroid-sparing immunosuppression was applied, and islets from at least two allogeneic donors were used to achieve insulin independence (Shapiro et al., 2000 ). More recent work has focused on improving upon the efficiency and long-term engraftment of allogeneic transplants leading to more prolonged graft function (to the 5-year mark) and successful transplantation from a single islet donor (Hering et al., 2016; Hering et al., 2005 ; Rickels et al., 2013 ). Critical to these efforts to improve the success rate was the recognition that the earlier generation of immunosuppressive agents to counter tissue rejection was toxic to islets (Delaunay et al., 1997 ; Paty et al., 2002 ; Soleimanpour et al., 2010 ) and that more appropriate and less toxic agents were needed (Hirshberg et al., 2003 ; Soleimanpour et al., 2012 ).

Certainly, islet transplantation as a therapeutic approach for patients with T1D has been scrutinized due to several challenges, including (but not limited to) the lack of available donor supply to contend with demand, limited long-term functional efficacy of islet allografts, the potential for re-emergence of autoimmune islet destruction and/or metabolic overload-induced islet failure, and significant adverse effects of prolonged immunosuppression (Harlan, 2016 ). Furthermore, although islet transplantation is not currently available for individuals with T2D, simultaneous pancreas-kidney transplantation in T2D had similar favorable outcomes to simultaneous pancreas-kidney transplantation in T1D; therefore, islet-kidney transplantation may eventually be a feasible option to treat T2D, as patients will already be on immunosuppressors (Sampaio et al., 2011 ; Westerman et al., 1983 ). An additional significant obstacle is the tremendous expense associated with islet transplantation therapy. Indeed, the maintenance, operation, and utilization of an FDA-approved and Good Manufacturing Practice–compliant islet laboratory can lead to operating costs at nearly $150,000 per islet transplant, which is not cost effective for the vast majority of patients with T1D (Naftanel and Harlan, 2004 ; Wallner et al., 2016 ). At present, the focus has been to obtain FDA approval for islet allo-transplantation as a therapy for T1D to allow for insurance compensation (Hering et al., 2016; Rickels and Robertson, 2019 ). In the interim, the islet biology, stem cell, immunology, and bioengineering communities have continued the development of cell-based therapies for T1D by other approaches to overcome the challenges identified during the islet transplantation boom of the 1990s and 2000s.

2. Pharmacologic Induction of Beta Cell Replication

Besides transplantation, progress in islet cell biology and especially in developmental biology of beta cells over several decades raised the additional possibility that beta cell mass reduction in diabetes might be countered by increasing beta cell number through mitogenic means. A key method to expand pancreatic beta cell mass is through the enhancement of beta cell replication. Although the study of pancreatic beta cell replication has been an area of intense focus in the beta cell biology field for several decades, only recently has this seemed truly feasible. Seminal studies identified that human beta cells are essentially postmitotic, with a rapid phase of growth occurring in the prenatal period that dramatically tapers off shortly thereafter (Gregg et al., 2012 ; Meier et al., 2008 ). The plasticity of rodent beta cells is considerably higher than that of human beta cells (Dai et al., 2016 ), which has led to a renewed focus on validation of pharmacologic agents to enhance rodent beta cell replication using isolated and/or engrafted human islets (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). Indeed, a large percentage of agents that were successful when applied to rodent systems were largely unsuccessful at inducing replication in human beta cells (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). However, several recent studies have begun to make significant progress on successfully pushing human beta cells to replicate.

Several groups have reported successful human beta cell proliferation, both in vitro and in vivo, in response to inhibitors of the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These inhibitors include harmine, INDY, GNF4877, 5-iodotubericidin, leucettine-42, TG003, AZ191, CC-401, and more specific, recently developed DYRK1A inhibitors (Ackeifi et al., 2020 ). Although DYRK1A is conclusively established as the important mediator of human beta cell proliferation, comprehensively determining other cellular targets and if additional gene inhibition amplifies the proliferative response is still in process. New evidence from Wang and Stewart shows dual specificity tyrosine phosphorylation-regulated kinase 1B to be an additional mitogenic target and also describes variability in the range of activated kinases within cells and/or levels of inhibition for the many DYRK1A inhibitors listed above (Ackeifi et al., 2020 ). Interestingly, opposite to these human studies, earlier mouse studies from the Scharfmann group demonstrated that Dyrk1a haploinsufficiency leads to decreased proliferation and loss of beta cell mass (Rachdi et al., 2014b ). In addition, overexpression of Dyrk1a in mice led to beta cell mass expansion with increased glucose tolerance (Rachdi et al., 2014a ).

Although important differences in beta cell proliferative capacity have been shown between human and rodent species, there are also significant differences in the mitogenic capacity of beta cells from juvenile, adult, and pregnant individuals. This demonstrates that proliferative stimuli appear to act within the complex islet, pancreas, and whole-body environments unique to each time point. For example, the administration of the hormones platelet-derived growth factor alpha or GLP-1 result in enhanced proliferation in juvenile human beta cells yet are ineffective in adult human beta cells (Chen et al., 2011 ; Dai et al., 2017 ). This has been shown to be due to a loss of platelet-derived growth factor alpha receptor expression as beta cells age but appears to be unrelated to GLP-1 receptor expression levels (Chen et al., 2011 ). Indeed, the GLP-1 receptor is highly expressed in adult beta cells, and GLP-1 secretion increases insulin secretion, as detailed previously; however, the induction of proliferative factors such as nuclear factor of activated T cells, cytoplasmic 1; forkhead box protein 1; and cyclin A1 is only seen in juvenile islets (Dai et al., 2017 ). Human studies using cadaveric pancreata from pregnant donors also showed increased beta cell mass, yet lactogenic hormones from the pituitary or placenta (prolactin, placental lactogen, or growth hormone) are unable to stimulate proliferation in human beta cells despite their ability to produce robust proliferation in mouse beta cells (reviewed in Baeyens et al., 2016 ). Experiments overexpressing mouse versus human signal transducer and activator of transcription 5, the final signaling factor inducing beta cell adaptation, in human beta cells allows for prolactin-mediated proliferation revealing fundamental differences in prolactin pathway competency in human (Chen et al., 2015 ). Overcoming the barrier of recapitulating human pregnancy’s effect on beta cells through isolating placental cells or blood serum during pregnancy may result in the discovery of a factor(s) that facilitates the increase in beta cell mass observed during human pregnancy.

Mechanisms that stimulate beta cell proliferation have also been discovered from studying genetic mutations that result in insulinomas, spontaneous insulin-producing beta cell adenomas. The most common hereditary mutation occurs in the multiple endocrine neoplasia type 1 (MEN1) gene. Indeed, administration of a MEN1 inhibitor in addition to a GLP-1 agonist (which cannot induce proliferation alone) is able to increase beta cell proliferation in isolated human islets through synergistic activation of KRAS proto-oncogene, GTPase downstream signals (Chamberlain et al., 2014 ). Interestingly, MEN1 mutations are uncommon in sporadic insulinomas, yet assaying genomic and epigenetic changes in a large cohort of non-MEN1 insulinomas found alterations in trithorax and polycomb chromatin modifying genes that were functionally related to MEN1 (Wang et al., 2017 ). Stewart and colleagues hypothesized that changes in histone 3 lysine 27 and histone 3 lysine 4 methylation status led to increased enhancer of zeste homolog 2 and lysine demethylase 6A, decreased cyclin-dependent kinase inhibitor 1C, and thereby increased beta cell proliferation, among other phenotypes. They also proposed that these findings help to explain why increased proliferation always occurs despite broad heterogeneity of mutations found between individual insulinomas (Wang et al., 2017 ).

Although factors that induce proliferation are continuing to be discovered, there are drawbacks that still limit their clinical application. Harmine and other DYRK1A inhibitors are not beta cell specific, nor have all their cellular targets been determined (Ackeifi et al., 2020 ). Targeting other pathways to induce human beta cell proliferation such as modulation of prostaglandin E2 receptors (i.e., inhibition of prostaglandin E receptor 3 alone or in combination with prostaglandin E receptor 4 activation) showed promising increases in proliferative rate yet suffers from the same lack of specificity (Carboneau et al., 2017 ). Induction of proliferation may also come at the expense of glucose sensing as in insulinomas, which have an increased expression of “disallowed genes” and alterations in glucose transporter and hexokinase expression (Wang et al., 2017 ). A further untoward consequence that must be avoided is the production of cancerous cells through unchecked proliferation. Finally, increasing beta cell mass through low rates of proliferation may increase the pool of functional insulin-secreting cells in T2D, but without additional measures, these beta cells will still ultimately be targeted for immune cell destruction in T1D.

3. Beta Cell Stress Relieving Therapies

Metabolic, inflammatory, and endoplasmic reticulum (ER) stress contribute to beta cell dysfunction and failure in both T1D and T2D. Although reduction of metabolic overload of beta cells by early exogenous insulin therapy or insulin sensitizers can temporarily reduce loss of beta cell mass/function early in diabetes, a focus on relieving ER and inflammatory stress is also of interest to preserve beta cell health.

ER stress is a well known contributor to beta cell demise both in T1D and T2D (Laybutt et al., 2007 ; Marchetti et al., 2007 ; Marhfour et al., 2012 ; Tersey et al., 2012 ) and a target of interest in the prevention of beta cell loss in both diseases. Preclinical studies suggest that the use of chemical chaperones, including 4-phenylbutyric acid and tauroursodeoxycholic acid (TUDCA), to alleviate ER stress improves beta cell function and insulin sensitivity in mouse models of T2D (Cnop et al., 2017 ; Ozcan et al., 2006 ). Furthermore, TUDCA has been shown to preserve beta cell mass and reduce ER stress in mouse models of T1D (Engin et al., 2013 ). Interestingly, TUDCA has shown promise at improving insulin action in obese nondiabetic human subjects, yet beta cell function and insulin secretion were not assessed (Kars et al., 2010 ). A clinical trial regarding the use of TUDCA for humans with new-onset T1D is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT02218619","term_id":"NCT02218619"}} NCT02218619 ). However, a note of caution regarding use of ER chaperones is that they may prevent low level ER stress necessary to potentiate beta cell replication during states of increased insulin demand (Sharma et al., 2015 ), suggesting that the broad use of ER chaperone therapies should be carefully considered.

The blockade of inflammatory stress has long been an area of interest for treatments of both T1D and T2D (Donath et al., 2019 ; Eguchi and Nagai, 2017 ). Indeed, use of nonsteroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase, have been observed to improve metabolic control in patients with diabetes since the turn of the 20th century (Williamson, 1901 ). Salicylates have been shown to improve insulin secretion and beta cell function in both obese human subjects and those with T2D (Fernandez-Real et al., 2008; Giugliano et al., 1985 ). However, another NSAID, salsalate, has not been shown to improve beta cell function while improving other metabolic outcomes (Kim et al., 2014 ; Penesova et al., 2015 ), possibly suggesting distinct mechanisms of action for anti-inflammatory compounds. The regular use of NSAIDs to enhance metabolic outcomes is also often limited to the tolerability of long-term use of these agents due to adverse effects. Recently, golilumab, a monoclonal antibody against the proinflammatory cytokine tumor necrosis factor alpha, was demonstrated to improve beta cell function in new-onset T1D, suggesting that targeting the underlying inflammatory milieu may have benefits to preserve beta cell mass and function in T1D (Quattrin et al., 2020). Taken together, both new and old approaches to target beta cell stressors still remain of long-term interest to improve beta cell viability and function in both T1D and T2D.

3. New Players to Induce Islet Immune Protection

Countless researchers have expended intense industry to determine T1D disease etiology and treatments focused on immunotherapy and tolerogenic methods. Multiple, highly comprehensive reviews are available describing these efforts (Goudy and Tisch, 2005 ; Rewers and Gottlieb, 2009 ; Stojanovic et al., 2017 ). Here we will focus on the protection of beta cells through programmed cell death protein-1 ligand (PD-L1) overexpression, major histocompatibility complex class I, A, B, C (HLA-A,B,C) mutated human embryonic stem cell–derived beta cells, and islet encapsulation methods.

Cancer immunotherapies that block immune checkpoints are beneficial for treating advanced stage cancers, yet induction of autoimmune diseases, including T1D, remains a potential side effect (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). A subset of these drugs target either the programmed cell death-1 protein on the surface of activated T lymphocytes or its receptor PD-L1 (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). PD-L1 expression was found in insulin-positive beta cells from T1D but not insulin-negative islets or nondiabetic islets, leading to the hypothesis that PD-L1 is upregulated in an attempt to drive immune cell attenuation (Osum et al., 2018 ; Colli et al., 2018 ). Adenoviral overexpression of PD-L1 specifically in beta cells rescued hyperglycemia in the NOD mouse model of T1D, but these animals eventually succumbed to diabetes by the study’s termination (El Khatib et al., 2015 ). A more promising report from Ben Nasr et al. ( 2017 ) demonstrated that pharmacologically or genetically induced overexpression of PD-L1 in hematopoietic stem and progenitor cells inhibited beta cell autoimmunity in the NOD mouse as well as in vitro using human hematopoietic stem and progenitor cells from patients with T1D.

As mentioned above, islet transplantation to treat T1D is limited by islet availability, cost, and the requirement for continuous immunosuppression. Islet cells generated by differentiating embryonic or induced pluripotent stem (iPS) cells could circumvent these limitations. Ideally, iPS-derived beta cells could be manipulated to eliminate the expression of polymorphic HLA-A,B,C molecules, which were found to be upregulated in T1D beta cells (Bottazzo et al., 1985 ; Richardson et al., 2016 ). These molecules allow peptide presentation to CD8+ T cells or cytotoxic T lymphocytes and may lead to beta cell removal. Interestingly, remaining insulin-positive cells in T1D donor pancreas are not HLA-A,B,C positive (Nejentsev et al., 2007; Rodriguez-Calvo et al., 2015 ). However, current differentiation protocols are still limited in their ability to produce fully glucose-responsive beta cells without transplantation into animal models to induce mature characteristics. Additionally, use of iPS-derived beta cells will still lead to concerns regarding DNA mutagenesis resulting from the methods used to obtain pluripotency or teratoma formation from cells that have escaped differentiation.

Encapsulation devices would protect islets or stem cells from immune cell infiltration while allowing for the proper exchange of nutrients and hormones. Macroencapsulation uses removable devices that would help assuage fears surrounding mutation or tumor formation; indeed, the first human trial using encapsulated hESC-derived beta cells will be completed in January 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ). Macroencapsulation of islets prior to transplantation using various alginate-based hydrogels has historically been impeded by a strong in vivo foreign body immune response (Desai and Shea, 2017 ; Doloff et al., 2017 ; Pueyo et al., 1993 ). More recently, chemically modified forms of alginate that avoid macrophage recognition and fibrous deposition have been successfully used in rodents and for up to 6 months in nonhuman primates (Vegas et al., 2016 ). Indeed, Bochenek et al. ( 2018 ) successfully transplanted alginate protected islets for 4 months without immunosuppression in the bursa omentalis of nonhuman primates demonstrating the feasibility for this approach to be extended to humans. It remains to be seen if these devices will be successful for long-term use, perhaps decades, in patients with diabetes.

III. Summary

Although existing drug therapies using classic oral antidiabetic drugs like sulfonylureas and metformin or injected insulin remain mainstays of diabetes treatment, newer drugs based on incretin hormone actions or SGLT2 inhibitors have increased the pharmacological armamentarium available to diabetologists ( Fig. 1 ). However, the explosion of progress in beta cell biology has identified potential avenues that can increase beta cell mass in sophisticated ways by employing stem cell differentiation or enhancement of beta cell proliferation. Taken together, there should be optimism that the increased incidence of both T1D and T2D is being matched by the creativity and hard work of the diabetes research community.

Abbreviations

Authorship contributions.

Wrote and contributed to the writing of the manuscript: Satin, Soleimanpour, Walker

This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK46409] (to L.S.S.), [Grant R01-DK108921] (to S.A.S.), and [Grant P30-DK020572 pilot and feasibility grant] (to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF) [Grant CDA-2016-189] (to L.S.S. and S.A.S.), [Grant SRA-2018-539] (to S.A.S.), and [Grant COE-2019-861] (to S.A.S.), and the US Department of Veterans Affairs [Grant I01 BX004444] (to S.A.S.). The JDRF Career Development Award to S.A.S. is partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.

https://doi.org/10.1124/pharmrev.120.000160

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Type 2 Diabetes Research At-a-Glance

The ADA is committed to continuing progress in the fight against type 2 diabetes by funding research, including support for potential new treatments, a better understating of genetic factors, addressing disparities, and more. For specific examples of projects currently funded by the ADA, see below.

Greg J. Morton, PhD

University of Washington

Project: Neurocircuits regulating glucose homeostasis

“The health consequences of diabetes can be devastating, and new treatments and therapies are needed. My research career has focused on understanding how blood sugar levels are regulated and what contributes to the development of diabetes. This research will provide insights into the role of the brain in the control of blood sugar levels and has potential to facilitate the development of novel approaches to diabetes treatment.”

The problem: Type 2 diabetes (T2D) is among the most pressing and costly medical challenges confronting modern society. Even with currently available therapies, the control and management of blood sugar levels remains a challenge in T2D patients and can thereby increase the risk of diabetes-related complications. Continued progress with newer, better therapies is needed to help people with T2D.

The project: Humans have special cells, called brown fat cells, which generate heat to maintain optimal body temperature. Dr. Morton has found that these cells use large amounts of glucose to drive this heat production, thus serving as a potential way to lower blood sugar, a key goal for any diabetes treatment. Dr. Morton is working to understand what role the brain plays in turning these brown fat cells on and off.

The potential outcome: This work has the potential to fundamentally advance our understanding of how the brain regulates blood sugar levels and to identify novel targets for the treatment of T2D.

Tracey Lynn McLaughlin, MD

Stanford University

Project: Role of altered nutrient transit and incretin hormones in glucose lowering after Roux-en-Y gastric bypass surgery

“This award is very important to me personally not only because the enteroinsular axis (gut-insulin-glucose metabolism) is a new kid on the block that requires rigorous physiologic studies in humans to better understand how it contributes to glucose metabolism, but also because the subjects who develop severe hypoglycemia after gastric bypass are largely ignored in society and there is no treatment for this devastating and very dangerous condition.”

The problem: Roux-en-Y gastric bypass (RYGB) surgery is the single-most effective treatment for type 2 diabetes, with persistent remission in 85% of cases. However, the underlying ways by which the surgery improves glucose control is not yet understood, limiting the ability to potentially mimic the surgery in a non-invasive way. Furthermore, a minority of RYGB patients develop severe, disabling, and life-threatening low-blood sugar, for which there is no current treatment.

The project: Utilizing a unique and rigorous human experimental model, the proposed research will attempt to gain a better understanding on how RYGB surgery improves glucose control. Dr. McLaughlin will also test a hypothesis which she believes could play an important role in the persistent low-blood sugar that is observed in some patients post-surgery.

The potential outcome: This research has the potential to identify novel molecules that could represent targets for new antidiabetic therapies. It is also an important step to identifying people at risk for low-blood sugar following RYGB and to develop postsurgical treatment strategies.

Rebekah J. Walker, PhD

Medical College of Wisconsin

Project: Lowering the impact of food insecurity in African Americans with type 2 diabetes

“I became interested in diabetes research during my doctoral training, and since that time have become passionate about addressing social determinants of health and health disparities, specifically in individuals with diabetes. Living in one of the most racially segregated cities in the nation, the burden to address the needs of individuals at particularly high risk of poor outcomes has become important to me both personally and professionally.”

The problem: Food insecurity is defined as the inability to or limitation in accessing nutritionally adequate food and may be one way to address increased diabetes risk in high-risk populations. Food insecure individuals with diabetes have worse diabetes outcomes and have more difficulty following a healthy diet compared to those who are not food insecure.

The project: Dr. Walker’s study will gather information to improve and then will test an intervention to improve blood sugar control, dietary intake, self-care management, and quality of life in food insecure African Americans with diabetes. The intervention will include weekly culturally appropriate food boxes mailed to the participants and telephone-delivered diabetes education and skills training. It will be one of the first studies focused on the unique needs of food insecure African American populations with diabetes using culturally tailored strategies.

The potential outcome: This study has the potential to guide and improve policies impacting low-income minorities with diabetes. In addition, Dr. Walker’s study will help determine if food supplementation is important in improving diabetes outcomes beyond diabetes education alone.

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These New Developments Could Make Living With Type 2 Diabetes More Manageable

E xperts often talk about the “burden” of a disease or illness. The word acts as a tidy container for all the unpleasantness people with that condition may experience—from their symptoms, to the cost of their care, to the restrictions imposed on their lifestyle, to the health complications that may arise. For people with Type 2 diabetes , this burden can be high.

Routine management of Type 2 diabetes often involves major changes to one’s diet and physical activity . And for many, especially those taking insulin to manage their blood sugar, the disease can necessitate daily blood-glucose monitoring, a process that entails pricking a finger to draw blood and then dabbing that blood onto a glucose monitor’s test strip. Doing this several times a week—month after month—can present overlapping challenges. According to a 2013 survey in the journal Diabetes Spectrum, people find finger-prick glucose monitoring to be painful, and the results can be confusing or unhelpful.

“Patients don’t want to prick their fingers, and they come in all the time and say, ‘I’m tired of this,’” says Dr. Francisco Pasquel, a diabetes specialist and associate professor of medicine at Emory University School of Medicine in Atlanta.

But relief is on the way. Continuous glucose monitors, or CGMs, are small devices-—often about the size of a quarter-—that use a small under-the-skin needle to continuously monitor blood-glucose levels. This information can be transmitted—in some cases wirelessly and automatically—to a smartphone app or other device. “You can look at glucose levels for a single point in time, but you can also look at trends in values over time,” says Dr. Roy Beck, medical director of the nonprofit Jaeb Center for Health Research in Tampa. Beck’s work has found that continuous glucose monitoring may provide a number of benefits for people with Type 2 diabetes.

These monitors are just one of several new advancements in Type 2 diabetes care and management. From connected technologies to new drug treatments, medical science is making steady and sometimes life-changing progress in the treatment of this condition. Here, experts describe some of the latest and greatest developments.

Continuous glucose monitors

People with Type 1 diabetes typically have to check their blood-sugar levels on a daily basis, or even multiple times each day. Because testing is such a big part of managing that disease, the research on continuous glucose monitors started with these patients. That work has shown that CGMs provide multiple benefits, including reduced hemoglobin A1C (HbA1c) levels, which is an important measure of healthy blood glucose. Continuous glucose monitors are now being studied in people with Type 2 diabetes, and research points to multiple benefits.

For a study published in 2021 in the Journal of the American Medical Association, Beck and his colleagues compared continuous glucose monitoring to standard finger-prick tests among people with Type 2 diabetes who were using insulin. They found that continuous monitoring was associated with a significantly greater drop in HbA1c. They also found that continuous monitoring helped people avoid risky and severe drops in blood sugar (a.k.a. hypoglycemia). “It’s pretty clear that there’s a benefit for people with Type 2 diabetes who are using insulin,” he says.

More than 90% of people with diabetes have Type 2 diabetes, and Beck says that roughly 30% of these people are using insulin. In other words, there are many people with Type 2 diabetes who stand to benefit from continuous glucose monitoring. However, use of these monitors is still mostly confined to people with Type 1 diabetes. “Use is slowly increasing in Type 2 patients, but I think it’s still too low considering this is a non-pharmacological approach”—something many people prefer because it avoids the side effects of medications—“that can help people,” he says.

Even for people with Type 2 diabetes who are not taking insulin, Beck says that continuous glucose monitoring could be helpful. “There’s a need for more studies to prove it, but it makes sense that it would likely have benefits,” he says. For example, monitoring blood sugar in real time could help people make diet or lifestyle changes that reduce their risks for long-term health complications. “Normally, blood glucose following a meal shouldn’t go above 140 [mg/dL],” he says. But based on factors like diet, meal timing, and exercise habits, someone with Type 2 diabetes may experience post-meal blood-sugar spikes that surpass 200 or even 300 mg/dL. These spikes could cause few symptoms or short-term consequences, Beck says, but over time they can contribute to the development of common diabetes-related complications such as kidney failure, heart disease, or diabetic retinopathy (an eye condition that can cause blurry vision or blindness). “The first time people use these continuous monitors, it can be a real eye-opener,” he adds. “I think they could be most helpful for self-management, and Type 2 diabetes is a disease where self-management through diet and exercise can make a huge difference.”

Other experts second this. “Patients using these devices can receive a graph of their glucose values over time, which helps them understand the effects of nutrition on glucose control, or how they could modify their exercise to make improvements,” says Dr. Ilias Spanakis, an associate professor of medicine in the division of endocrinology, diabetes, and nutrition at the University of Maryland School of Medicine.

For patients who are reliant on insulin to manage their blood glucose, combining continuous glucose monitors with insulin pumps—devices that automatically inject insulin as needed—could also lead to major improvements. “Smart algorithms that connect the two can automatically adjust glucose based on glucose values,” Spanakis says. This is already possible, and it’s likely to become much more commonplace, he adds.

For many people with diabetes, continuous glucose monitoring could provide a safer and simpler path forward.

Read More: The Link Between Type 2 Diabetes and Psychiatric Disorders

Bariatric surgery for Type 2 diabetes

Historically, bariatric (weight-loss) surgery has been used primarily to help people manage severe obesity, which the U.S. Centers for Disease Control and Prevention defines as a BMI of 40 or higher. Many people who are severely obese also have diabetes, and research has found that these surgical procedures can help reduce the burden of Type 2 diabetes or even send it into remission.

A 2018 study from researchers at the University of Oklahoma found that Roux-en-Y gastric bypass surgery, a common bariatric procedure, vastly outperformed typical medical management techniques—such as diet changes, doctor’s visits, and prescription drugs—among people with Type 2 diabetes. Surgery led to diabetes remission in roughly 28% of patients, compared with a remission rate of just 4% among the non-surgery group, according to the study results. More research has found that bariatric surgery may effectively send Type 2 diabetes into remission.

“Surgery does not just lead to weight loss, but also to an improvement in glycemic control, which happens even before the weight loss occurs,” says Emory’s Pasquel, who has published work on the benefits of bariatric surgery for people with Type 2 diabetes. Exactly how the surgery does this isn’t well understood, he says. However, bariatric surgery affects appetite, food intake, caloric absorption, and multiple neuroendocrine pathways—all of which could contribute to its beneficial actions for people with Type 2 diabetes.

In the future, Pasquel says these procedures are likely to become more commonplace even for people with Type 2 diabetes who are not severely obese.

More from TIME

New pharmaceutical drugs.

There are a lot of different diabetes drugs on the market, each with its own risks and benefits. But experts say two types are emerging as potential “game changers” when it comes to Type 2 diabetes treatment.

Glucagon-like peptide 1 (GLP-1) is a hormone released in the gut during digestion—one that plays a role in blood-sugar homeostasis. A class of drugs known as GLP-1 receptor agonists can interact with GLP-1 receptors in ways that lower appetite, slow digestion, and provide other benefits for people with Type 2 diabetes. These GLP-1 drugs aren’t new. But Pasquel says the latest versions are different in that they work on two different receptors, not one. “Recent evidence shows that activating both receptors has a remarkable impact on weight loss and glycemic control,” he says. Especially for people with Type 2 diabetes who are at high risk for heart or arterial disease, he says that these new drugs seem to be a big upgrade over previous medications.

A second category of drug has also emerged as a standout in the treatment of Type 2 diabetes. Known as sodium-glucose cotransporter-2 (SGLT-2) inhibitors, these drugs help the kidneys remove sugar from a person’s blood. Not only does this improve blood-sugar control in people with Type 2 diabetes, but it also helps protect them from heart failure and kidney disease—two common and serious complications. Pasquel says these drugs are so effective that they’re now being used in people with heart failure or kidney disease who do not have Type 2 diabetes.

Read More: The Truth About Fasting and Type 2 Diabetes

Emerging ways to think about weight loss

Experts have long understood that weight loss can help people reduce their Type 2 diabetes symptoms and risks . This recognition has led to research on a number of weight-loss diets . More research is needed, but some of the latest studies suggest that fasting plans—in particular, intermittent fasting—may be particularly beneficial for people with Type 2 diabetes.

Intermittent fasting involves cutting out calorie-containing foods and drinks for an extended period of time—anywhere from 12 hours to two days depending on the approach a person chooses. A 2019 research review in the journal Nutrients found that intermittent fasting promotes weight loss, increases insulin sensitivity, and reduces insulin levels in the blood. All of this is helpful for people with Type 2 diabetes. “Essentially, fasting is doing what we prescribe diabetes medications to do, which is to improve insulin sensitivity,” says Benjamin Horne, director of cardiovascular and genetic epidemiology at Intermountain Healthcare in Utah.

It’s not yet clear which form of intermittent fasting is best. But Horne says that time-restricted eating—a type of fasting that involves squeezing all the day’s calories into single six- or eight-hour feeding windows—is leading the pack, largely because patients are able to stick with it.

There are more new advancements in Type 2 diabetes care. The interventions described here—from continuous glucose monitors to novel drugs—are some of the most promising, but they have company. It’s safe to say that, looking ahead, more people with Type 2 diabetes will be able to effectively manage or mitigate their symptoms.

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New findings on pancreatic anatomy may affect diabetes research and treatment

by Claes Björnberg, Umea University

Researchers at Umeå University have succeeded in imaging an entire human organ, a pancreas, in microscopic resolution. By staining different cell-types with antibodies and then using optical 3D imaging techniques to study the entire organ, their data provides a partially new picture of the pancreas.

The results may be of great importance for diabetes research , especially when developing various new forms of treatment. The study is published in Nature Communications .

The pancreas is a key organ for the development of diabetes, a disease that today affects over half a billion people. It contains millions of small cell clusters, the so-called islets of Langerhans, which function to regulate blood sugar levels in the body.

The islets chiefly contain beta- and alpha-cells that produce the hormones insulin and glucagon, respectively. Insulin is secreted into the bloodstream and acts much like a key to unlock the body's cells so that they can take up sugar (glucose) after a meal, the main form of energy used by the body. Glucagon in turn releases glucose stores when we need a supply of energy. These two cell-types also communicate directly with each other to optimize the correct glucose level in the body.

"Both insulin and glucagon cells were discovered over a hundred years ago, and it has long been believed that the islets should contain both cell types to form a fully functioning unit," says Ulf Ahlgren, professor at the Department of Medical and Translational Biology.

Since the islets of Langerhans make up only a small percentage of the pancreas, even though they occur in such large numbers, they have historically been very difficult to study directly within the pancreas. In most cases, researchers have had to study tissue sections that only provide a 2D image of a very small part of the organ. Now, Umeå researchers have used optical 3D techniques in which different cell-types can be marked with fluorescently colored antibodies.

Entire organ at microscopic resolution

"By dividing the entire organ into smaller parts, we enable the antibodies to get where they need to go. Since we know where each piece comes from, we can then, after scanning the different parts individually, 'reassemble' the entire pancreas again using computer software. This allows us to perform a plethora of calculations and study which cell-types are present, as well as where they are located in 3D space, as we know the 3D coordinates, their volume, shape and other parameters for each and every stained object in the entire organ," says Ahlgren.

In addition to new data on how insulin-producing cells are distributed in the pancreas, the researchers now show that glucagon-producing cells are not present in as many as 50% of the islets of Langerhans that do contain insulin cells. This is contrary to what was previously thought, where islets were believed to contain both insulin- and glucagon-expressing cell-types with the same islet.

"This was a surprise to us, and I believe that these results may be of great importance for diabetes research. First, it shows that the islets have a much more uneven composition, or cellularity, than previously thought. This could mean that islets of different composition might be specifically specialized to respond to different signals and/or operate in different metabolic environments. Of course, we really want to find this out," says Ahlgren.

"Second, a great deal of research in the diabetes field is carried out on isolated islets of Langerhans from deceased donors. Since we also show that this uneven composition is largely linked to islet size, it means that results from such experiments may not fully reflect how the islets are structured and function in the living pancreas. This could potentially be important for everything from islet transplants in type 1 diabetes to studies trying to produce islets of Langerhans from stem cells."

Basis for future studies

The research team will now continue to work to see if their methods can be used to determine whether other cell types in the pancreas also contribute to the formation of the islets in a way that has not previously been known. In addition, they will study whether it looks similar in mouse models, which could affect the use of mice for preclinical diabetes research.

"The methods and data we are now publishing will be able to form an important basis for future studies of human material in order to better understand what happens in the pancreas in the development of type 1 and type 2 diabetes, but also for diseases such as pancreatic cancer," says Ahlgren.

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Type 2 diabetes is not one-size - fits-all : Subtypes affect complications and treatment options

PhD Student, Biochemistry, Carleton University

Associate professor, Department of Biology and Institute of Biochemistry, Carleton University

Disclosure statement

Lili Grieco-St-Pierre receives funding from Fonds de recherche du Québec - Santé (FRQS).

Jennifer Bruin receives funding from the Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), JDRF, Diabetes Canada.

Carleton University provides funding as a member of The Conversation CA.

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You may have heard of Ozempic, the “miracle drug” for weight loss, but did you know that it was actually designed as a new treatment to manage diabetes? In Canada, diabetes affects approximately 10 per cent of the general population . Of those cases, 90 per cent have Type 2 diabetes.

This metabolic disorder is characterized by persistent high blood sugar levels, which can be accompanied by secondary health challenges, including a higher risk of stroke and kidney disease .

Locks and keys

In Type 2 diabetes, the body struggles to maintain blood sugar levels in an acceptable range. Every cell in the body needs sugar as an energy source, but too much sugar can be toxic to cells. This equilibrium needs to be tightly controlled and is regulated by a lock and key system.

In the body’s attempt to manage blood sugar levels and ensure that cells receive the right amount of energy, the pancreatic hormone, insulin, functions like a key . Cells cover themselves with locks that respond perfectly to insulin keys to facilitate the entry of sugar into cells.

Unfortunately, this lock and key system doesn’t always perform as expected. The body can encounter difficulties producing an adequate number of insulin keys, and/or the locks can become stubborn and unresponsive to insulin.

All forms of diabetes share the challenge of high blood sugar levels; however, diabetes is not a singular condition; it exists as a spectrum. Although diabetes is broadly categorized into two main types, Type 1 and Type 2, each presents a diversity of subtypes, especially Type 2 diabetes.

These subtypes carry their own characteristics and risks, and do not respond uniformly to the same treatments .

To better serve people living with Type 2 diabetes, and to move away from a “one size fits all” approach, it is beneficial to understand which subtype of Type 2 diabetes a person lives with. When someone needs a blood transfusion, the medical team needs to know the patient’s blood type. It should be the same for diabetes so a tailored and effective game plan can be implemented.

This article explores four unique subtypes of Type 2 diabetes, shedding light on their causes, complications and some of their specific treatment avenues.

Severe insulin-deficient diabetes: We’re missing keys!

Insulin is produced by beta cells, which are found in the pancreas. In the severe insulin-deficient diabetes (SIDD) subtype, the key factories — the beta cells — are on strike. Ultimately, there are fewer keys in the body to unlock the cells and allow entry of sugar from the blood.

SIDD primarily affects younger, leaner individuals, and unfortunately, increases the risk of eye disease and blindness , among other complications. Why the beta cells go on strike remains largely unknown, but since there is an insulin deficiency, treatment often involves insulin injections.

Severe insulin-resistant diabetes: But it’s always locked!

In the severe insulin-resistant diabetes (SIRD) subtype, the locks are overstimulated and start ignoring the keys. As a result, the beta cells produce even more keys to compensate. This can be measured as high levels of insulin in the blood, also known as hyperinsulinemia.

This resistance to insulin is particularly prominent in individuals with higher body weight. Patients with SIRD have an increased risk of complications such as fatty liver disease . There are many treatment avenues for these patients but no consensus about the optimal approach ; patients often require high doses of insulin.

Mild obesity-related diabetes: The locks are sticky!

Mild obesity-related (MOD) diabetes represents a nuanced aspect of Type 2 diabetes, often observed in individuals with higher body weight. Unlike more severe subtypes, MOD is characterized by a more measured response to insulin. The locks are “sticky,” so it is challenging for the key to click in place and open the lock. While MOD is connected to body weight, the comparatively less severe nature of MOD distinguishes it from other diabetes subtypes.

To minimize complications, treatment should include maintaining a healthy diet, managing body weight, and incorporating as much aerobic exercise as possible. This is where drugs like Ozempic can be prescribed to control the evolution of the disease, in part by managing body weight.

Mild age-related diabetes: I’m tired of controlling blood sugar!

Mild age-related diabetes (MARD) happens more often in older people and typically starts later in life. With time, the key factory is not as productive, and the locks become stubborn. People with MARD find it tricky to manage their blood sugar, but it usually doesn’t lead to severe complications.

Among the different subtypes of diabetes, MARD is the most common .

Unique locks, varied keys

While efforts have been made to classify diabetes subtypes, new subtypes are still being identified, making proper clinical assessment and treatment plans challenging.

In Canada, unique cases of Type 2 diabetes were identified in Indigenous children from Northern Manitoba and Northwestern Ontario by Dr. Heather Dean and colleagues in the 1980s and 90s. Despite initial skepticism from the scientific community, which typically associated Type 2 diabetes with adults rather than children, clinical teams persisted in identifying this as a distinct subtype of Type 2 diabetes, called childhood-onset Type 2 diabetes.

Read more: Indigenous community research partnerships can help address health inequities

Childhood-onset Type 2 diabetes is on the rise across Canada, but disproportionately affects Indigenous youth. It is undoubtedly linked to the intergenerational trauma associated with colonization in these communities . While many factors are likely involved, recent studies have discovered that exposure of a fetus to Type 2 diabetes during pregnancy increases the risk that the baby will develop diabetes later in life .

Acknowledging this distinct subtype of Type 2 diabetes in First Nations communities has led to the implementation of a community-based health action plan aimed at addressing the unique challenges faced by Indigenous Peoples. It is hoped that partnered research between communities and researchers will continue to help us understand childhood-onset Type 2 diabetes and how to effectively prevent and treat it.

A mosaic of conditions

Type 2 diabetes is not uniform; it’s a mosaic of conditions, each with its own characteristics. Since diabetes presents so uniquely in every patient, even categorizing into subtypes does not guarantee how the disease will evolve . However, understanding these subtypes is a good starting point to help doctors create personalized plans for people living with the condition.

While Indigenous communities, lower-income households and individuals living with obesity already face a higher risk of developing Type 2 diabetes than the general population, tailored solutions may offer hope for better management. This emphasizes the urgent need for more precise assessments of diabetes subtypes to help customize therapeutic strategies and management strategies. This will improve care for all patients, including those from vulnerable and understudied populations.

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Clinical Research in Type 2 Diabetes

Studies in humans aimed at the prevention, treatment, and diagnosis of Type 2 Diabetes and the mechanistic aspects of its etiology.

The Clinical Research in Type 2 Diabetes (T2D) program supports human studies across the lifespan aimed at understanding, preventing and treating T2D. This program includes clinical trials that test pharmacologic, behavioral, surgical or practice-level approaches to the treatment and/or prevention of T2D, including promoting the preservation of beta cell function. Studies may also advance the development of new surrogate markers for use in clinical trials. Studies can be designed to understand the pathophysiology of T2D, including the role of gestational diabetes and metabolic imprinting on the development of T2D, as well as factors influencing the response to treatment. The program also encompasses epidemiologic studies that improve our understanding of the natural history and pathogenesis of T2D, and the development of diagnostic criteria to distinguish type 1 and type 2 diabetes, especially in the pediatric population. The program also supports research to understand and test approaches to accelerate the translation of efficacious interventions into real-world practice and adoption; and to address health equity by reducing health disparities in the incidence and/or clinical outcomes of T2D.

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• Hanyu Liang, M.D., Ph.D. Hepatic Metabolism; Insulin Resistance; Type 2 Diabetes; Obesity; Bariatric Surgery
• Barbara Linder, M.D., Ph.D. Type 2 diabetes in children and youth; human studies of metabolic imprinting
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Diabetes articles from across Nature Portfolio

Diabetes describes a group of metabolic diseases characterized by high blood sugar levels. Diabetes can be caused by the pancreas not producing insulin (type 1 diabetes) or by insulin resistance (cells do not respond to insulin; type 2 diabetes).

Macrophage vesicles in antidiabetic drug action

Thiazolidinediones (TZDs) are potent insulin-sensitizing drugs, but their use is accompanied by adverse side-effects. Rohm et al. now report that TZD-stimulated macrophages release miR-690-containing vesicles that improve insulin sensitization and bypass unwanted side-effects.

• Rinke Stienstra
• Eric Kalkhoven

Genetic risk variants lead to type 2 diabetes development through different pathways

The largest genome-wide association study for type 2 diabetes so far, which included several ancestry groups, led to the identification of eight clusters of genetic risk variants. The clusters capture different biological pathways that contribute to the disease, and some clusters are associated with vascular complications.

Blood glucose concentration measurement without finger pricking

A new sensor that detects optoacoustic signals generated by mid-infrared light enables measurement of glucose concentration from intracutaneous tissue rich in blood. This technology does not rely on glucose measurements in interstitial fluid or blood sampling and might yield the next generation of non-invasive glucose-sensing devices for improved diabetes management.

Related Subjects

• Diabetes complications
• Diabetes insipidus
• Gestational diabetes
• Type 1 diabetes
• Type 2 diabetes

Latest Research and Reviews

Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes

• Fucheng Guo
• Xiaoling Zhang

Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials

• Kabelo Mokgalaboni
• Given. R. Mashaba
• Sogolo. L. Lebelo

The usefulness of quantitative 99m Tc-HMPAO WBC SPECT/CT for predicting lower extremity amputation in diabetic foot infection

• Soo Bin Park
• Chae Hong Lim
• Jung Mi Park

An estrogen receptor α-derived peptide improves glucose homeostasis during obesity

Type 2 diabetes mellitus is an increasing global health issue, which is caused by systemic insulin resistance. Here, the authors show a ligand-independent effect of hepatic ERα in regulating insulin sensitivity and identify an ERα-derived peptide that functions as an insulin sensitizer.

• Wanbao Yang
• Shaodong Guo

Effective interventions in preventing gestational diabetes mellitus: A systematic review and meta-analysis

Takele et al. conduct a systematic review and meta-analysis of the effects of intervention characteristics on preventing gestational diabetes. Group or healthcare facility-based physical activity interventions are found to be more effective in preventing gestational diabetes than community-based interventions.

• Wubet Worku Takele
• Kimberly K. Vesco

Illuminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans

The pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis through the regulated secretion of the hormones insulin and glucagon. Here, the authors use deep tissue 3D imaging to re-construct the entire human pancreas at microscopic resolution and display previously unrecognized heterogeneities in the islet’s cellularity with pre-clinical and clinical implications.

• Joakim Lehrstrand
• Wayne I. L. Davies
• Ulf Ahlgren

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Repurposing a diabetes drug to treat Parkinson’s disease

In a multicenter clinical trial, patients with early-stage Parkinson’s disease treated with lixisenatide, a drug currently used for the treatment of diabetes, showed improvement in their motor scores compared with those on placebo.

• Sonia Muliyil

A novel system for non-invasive measurement of blood levels of glucose

• Olivia Tysoe

Diabetes drug slows development of Parkinson’s disease

The drug, which is in the same family as blockbuster weight-loss drugs such as Wegovy, slowed development of symptoms by a small but statistically significant amount.

Metformin acts through appetite-suppressing metabolite: Lac-Phe

• Shimona Starling

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Clinical Trials

Type 2 diabetes.

Displaying 96 studies

The purpose of this study is to identify changes to the metabolome (range of chemicals produced in the body) and microbiome (intestine microbe environment) that are unique to Roux-en-Y gastric bypass surgery and assess the associated effect on the metabolism of patients with type 2 diabetes.

The purpose of this study is to evaluate the impact of a digital storytelling intervention derived through a community-based participatory research (CBPR) approach on type 2 diabetes mellitus (T2D) outcomes among Hispanic adults with poorly controlled type 2 diabetes mellitus (T2D) in primary care settings through a randomized clinical trial.

The purpose of this study is to assess the impact of a whole food plant-based diet on blood sugar control in diabetic patients versus a control group on the American Diabetics Association diet before having a total hip, knee, or shoulder replacement surgery.

The purpose of  this study is to learn more about if the medication, Entresto, could help the function of the heart and kidneys.

The primary aim of this study is to compare the outcome measures of adult ECH type 2 diabetes patients who were referred to onsite pharmacist services for management of their diabetes to similar patients who were not referred for pharmacy service management of their diabetes. A secondary aim of the study is to assess the Kasson providers’ satisfaction level and estimated pharmacy service referral frequency to their patients. A tertiary aim of the study is to compare the hospitalization rates of type 2 diabetes rates who were referred to onsite pharmacist services for management of their diabetes to similar patients ...

To explore the feasibility of conducting a family centered wellness coaching program for patients at high risk for developing diabetes, in a primary care setting.

To determine engagement patterns.

To describe characteristics of families who are likely to participate.

To identify barriers/limitations to family centered wellness coaching.

To assess whether a family centered 8 week wellness coaching intervention for primary care patients at high risk for diabetes will improve self-care behaviors as measured by self-reported changes in physical activity level and food choices.

This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.

The purpose of this study is to assess the effectiveness of Revita® DMR for improving HbA1c to ≤ 7% without the need of insulin in subjects with T2D compared to sham and to assess the effectiveness of DMR versus Sham on improvement in Glycemic, Hepatic and Cardiovascular endpoints.

The purpose of this study is to evaluate 6 weeks of home use of the Control-IQ automated insulin delivery system in individuals with type 2 diabetes.

This study will evaluate whether bile acids are able to increase insulin sensitivity and enhance glycemic control in T2DM patients, as well as exploring the mechanisms that enhance glycemic control. These observations will provide the preliminary data for proposing future therapeutic as well as further mechanistic studies of the role of bile acids in the control of glycemia in T2DM.

The purpose of this study is to determine if Inpatient Stress Hyperglycemia is an indicator of future risk of developing type 2 Diabetes Mellitus.

The purpose of this study is to assess the effectiveness of a digital storytelling intervention derived through a community based participatory research (CBPR) approach on self-management of type 2 diabetes (T2D) among Somali adults. 

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion ...

The purpose of this study is to test the hypothesis that patients with T2DM will have greater deterioration in BMSi and in cortical porosity over 3 yrs as compared to sex- and age-matched non-diabetic controls; and identify the circulating hormonal (e.g., estradiol [E2], testosterone [T]) and biochemical (e.g., bone turnover markers, AGEs) determinants of changes in these key parameters of bone quality, and evaluate the possible relationship between existing diabetic complications and skeletal deterioration over time in the T2DM patients.

The purpose of this study is to determine the effect of endogenous GLP-1 secretion on islet function in people with Typr 2 Diabetes Mellitus (T2DM).

GLP-1 is a hormone made by the body that promotes the production of insulin in response to eating. However, there is increasing evidence that this hormone might help support the body’s ability to produce insulin when diabetes develops. 

The purpose of this study is to assess whether psyllium is more effective in lowering fasting blood sugar and HbA1c, and to evaluate the effect of psyllium compared to wheat dextrin on the following laboratory markers:  LDL-C, inflammatory markers such as ceramides and hsCRP, and branch chain amino acids which predict Diabetes Mellitus (DM).

This trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, phase 2 study in subjects with Type 2 Diabetes Mellitus to evaluate the effect of TTP399 on HbA1c following administration for 6 months.

The purpose of this study is to find the inheritable changes in genetic makeup that are related to the development of type 2 diabetes in Latino families.

The objective of this early feasibility study is to assess the feasibility and preliminary safety of the Endogenex Divice for endoscopic duodenal mucosal regeneration in patients with type 2 diabetes (T2D) inadequately controlled on 2-3 non-insulin glucose-lowering medications. 

This mixed methods study aims to answer the question: "What is the work of being a patient with type 2 diabetes mellitus?" .

The purpose of this study is to assess penile length pre- and post-completion of RestoreX® traction therapy compared to control groups (no treatment) among men with type II diabetes.

This observational study is conducted to determine how the duodenal layer thicknesses (mucosa, submucosa, and muscularis) vary with several factors in patients with and without type 2 diabetes.

The purpose of this study is to evaluate if breathing pure oxygen overnight affects insulin sensitivity in participants with diabetes.   

The purpose of this study is to determine the impact of patient decision aids compared to usual care on measures of patient involvement in decision-making, diabetes care processes, medication adherence, glycemic and cardiovascular risk factor control, and use of resources in nonurban practices in the Midwestern United States.

The purpose of this study is to estimate the risk of diabetes related complications after total pancreatectomy.  We will contact long term survivors after total pancreatectomy to obtain data regarding diabetes related end organ complications.

The purpose of this study is to understand nighttime glucose regulation in humans and find if the pattern is different in people with Type 2 diabetes

The study is being undertaken to understand how a gastric bypass can affect a subject's diabetes even prior to their losing significant amounts of weight. The hypothesis of this study is that increased glucagon-like peptide-1 (GLP-1) secretion explains the amelioration in insulin secretion after Roux-en-Y Gastric Bypass (RYGB) surgery.

The study purpose is to understand patients’ with the diagnosis of Diabetes Mellitus type 1 or 2 perception of the care they receive in the Diabetes clinic or Diabetes technology clinic at Mayo Clinic and to explore and to identify the healthcare system components patients consider important to be part of the comprehensive regenerative care in the clinical setting.

However, before we can implement structural changes or design interventions to promote comprehensive regenerative care in clinical practice, we first need to characterize those regenerative practices occurring today, patients expectations, perceptions and experiences about comprehensive regenerative care and determine the ...

It is unknown how patient preferences and values impact the comparative effectiveness of second-line medications for Type 2 diabetes (T2D). The purpose of this study is to elicit patient preferences toward various treatment outcomes (e.g., hospitalization, kidney disease) using a participatory ranking exercise, use these rankings to generate individually weighted composite outcomes, and estimate patient-centered treatment effects of four different second-line T2D medications that reflect the patient's value for each outcome. 

The purpose of this mixed-methods study is to deploy the tenets of Health and Wellness Coaching (HWC) through a program called BeWell360 model , tailored to the needs of Healthcare Workers (HCWs) as patients living with poorly-controlled Type 2 Diabetes (T2D). The objective of this study is to pilot-test this novel, scalable, and sustainable BeWell360 model that is embedded and integrated as part of primary care for Mayo Clinic Employees within Mayo Clinic Florida who are identified as patients li)ving with poorly-controlled T2D. 

The investigators will determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat /high glycemic diet and thus exhibit elevated cellular oxidative damage. The investigators previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and the investigators hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. The investigators will ...

The purpose of this research is to find out how genetic variations in GLP1R, alters insulin secretion, in the fasting state and when blood sugars levels are elevated. Results from this study may help us identify therapies to prevent or reverse type 2 diabetes mellitus.

Can QBSAfe be implemented in a clinical practice setting and improve quality of life, reduce treatment burden and hypoglycemia among older, complex patients with type 2 diabetes?

Questionnaire administered to diabetic patients in primary care practice (La Crosse Mayo Family Medicine Residency /Family Health Clinic) to assess patient’s diabetic knowledge. Retrospective chart review will also be done to assess objective diabetic control based on most recent hemoglobin A1c.    

To determine if the EndoBarrier safely and effectively improves glycemic control in obese subjects with type 2 diabetes.

The purpose of this study is to assess key characteristics of bone quality, specifically material strength and porosity, in patients who have type 2 diabetes. These patients are at an unexplained increased risk for fractures and there is an urgent need to refine clinical assessment for this risk.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for muscle insulin resistance, although it has been shown that raising FFA with Intralipid can cause muscle insulin resistance within 4 hours. We do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We propose to alter the profile and concentrations of FFA of healthy, non-obese adults using an overnight, intra-duodenal palm oil infusion vs. ...

The objectives of this study are to identify circulating extracellular vesicle (EV)-derived protein and RNA signatures associated with Type 2 Diabetes (T2D), and to identify changes in circulating EV cargo in patients whose T2D resolves after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB).

This research study is being done to develop educational materials that will help patients and clinicians talk about diabetes treatment and management options.

The purpose of this study evaluates a subset of people with isolated Impaired Fasting Glucose with Normal Glucose Tolerance (i.e., IFG/NGT) believed to have normal β-cell function in response to a glucose challenge, suggesting that – at least in this subset of prediabetes – fasting glucose is regulated independently of glucose in the postprandial period. To some extent this is borne out by genetic association studies which have identified loci that affect fasting glucose but not glucose tolerance and vice-versa.

The purpose of this study is to evaluate whether or not a 6 month supply (1 meal//day) of healthy food choices readily available in the patient's home and self management training including understanding of how foods impact diabetes, improved food choices and how to prepare those foods, improve glucose control.  In addition, it will evaluate whether or not there will be lasting behavior change modification after the program.

Assessment of glucose metabolism and liver fat after 12 week dietary intervention in pre diabetes subjects. Subjects will be randomized to either high fat (olive oil supplemented),high carb/high fiber (beans supplemented) and high carb/low fiber diets. Glucose metabolism will be assessed by labeled oral glucose tolerance test and liver fat by magnetic resonance spectroscopy pre randomization and at 8 and 12 week after starting dietary intervention.

To study the effect of an ileocolonic formulation of ox bile extract on insulin sensitivity, postprandial glycemia and incretin levels, gastric emptying, body weight and fasting serum FGF-19 (fibroblast growth factor) levels in overweight or obese type 2 diabetic subjects on therapy with DPP4 (dipeptidyl peptidase-4) inhibitors (e.g. sitagliptin) alone or in combination with metformin.

The purpose of this study is to compare the rate of progression from prediabetes at 4 months to frank diabetes at 12 months (as defined by increase in HbA1C or fasting BS to diabetic range based on the ADA criteria) after transplantation in kidney transplant recipients on Exenatide SR + SOC vs. standard-of-care alone.

The purpose of this study is to learn more about how the body stores dietary fat. Medical research has shown that fat stored in different parts of the body can affect the risk for diabetes, heart disease and other major health conditions.

The purpose of this study is to see why the ability of fat cells to respond to insulin is different depending on body shape and how fat tissue inflammation is involved.

The purpose of this study is to determine the mechanism(s) by which common bariatric surgical procedures alter carbohydrate metabolism. Understanding these mechanisms may ultimately lead to the development of new interventions for the prevention and treatment of type 2 diabetes and obesity.

A research study to enhance clinical discussion between patients and pharmacists using a shared decision making tool for type 2 diabetes or usual care.

While the potential clinical uses of pulsed electromagnetic field therapy (PEMF) are extensive, we are focusing on the potential benefits of PEMF on vascular health. We are targeting, the pre diabetic - metabolic syndrome population, a group with high prevalence in the American population. This population tends to be overweight, low fitness, high blood pressure, high triglycerides and borderline high blood glucose.

The purpose of this study is to evaluate the effects of improving glycemic control, and/or reducing glycemic variability on gastric emptying, intestinal barrier function, autonomic nerve functions, and epigenetic changes in subjects with type 1 diabetes mellitus (T1DM) and  type 2 diabetes mellitus (T2DM) who are switched to intensive insulin therapy as part of clinical practice.

This study is designed to compare an intensive lifestyle and activity coaching program ("Sessions") to usual care for diabetic patients who are sedentary. The question to be answered is whether the Sessions program improves clinical or patient centric outcomes. Recruitment is through invitiation only.

This is a study to evaluate a new Point of Care test for blood glucose monitoring.

The purpose of this study is to determine the metabolic effects of Colesevelam, particularly for the ability to lower blood sugar after a meal in type 2 diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.

The purpose of this study is to test whether markers of cellular aging and the SASP are elevated in subjects with obesity and further increased in patients with obesity and Type 2 Diabetes Mellitus (T2DM) and to relate markers of cellular aging (senescence) and the SASP to skeletal parameters (DXA, HRpQCT, bone turnover markers) in each of these groups.

Integration of Diabetes Prevention Program (DPP) and Diabetes Self Management Program (DSMP) into WellConnect.

This protocol is being conducted to determine the mechanisms responsible for insulin resistance, obesity and type 2 diabetes.

The purpose of this study is to assess the effects of a nighttime rise in cortisol on the body's glucose production in type 2 diabetes.

The goal of this study is to evaluate a new format for delivery of a culturally tailored digital storytelling intervention by incorporating a facilitated group discussion following the videos, for management of type II diabetes in Latino communities.

Using stem cell derived intestinal epithelial cultures (enteroids) derived from obese (BMI> 30) patients and non-obese and metabolically normal patients (either post-bariatric surgery (BS) or BS-naïve with BMI < 25), dietary glucose absorption was measured. We identified that enteroids from obese patients were characterized by glucose hyper-absorption (~ 5 fold) compared to non-obese patients. Significant upregulation of major intestinal sugar transporters, including SGLT1, GLU2 and GLUT5 was responsible for hyper-absorptive phenotype and their pharmacologic inhibition significantly decreased glucose absorption. Importantly, we observed that enteroids from post-BS non-obese patients exhibited low dietary glucose absorption, indicating that altered glucose absorption ...

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for the abnormal response to insulin. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We will measure muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates under both saline control (high overnight FFA) and after an overnight infusion of intravenous ...

The purpose of this study is to improve our understanding of why gastrointestinal symptoms occur in diabetes mellitus patients and identify new treatment(s) in the future.  

These symptoms are often distressing and may impair glycemic control. We do not understand how diabetes mellitus affects the GI tracy. In 45 patients undergoing sleeve gastrectomy, we plan to compare the cellular composition of circulating peripheral mononuclear cells, stomach immune cells, and interstitial cells of Cajal in the stomach. 

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM), whereas lower body obesity (LBO) is characterized by near-normal insulin sensitivity. It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking differs between different obesity phenotypes. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. By measuring muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates we will provide the first integrated examination ...

The goal of this study is to evaluate the presence of podocytes (special cells in the kidney that prevent protein loss) in the urine in patients with diabetes or glomerulonephritis (inflammation in the kidneys). Loss of podocyte in the urine may be an earlier sign of kidney injury (before protein loss) and the goal of this study is to evaluate the association between protein in the urine and podocytes in the urine.

The purpose of this study is to evaluate the effects of multiple dose regimens of RM-131 on vomiting episodes, stomach emptying and stomach paralysis symptoms in patients with Type 1 and Type 2 diabetes and gastroparesis.

The purpose of this study is assess the feasibility, effectiveness, and acceptability of Diabetes-REM (Rescue, Engagement, and Management), a comprehensive community paramedic (CP) program to improve diabetes self-management among adults in Southeast Minnesota (SEMN) treated for servere hypoglycemia by the Mayo Clinic Ambulance Services (MCAS).

The purpose of this study is to determine if a blood test called "pancreatic polypeptide" can help distinguish between patients with diabetes mellitus with and without pancreatic cancer.

The purpose of this study is to create a prospective cohort of subjects with increased probability of being diagnosed with pancreatic cancer and then screen this cohort for pancreatic cancer

The purpose of this study is to evaluate the effectiveness and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

Women with gestational diabetes mellitus (GDM) are likely to have insulin resistance that persists long after pregnancy, resulting in greater risk of developing type 2 diabetes mellitus (T2DM). The study will compare women with and without a previous diagnosis of GDM to determine if women with a history of GDM have abnormal fatty acid metabolism, specifically impaired adipose tissue lipolysis. The study will aim to determine whether women with a history of GDM have impaired pancreatic β-cell function. The study will determine whether women with a history of GDM have tissue specific defects in insulin action, and also identify the effect of a ...

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research ...

The purpose of this study is to demonstrate feasibility of dynamic 11C-ER176 PET imaging to identify macrophage-driven immune dysregulation in gastric muscle of patients with DG. Non-invasive quantitative assessment with PET can significantly add to our diagnostic armamentarium for patients with diabetic gastroenteropathy.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of this study is to look at how participants' daily life is affected by their heart failure. The study will also look at the change in participants' body weight. This study will compare the effect of semaglutide (a new medicine) compared to "dummy" medicine on body weight and heart failure symptoms. Participants will either get semaglutide or "dummy" medicine, which treatment participants get is decided by chance. Participants will need to take 1 injection once a week. 

This study aims to measure the percentage of time spent in hyperglycemia in patients on insulin therapy and evaluate diabetes related patient reported outcomes in kidney transplant recipients with type 2 diabetes. It also aimes to evaluate immunosuppression related patient reported outcomes in kidney transplant recipients with type 2 diabetes.

The purpose of this study is to evaluate whether or not semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will receive semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when ...

The objectives of this study are to evaluate the safety of IW-9179 in patients with diabetic gastroparesis (DGP) and the effect of treatment on the cardinal symptoms of DGP.

The purpose of this study is to understand why patients with indigestion, with or without diabetes, have gastrointestinal symptoms and, in particular, to understand where the symptoms are related to increased sensitivity to nutrients.Subsequently, look at the effects of Ondansetron on these patients' symptoms.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and exploratory effectiveness of nimacimab in patients with diabetic gastroparesis.

The purpose of this study is to prospectively assemble a cohort of subjects >50 and ≤85 years of age with New-onset Diabetes (NOD):

• Estimate the probability of pancreatic ductal adenocarcinoma (PDAC) in the NOD Cohort;
• Establish a biobank of clinically annotated biospecimens including a reference set of biospecimens from pre-symptomatic PDAC and control new-onset type 2 diabetes mellitus (DM) subjects;
• Facilitate validation of emerging tests for identifying NOD subjects at high risk for having PDAC using the reference set; and
• Provide a platform for development of an interventional protocol for early detection of sporadic PDAC ...

The purpose of this study is to demonstrate the performance of the Guardian™ Sensor (3) with an advanced algorithm in subjects age 2 - 80 years, for the span of 170 hours (7 days).

The purpose of this study is to look at the relationship of patient-centered education, the Electronic Medical Record (patient portal) and the use of digital photography to improve the practice of routine foot care and reduce the number of foot ulcers/wounds in patients with diabetes.

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels. This is a frequent problem that is most commonly due to type 2 diabetes. However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as chronic pancreatitis or pancreatic cancer, as the cause of their diabetes. Currently, there is no test to identify the small number of patients who have diabetes caused by a primary problem with their pancreas.

The goal of this study is to develop a test to distinguish these ...

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with type 2 diabetes or prediabetes and chronic heart failure with preserved systolic function.

The primary purpose of this study is to prospectively assess symptoms of bloating (severity, prevalence) in patients with diabetic gastroparesis.

The purpose of this study is to track the treatment burden experienced by patients living with Type 2 Diabetes Mellitus (T2DM) experience as they work to manage their illness in the context of social distancing measures. 

To promote social distancing during the COVID-19 pandemic, health care institutions around the world have rapidly expanded their use of telemedicine to replace in-office appointments where possible.1 For patients with diabetes, who spend considerable time and energy engaging with various components of the health care system,2,3 this unexpected and abrupt transition to virtual health care may signal significant changes to ...

The purpose of this study is to evaluate the safety and efficacy of oral Pyridorin 300 mg BID in reducing the rate of progression of nephropathy due to type 2 diabetes mellitus.

The purpose of this study is to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease (fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes).

The purpose of this study is to evaluate the ability of appropriately-trained family physicians to screen for and identify Diabetic Retinopathy using retinal camera and, secondarily, to describe patients’ perception of the convenience and cost-effectiveness of retinal imaging.

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients who have type 2 diabetes and chronic heart failure with reduced systolic function.

Hypothesis: We hypothesize that patients from the Family Medicine Department at Mayo Clinic Florida who participate in RPM will have significantly reduced emergency room visits, hospitalizations, and hospital contacts.  

Aims, purpose, or objectives: In this study, we will compare the RPM group to a control group that does not receive RPM. The primary objective is to determine if there are significant group differences in emergency room visits, hospitalizations, outpatient primary care visits, outpatient specialty care visits, and hospital contacts (inbound patient portal messages and phone calls). The secondary objective is to determine if there are ...

The purpose of this research is to determine if CGM (continuous glucose monitors) used in the hospital in patients with COVID-19 and diabetes treated with insulin will be as accurate as POC (point of care) glucose monitors. Also if found to be accurate, CGM reading data will be used together with POC glucometers to dose insulin therapy.

The purpose of this study is to evaluate the effect of fenofibrate compared with placebo for prevention of diabetic retinopathy (DR) worsening or center-involved diabetic macular edema (CI-DME) with vision loss through 4 years of follow-up in participants with mild to moderately severe non-proliferative DR (NPDR) and no CI-DME at baseline.

The purpose of this study is to assess painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation.

The purpose of this study is to examine the evolution of diabetic kindey injury over an extended period in a group of subjects who previously completed a clinical trial which assessed the ability of losartan to protect the kidney from injury in early diabetic kidney disease. We will also explore the relationship between diabetic kidney disease and other diabetes complications, including neuropathy and retinopathy.

The purpose of this study is to evaluate the effietiveness of remdesivir (RDV) in reducing the rate of of all-cause medically attended visits (MAVs; medical visits attended in person by the participant and a health care professional) or death in non-hospitalized participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting.

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• Patient Care & Health Information
• Diseases & Conditions
• Type 2 diabetes

Type 2 diabetes is usually diagnosed using the glycated hemoglobin (A1C) test. This blood test indicates your average blood sugar level for the past two to three months. Results are interpreted as follows:

• Below 5.7% is normal.
• 5.7% to 6.4% is diagnosed as prediabetes.
• 6.5% or higher on two separate tests indicates diabetes.

If the A1C test isn't available, or if you have certain conditions that interfere with an A1C test, your health care provider may use the following tests to diagnose diabetes:

Random blood sugar test. Blood sugar values are expressed in milligrams of sugar per deciliter ( mg/dL ) or millimoles of sugar per liter ( mmol/L ) of blood. Regardless of when you last ate, a level of 200 mg/dL (11.1 mmol/L ) or higher suggests diabetes, especially if you also have symptoms of diabetes, such as frequent urination and extreme thirst.

Fasting blood sugar test. A blood sample is taken after you haven't eaten overnight. Results are interpreted as follows:

• Less than 100 mg/dL (5.6 mmol/L ) is considered healthy.
• 100 to 125 mg/dL (5.6 to 6.9 mmol/L ) is diagnosed as prediabetes.
• 126 mg/dL (7 mmol/L ) or higher on two separate tests is diagnosed as diabetes.

Oral glucose tolerance test. This test is less commonly used than the others, except during pregnancy. You'll need to not eat for a certain amount of time and then drink a sugary liquid at your health care provider's office. Blood sugar levels then are tested periodically for two hours. Results are interpreted as follows:

• Less than 140 mg/dL (7.8 mmol/L ) after two hours is considered healthy.
• 140 to 199 mg/dL (7.8 mmol/L and 11.0 mmol/L ) is diagnosed as prediabetes.
• 200 mg/dL (11.1 mmol/L ) or higher after two hours suggests diabetes.

Screening. The American Diabetes Association recommends routine screening with diagnostic tests for type 2 diabetes in all adults age 35 or older and in the following groups:

• People younger than 35 who are overweight or obese and have one or more risk factors associated with diabetes.
• Women who have had gestational diabetes.
• People who have been diagnosed with prediabetes.
• Children who are overweight or obese and who have a family history of type 2 diabetes or other risk factors.

After a diagnosis

If you're diagnosed with diabetes, your health care provider may do other tests to distinguish between type 1 and type 2 diabetes because the two conditions often require different treatments.

Your health care provider will test A1C levels at least two times a year and when there are any changes in treatment. Target A1C goals vary depending on age and other factors. For most people, the American Diabetes Association recommends an A1C level below 7%.

You also receive tests to screen for complications of diabetes and other medical conditions.

More Information

• Glucose tolerance test

Management of type 2 diabetes includes:

• Healthy eating.
• Regular exercise.
• Weight loss.
• Possibly, diabetes medication or insulin therapy.
• Blood sugar monitoring.

These steps make it more likely that blood sugar will stay in a healthy range. And they may help to delay or prevent complications.

Healthy eating

There's no specific diabetes diet. However, it's important to center your diet around:

• A regular schedule for meals and healthy snacks.
• Smaller portion sizes.
• More high-fiber foods, such as fruits, nonstarchy vegetables and whole grains.
• Fewer refined grains, starchy vegetables and sweets.
• Modest servings of low-fat dairy, low-fat meats and fish.
• Healthy cooking oils, such as olive oil or canola oil.
• Fewer calories.

Your health care provider may recommend seeing a registered dietitian, who can help you:

• Identify healthy food choices.
• Plan well-balanced, nutritional meals.
• Develop new habits and address barriers to changing habits.
• Monitor carbohydrate intake to keep your blood sugar levels more stable.

Physical activity

Exercise is important for losing weight or maintaining a healthy weight. It also helps with managing blood sugar. Talk to your health care provider before starting or changing your exercise program to ensure that activities are safe for you.

• Aerobic exercise. Choose an aerobic exercise that you enjoy, such as walking, swimming, biking or running. Adults should aim for 30 minutes or more of moderate aerobic exercise on most days of the week, or at least 150 minutes a week.
• Resistance exercise. Resistance exercise increases your strength, balance and ability to perform activities of daily living more easily. Resistance training includes weightlifting, yoga and calisthenics. Adults living with type 2 diabetes should aim for 2 to 3 sessions of resistance exercise each week.
• Limit inactivity. Breaking up long periods of inactivity, such as sitting at the computer, can help control blood sugar levels. Take a few minutes to stand, walk around or do some light activity every 30 minutes.

Weight loss

Weight loss results in better control of blood sugar levels, cholesterol, triglycerides and blood pressure. If you're overweight, you may begin to see improvements in these factors after losing as little as 5% of your body weight. However, the more weight you lose, the greater the benefit to your health. In some cases, losing up to 15% of body weight may be recommended.

Your health care provider or dietitian can help you set appropriate weight-loss goals and encourage lifestyle changes to help you achieve them.

Monitoring your blood sugar

Your health care provider will advise you on how often to check your blood sugar level to make sure you remain within your target range. You may, for example, need to check it once a day and before or after exercise. If you take insulin, you may need to check your blood sugar multiple times a day.

Monitoring is usually done with a small, at-home device called a blood glucose meter, which measures the amount of sugar in a drop of blood. Keep a record of your measurements to share with your health care team.

Continuous glucose monitoring is an electronic system that records glucose levels every few minutes from a sensor placed under the skin. Information can be transmitted to a mobile device such as a phone, and the system can send alerts when levels are too high or too low.

Diabetes medications

If you can't maintain your target blood sugar level with diet and exercise, your health care provider may prescribe diabetes medications that help lower glucose levels, or your provider may suggest insulin therapy. Medicines for type 2 diabetes include the following.

Metformin (Fortamet, Glumetza, others) is generally the first medicine prescribed for type 2 diabetes. It works mainly by lowering glucose production in the liver and improving the body's sensitivity to insulin so it uses insulin more effectively.

Some people experience B-12 deficiency and may need to take supplements. Other possible side effects, which may improve over time, include:

• Abdominal pain.

Sulfonylureas help the body secrete more insulin. Examples include glyburide (DiaBeta, Glynase), glipizide (Glucotrol XL) and glimepiride (Amaryl). Possible side effects include:

• Low blood sugar.
• Weight gain.

Glinides stimulate the pancreas to secrete more insulin. They're faster acting than sulfonylureas. But their effect in the body is shorter. Examples include repaglinide and nateglinide. Possible side effects include:

Thiazolidinediones make the body's tissues more sensitive to insulin. An example of this medicine is pioglitazone (Actos). Possible side effects include:

• Risk of congestive heart failure.
• Risk of bladder cancer (pioglitazone).
• Risk of bone fractures.

DPP-4 inhibitors help reduce blood sugar levels but tend to have a very modest effect. Examples include sitagliptin (Januvia), saxagliptin (Onglyza) and linagliptin (Tradjenta). Possible side effects include:

• Risk of pancreatitis.
• Joint pain.

GLP-1 receptor agonists are injectable medications that slow digestion and help lower blood sugar levels. Their use is often associated with weight loss, and some may reduce the risk of heart attack and stroke. Examples include exenatide (Byetta, Bydureon Bcise), liraglutide (Saxenda, Victoza) and semaglutide (Rybelsus, Ozempic, Wegovy). Possible side effects include:

SGLT2 inhibitors affect the blood-filtering functions in the kidneys by blocking the return of glucose to the bloodstream. As a result, glucose is removed in the urine. These medicines may reduce the risk of heart attack and stroke in people with a high risk of those conditions. Examples include canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance). Possible side effects include:

• Vaginal yeast infections.
• Urinary tract infections.
• Low blood pressure.
• High cholesterol.
• Risk of gangrene.
• Risk of bone fractures (canagliflozin).
• Risk of amputation (canagliflozin).

Other medicines your health care provider might prescribe in addition to diabetes medications include blood pressure and cholesterol-lowering medicines, as well as low-dose aspirin, to help prevent heart and blood vessel disease.

Insulin therapy

Some people who have type 2 diabetes need insulin therapy. In the past, insulin therapy was used as a last resort, but today it may be prescribed sooner if blood sugar targets aren't met with lifestyle changes and other medicines.

Different types of insulin vary on how quickly they begin to work and how long they have an effect. Long-acting insulin, for example, is designed to work overnight or throughout the day to keep blood sugar levels stable. Short-acting insulin generally is used at mealtime.

Your health care provider will determine what type of insulin is right for you and when you should take it. Your insulin type, dosage and schedule may change depending on how stable your blood sugar levels are. Most types of insulin are taken by injection.

Side effects of insulin include the risk of low blood sugar — a condition called hypoglycemia — diabetic ketoacidosis and high triglycerides.

Weight-loss surgery

Weight-loss surgery changes the shape and function of the digestive system. This surgery may help you lose weight and manage type 2 diabetes and other conditions related to obesity. There are several surgical procedures. All of them help people lose weight by limiting how much food they can eat. Some procedures also limit the amount of nutrients the body can absorb.

Weight-loss surgery is only one part of an overall treatment plan. Treatment also includes diet and nutritional supplement guidelines, exercise and mental health care.

Generally, weight-loss surgery may be an option for adults living with type 2 diabetes who have a body mass index (BMI) of 35 or higher. BMI is a formula that uses weight and height to estimate body fat. Depending on the severity of diabetes or the presence of other medical conditions, surgery may be an option for someone with a BMI lower than 35.

Weight-loss surgery requires a lifelong commitment to lifestyle changes. Long-term side effects may include nutritional deficiencies and osteoporosis.

People living with type 2 diabetes often need to change their treatment plan during pregnancy and follow a diet that controls carbohydrates. Many people need insulin therapy during pregnancy. They also may need to stop other treatments, such as blood pressure medicines.

There is an increased risk during pregnancy of developing a condition that affects the eyes called diabetic retinopathy. In some cases, this condition may get worse during pregnancy. If you are pregnant, visit an ophthalmologist during each trimester of your pregnancy and one year after you give birth. Or as often as your health care provider suggests.

Signs of trouble

Regularly monitoring your blood sugar levels is important to avoid severe complications. Also, be aware of symptoms that may suggest irregular blood sugar levels and the need for immediate care:

High blood sugar. This condition also is called hyperglycemia. Eating certain foods or too much food, being sick, or not taking medications at the right time can cause high blood sugar. Symptoms include:

• Frequent urination.
• Increased thirst.
• Blurred vision.

Hyperglycemic hyperosmolar nonketotic syndrome (HHNS). This life-threatening condition includes a blood sugar reading higher than 600 mg/dL (33.3 mmol/L ). HHNS may be more likely if you have an infection, are not taking medicines as prescribed, or take certain steroids or drugs that cause frequent urination. Symptoms include:

• Extreme thirst.
• Drowsiness.
• Dark urine.

Diabetic ketoacidosis. Diabetic ketoacidosis occurs when a lack of insulin results in the body breaking down fat for fuel rather than sugar. This results in a buildup of acids called ketones in the bloodstream. Triggers of diabetic ketoacidosis include certain illnesses, pregnancy, trauma and medicines — including the diabetes medicines called SGLT2 inhibitors.

The toxicity of the acids made by diabetic ketoacidosis can be life-threatening. In addition to the symptoms of hyperglycemia, such as frequent urination and increased thirst, ketoacidosis may cause:

• Shortness of breath.
• Fruity-smelling breath.

Low blood sugar. If your blood sugar level drops below your target range, it's known as low blood sugar. This condition also is called hypoglycemia. Your blood sugar level can drop for many reasons, including skipping a meal, unintentionally taking more medication than usual or being more physically active than usual. Symptoms include:

• Irritability.
• Heart palpitations.
• Slurred speech.

If you have symptoms of low blood sugar, drink or eat something that will quickly raise your blood sugar level. Examples include fruit juice, glucose tablets, hard candy or another source of sugar. Retest your blood in 15 minutes. If levels are not at your target, eat or drink another source of sugar. Eat a meal after your blood sugar level returns to normal.

If you lose consciousness, you need to be given an emergency injection of glucagon, a hormone that stimulates the release of sugar into the blood.

• Medications for type 2 diabetes
• GLP-1 agonists: Diabetes drugs and weight loss
• Bariatric surgery
• Endoscopic sleeve gastroplasty
• Gastric bypass (Roux-en-Y)

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Clinical trials

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Lifestyle and home remedies

Careful management of type 2 diabetes can reduce the risk of serious — even life-threatening — complications. Consider these tips:

• Commit to managing your diabetes. Learn all you can about type 2 diabetes. Make healthy eating and physical activity part of your daily routine.
• Work with your team. Establish a relationship with a certified diabetes education specialist, and ask your diabetes treatment team for help when you need it.
• Identify yourself. Wear a necklace or bracelet that says you are living with diabetes, especially if you take insulin or other blood sugar-lowering medicine.
• Schedule a yearly physical exam and regular eye exams. Your diabetes checkups aren't meant to replace regular physicals or routine eye exams.
• Keep your vaccinations up to date. High blood sugar can weaken your immune system. Get a flu shot every year. Your health care provider also may recommend the pneumonia vaccine. The Centers for Disease Control and Prevention (CDC) also recommends the hepatitis B vaccination if you haven't previously received this vaccine and you're 19 to 59 years old. Talk to your health care provider about other vaccinations you may need.
• Take care of your teeth. Diabetes may leave you prone to more-serious gum infections. Brush and floss your teeth regularly and schedule recommended dental exams. Contact your dentist right away if your gums bleed or look red or swollen.
• Pay attention to your feet. Wash your feet daily in lukewarm water, dry them gently, especially between the toes, and moisturize them with lotion. Check your feet every day for blisters, cuts, sores, redness and swelling. Contact your health care provider if you have a sore or other foot problem that isn't healing.
• Keep your blood pressure and cholesterol under control. Eating healthy foods and exercising regularly can go a long way toward controlling high blood pressure and cholesterol. Take medication as prescribed.
• If you smoke or use other types of tobacco, ask your health care provider to help you quit. Smoking increases your risk of diabetes complications. Talk to your health care provider about ways to stop using tobacco.
• Use alcohol sparingly. Depending on the type of drink, alcohol may lower or raise blood sugar levels. If you choose to drink alcohol, only do so with a meal. The recommendation is no more than one drink daily for women and no more than two drinks daily for men. Check your blood sugar frequently after drinking alcohol.
• Make healthy sleep a priority. Many people with type 2 diabetes have sleep problems. And not getting enough sleep may make it harder to keep blood sugar levels in a healthy range. If you have trouble sleeping, talk to your health care provider about treatment options.
• Caffeine: Does it affect blood sugar?

Alternative medicine

Many alternative medicine treatments claim to help people living with diabetes. According to the National Center for Complementary and Integrative Health, studies haven't provided enough evidence to recommend any alternative therapies for blood sugar management. Research has shown the following results about popular supplements for type 2 diabetes:

• Chromium supplements have been shown to have few or no benefits. Large doses can result in kidney damage, muscle problems and skin reactions.
• Magnesium supplements have shown benefits for blood sugar control in some but not all studies. Side effects include diarrhea and cramping. Very large doses — more than 5,000 mg a day — can be fatal.
• Cinnamon, in some studies, has lowered fasting glucose levels but not A1C levels. Therefore, there's no evidence of overall improved glucose management.

Talk to your health care provider before starting a dietary supplement or natural remedy. Do not replace your prescribed diabetes medicines with alternative medicines.

Coping and support

Type 2 diabetes is a serious disease, and following your diabetes treatment plan takes commitment. To effectively manage diabetes, you may need a good support network.

Anxiety and depression are common in people living with diabetes. Talking to a counselor or therapist may help you cope with the lifestyle changes and stress that come with a type 2 diabetes diagnosis.

Support groups can be good sources of diabetes education, emotional support and helpful information, such as how to find local resources or where to find carbohydrate counts for a favorite restaurant. If you're interested, your health care provider may be able to recommend a group in your area.

You can visit the American Diabetes Association website to check out local activities and support groups for people living with type 2 diabetes. The American Diabetes Association also offers online information and online forums where you can chat with others who are living with diabetes. You also can call the organization at 800-DIABETES ( 800-342-2383 ).

Preparing for your appointment

At your annual wellness visit, your health care provider can screen for diabetes and monitor and treat conditions that increase your risk of diabetes, such as high blood pressure, high cholesterol or a high BMI .

If you are seeing your health care provider because of symptoms that may be related to diabetes, you can prepare for your appointment by being ready to answer the following questions:

• When did your symptoms begin?
• Does anything improve the symptoms or worsen the symptoms?
• What medicines do you take regularly, including dietary supplements and herbal remedies?
• What are your typical daily meals? Do you eat between meals or before bedtime?
• How much alcohol do you drink?
• How much daily exercise do you get?
• Is there a history of diabetes in your family?

If you are diagnosed with diabetes, your health care provider may begin a treatment plan. Or you may be referred to a doctor who specializes in hormonal disorders, called an endocrinologist. Your care team also may include the following specialists:

• Certified diabetes education specialist.
• Foot doctor, also called a podiatrist.
• Doctor who specializes in eye care, called an ophthalmologist.

Talk to your health care provider about referrals to other specialists who may be providing care.

Questions for ongoing appointments

Before any appointment with a member of your treatment team, make sure you know whether there are any restrictions, such as not eating or drinking before taking a test. Questions that you should regularly talk about with your health care provider or other members of the team include:

• How often do I need to monitor my blood sugar, and what is my target range?
• What changes in my diet would help me better manage my blood sugar?
• What is the right dosage for prescribed medications?
• When do I take the medications? Do I take them with food?
• How does management of diabetes affect treatment for other conditions? How can I better coordinate treatments or care?
• When do I need to make a follow-up appointment?
• Under what conditions should I call you or seek emergency care?
• Are there brochures or online sources you recommend?
• Are there resources available if I'm having trouble paying for diabetes supplies?

What to expect from your doctor

Your health care provider is likely to ask you questions at your appointments. Those questions may include:

• Do you understand your treatment plan and feel confident you can follow it?
• How are you coping with diabetes?
• Have you had any low blood sugar?
• Do you know what to do if your blood sugar is too low or too high?
• What's a typical day's diet like?
• Are you exercising? If so, what type of exercise? How often?
• Do you sit for long periods of time?
• What challenges are you experiencing in managing your diabetes?
• Professional Practice Committee: Standards of Medical Care in Diabetes — 2020. Diabetes Care. 2020; doi:10.2337/dc20-Sppc.
• Diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed Dec. 7, 2020.
• Melmed S, et al. Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 3, 2020.
• Diabetes overview. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/all-content. Accessed Dec. 4, 2020.
• AskMayoExpert. Type 2 diabetes. Mayo Clinic; 2018.
• Feldman M, et al., eds. Surgical and endoscopic treatment of obesity. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 20, 2020.
• Hypersmolar hyperglycemic state (HHS). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hyperosmolar-hyperglycemic-state-hhs. Accessed Dec. 11, 2020.
• Diabetic ketoacidosis (DKA). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka. Accessed Dec. 11, 2020.
• Hypoglycemia. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hypoglycemia. Accessed Dec. 11, 2020.
• 6 things to know about diabetes and dietary supplements. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/tips/things-to-know-about-type-diabetes-and-dietary-supplements. Accessed Dec. 11, 2020.
• Type 2 diabetes and dietary supplements: What the science says. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/providers/digest/type-2-diabetes-and-dietary-supplements-science. Accessed Dec. 11, 2020.
• Preventing diabetes problems. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/all-content. Accessed Dec. 3, 2020.
• Schillie S, et al. Prevention of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recommendations and Reports. 2018; doi:10.15585/mmwr.rr6701a1.
• Diabetes prevention: 5 tips for taking control
• Hyperinsulinemia: Is it diabetes?

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How to Thrive as You Age

A cheap drug may slow down aging. a study will determine if it works.

Allison Aubrey

A drug taken by millions of people to control diabetes may do more than lower blood sugar.

Research suggests metformin has anti-inflammatory effects that could help protect against common age-related diseases including heart disease, cancer, and cognitive decline.

Scientists who study the biology of aging have designed a clinical study, known as The TAME Trial, to test whether metformin can help prevent these diseases and promote a longer healthspan in healthy, older adults.

Michael Cantor, an attorney, and his wife Shari Cantor , the mayor of West Hartford, Connecticut both take metformin. "I tell all my friends about it," Michael Cantor says. "We all want to live a little longer, high-quality life if we can," he says.

Michael Cantor started on metformin about a decade ago when his weight and blood sugar were creeping up. Shari Cantor began taking metformin during the pandemic after she read that it may help protect against serious infections.

Shari and Michael Cantor both take metformin. They are both in their mid-60s and say they feel healthy and full of energy. Theresa Oberst/Michael Cantor hide caption

Shari and Michael Cantor both take metformin. They are both in their mid-60s and say they feel healthy and full of energy.

The Cantors are in their mid-60s and both say they feel healthy and have lots of energy. Both noticed improvements in their digestive systems – feeling more "regular" after they started on the drug,

Metformin costs less than a dollar a day, and depending on insurance, many people pay no out-of-pocket costs for the drug.

"I don't know if metformin increases lifespan in people, but the evidence that exists suggests that it very well might," says Steven Austad , a senior scientific advisor at the American Federation for Aging Research who studies the biology of aging.

An old drug with surprising benefits

Metformin was first used to treat diabetes in the 1950s in France. The drug is a derivative of guanidine , a compound found in Goat's Rue, an herbal medicine long used in Europe.

The FDA approved metformin for the treatment of type 2 diabetes in the U.S. in the 1990s. Since then, researchers have documented several surprises, including a reduced risk of cancer. "That was a bit of a shock," Austad says. A meta-analysis that included data from dozens of studies, found people who took metformin had a lower risk of several types of cancers , including gastrointestinal, urologic and blood cancers.

Austad also points to a British study that found a lower risk of dementia and mild cognitive decline among people with type 2 diabetes taking metformin. In addition, there's research pointing to improved cardiovascular outcomes in people who take metformin including a reduced risk of cardiovascular death .

As promising as this sounds, Austad says most of the evidence is observational, pointing only to an association between metformin and the reduced risk. The evidence stops short of proving cause and effect. Also, it's unknown if the benefits documented in people with diabetes will also reduce the risk of age-related diseases in healthy, older adults.

"That's what we need to figure out," says Steve Kritchevsky , a professor of gerontology at Wake Forest School of Medicine, who is a lead investigator for the Tame Trial.

The goal is to better understand the mechanisms and pathways by which metformin works in the body. For instance, researchers are looking at how the drug may help improve energy in the cells by stimulating autophagy, which is the process of clearing out or recycling damaged bits inside cells.

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Researchers also want to know more about how metformin can help reduce inflammation and oxidative stress, which may slow biological aging.

"When there's an excess of oxidative stress, it will damage the cell. And that accumulation of damage is essentially what aging is," Kritchevsky explains.

When the forces that are damaging cells are running faster than the forces that are repairing or replacing cells, that's aging, Kritchevsky says. And it's possible that drugs like metformin could slow this process down.

By targeting the biology of aging, the hope is to prevent or delay multiple diseases, says Dr. Nir Barzilai of Albert Einstein College of Medicine, who leads the effort to get the trial started.

The ultimate in preventative medicine

Back in 2015, Austad and a bunch of aging researchers began pushing for a clinical trial.

"A bunch of us went to the FDA to ask them to approve a trial for metformin,' Austad recalls, and the agency was receptive. "If you could help prevent multiple problems at the same time, like we think metformin may do, then that's almost the ultimate in preventative medicine," Austad says.

The aim is to enroll 3,000 people between the ages of 65 and 79 for a six-year trial. But Dr. Barzilai says it's been slow going to get it funded. "The main obstacle with funding this study is that metformin is a generic drug, so no pharmaceutical company is standing to make money," he says.

Barzilai has turned to philanthropists and foundations, and has some pledges. The National Institute on Aging, part of the National Institutes of Health, set aside about $5 million for the research, but that's not enough to pay for the study which is estimated to cost between $45 and $70 million.

The frustration over the lack of funding is that if the trial points to protective effects, millions of people could benefit. "It's something that everybody will be able to afford," Barzilai says.

Currently the FDA doesn't recognize aging as a disease to treat, but the researchers hope this would usher in a paradigm shift — from treating each age-related medical condition separately, to treating these conditions together, by targeting aging itself.

For now, metformin is only approved to treat type 2 diabetes in the U.S., but doctors can prescribe it off-label for conditions other than its approved use .

Michael and Shari Cantor's doctors were comfortable prescribing it to them, given the drug's long history of safety and the possible benefits in delaying age-related disease.

"I walk a lot, I hike, and at 65 I have a lot of energy," Michael Cantor says. I feel like the metformin helps," he says. He and Shari say they have not experienced any negative side effects.

Research shows a small percentage of people who take metformin experience GI distress that makes the drug intolerable. And, some people develop a b12 vitamin deficiency. One study found people over the age of 65 who take metformin may have a harder time building new muscle.

Millions of women are 'under-muscled.' These foods help build strength

"There's some evidence that people who exercise who are on metformin have less gain in muscle mass, says Dr. Eric Verdin , President of the Buck Institute for Research on Aging. That could be a concern for people who are under-muscled .

But Verdin says it may be possible to repurpose metformin in other ways "There are a number of companies that are exploring metformin in combination with other drugs," he says. He points to research underway to combine metformin with a drug called galantamine for the treatment of sarcopenia , which is the medical term for age-related muscle loss. Sarcopenia affects millions of older people, especially women .

The science of testing drugs to target aging is rapidly advancing, and metformin isn't the only medicine that may treat the underlying biology.

"Nobody thinks this is the be all and end all of drugs that target aging," Austad says. He says data from the clinical trial could stimulate investment by the big pharmaceutical companies in this area. "They may come up with much better drugs," he says.

Michael Cantor knows there's no guarantee with metformin. "Maybe it doesn't do what we think it does in terms of longevity, but it's certainly not going to do me any harm," he says.

Cantor's father had his first heart attack at 51. He says he wants to do all he can to prevent disease and live a healthy life, and he thinks Metformin is one tool that may help.

For now, Dr. Barzilai says the metformin clinical trial can get underway when the money comes in.

7 habits to live a healthier life, inspired by the world's longest-lived communities

This story was edited by Jane Greenhalgh

Proteomic Analyses in Diverse Populations Improved Risk Prediction and Identified New Drug Targets for Type 2 Diabetes

Affiliations.

• 1 Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.
• 2 Medical Research Council Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.
• 3 Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
• 4 Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China.
• 5 Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
• PMID: 38623619
• DOI: 10.2337/dc23-2145

Objective: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D).

Research design and methods: We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D.

Results: Overall, 33 proteins were significantly associated (false discovery rate < 0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D.

Conclusions: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D.

© 2024 by the American Diabetes Association.

Grants and funding

• C16077/A29186, C500/A16896/CRUK_/Cancer Research UK/United Kingdom
• CH/1996001/9454/BHF_/British Heart Foundation/United Kingdom

Siblings with unique genetic change help scientists progress drug search for type 1 diabetes

Two siblings who have the only known mutations in a key gene anywhere in the world have helped scientists gain new insights that could help progress the search for new treatments in type 1 diabetes.

Type 1 diabetes (also known as autoimmune diabetes) is a devastating and life-long disease, in which the patient's immune cells wrongly destroy the insulin producing beta cells in the pancreas. People living with autoimmune diabetes need to test their blood sugar and inject insulin throughout their lives to control their blood sugars and prevent complications.

Autoimmune diabetes with clinical onset in very early childhood is rare and can result from a variety of genetic variants. However, there are many cases of early onset diabetes without known genetic explanation. In addition, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors -- which target the same pathway that the mutation was found in -- are prone to developing autoimmune diabetes. The reason why only this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood. Like type 1 diabetes, genetic or immunotherapy-associated autoimmune diabetes requires life-long insulin replacement therapy -- there is currently no cure.

The new research, published in the Journal of Experimental Medicine , began when researchers studied two siblings who were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. The University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before they are nine months old. For most of these babies, this service provides a genetic diagnosis and in around half of these babies, it allows for a change in treatment.

When researchers tested the two siblings in the study, no mutation in any of the known causes was identified. The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. Through this sequencing, they found a mutation in the gene encoding PD-L1 in the siblings and realised it could be responsible for their very-early-onset autoimmune diabetes.

Study authorDr Matthew Johnson, from the University of Exeter, UK, said: "PD-L1 has been particularly well studied in animal models because of its crucial function in sending a stop signal to the immune system and its relevance to cancer immunotherapy. But, to our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1. We searched the globe, looking at all the large-scale datasets that we know of, and we haven't been able to find another family. These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans."

The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed exclusively on immune cells. When the two proteins bind together it provides a stop signal to the immune system, preventing collateral damage to the bodies tissues and organs.

Researchers from the Rockefeller Institute in New York and King's College London joined forces with Exeter to study the siblings, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health. After contacting the family's clinician in Morocco, the Exeter team visited the siblings where they were living to collect samples and return them to King's College London, within the crucial ten-hour window for analysis while the immune cells were still alive. The London and New York teams then performed extensive analysis on the siblings' cells.

Study co-author Dr Masato Ogishi, from the Rockefeller University in New York, said: "We first showed that the mutation completely disabled the function of PD-L1 protein. We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes. As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings. To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study. Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of human immune system. We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy."

Study co-author Professor Timothy Tree, from King's College London, said: "Through studying this one set of siblings -- unique in the world to our knowledge -- we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for 'everyday' immune function. This leads us to the grand question; 'what is the role of PD-L1 in our pancreas making it critical for preventing our immune cells destroying our beta cells?' We know that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to work out the "communication" between different cell types that is critical for preventing autoimmune diabetes.

"This finding increases our knowledge of how autoimmune forms of diabetes such as type 1 diabetes develop. It opens up a new potential target for treatments that could prevent diabetes in the future. Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a type 1 diabetes treatment -- our findings will help accelerate the search for new and better drugs."

Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: "Pioneering treatments that alter the behaviour of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the USA, and are awaiting approval here in the UK.

"By zeroing in on the precise role of an important player in the type 1 diabetes immune attack, this exciting discovery could pave the way for treatments that are more effective, more targeted and more transformational for people with or at risk of type 1 diabetes."

Helmsley Program Officer Ben Williams said: "New drugs often fail in development because scientific discoveries made in animal models don't translate into humans. As such, drug developers strongly prefer to pursue new drugs where human genetic evidence supports the drug's target. This study provides such compelling evidence that PD-L1 is a high-priority target to treat T1D, and should be pursued with the ambition of eventually reducing the burden of this difficult to manage disease."

The paper is entitled 'Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency' and is published in the Journal of Experimental Medicine. The research was supported by the National Institute of Health and Care Research (NIHR) Exeter Biomedical Research Centre and The NIHR Exeter Clinical Research Facility.

• Immune System
• Personalized Medicine
• Diseases and Conditions
• Hormone Disorders
• Medical Topics
• Diabetes mellitus type 1
• Diabetes mellitus type 2
• Erectile dysfunction
• Gene therapy
• Alzheimer's disease

Story Source:

Materials provided by University of Exeter . Original written by Louise Vennells. Note: Content may be edited for style and length.

Journal Reference :

• Matthew B. Johnson et al. Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency . JEM , 2024 DOI: 10.1084/jem.20231704

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