new research on diabetes care

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Pharmacological Reviews

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

• Ackeifi C, Swartz E, Kumar K, Liu H, Chalada S, Karakose E, Scott DK, Garcia-Ocaña A, Sanchez R, DeVita RJ, et al. (2020) Pharmacologic and genetic approaches define human pancreatic β cell mitogenic targets of DYRK1A inhibitors . JCI Insight 5 :e132594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Adachi T, Yasuda K, Okamoto Y, Shihara N, Oku A, Ueta K, Kitamura K, Saito A, Iwakura I, Yamada Y, et al. (2000) T-1095, a renal Na+-glucose transporter inhibitor, improves hyperglycemia in streptozotocin-induced diabetic rats . Metabolism 49 :990–995. [ PubMed ] [ Google Scholar ]
• Alexiadou K, Tan TM (2020) Gastrointestinal peptides as therapeutic targets to mitigate obesity and metabolic syndrome . Curr Diab Rep 20 :26. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, Tsai LF, Robertson D, Jain M, Petrone M, et al. (2018) MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study . Lancet 391 :2607–2618. [ PubMed ] [ Google Scholar ]
• Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta-cell . Prog Biophys Mol Biol 54 :87–143. [ PubMed ] [ Google Scholar ]
• Ashcroft FM, Rorsman P (1990) ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion . Biochem Soc Trans 18 :109–111. [ PubMed ] [ Google Scholar ]
• Baeyens L, Hindi S, Sorenson RL, German MS (2016) β-Cell adaptation in pregnancy . Diabetes Obes Metab 18 ( Suppl 1 ):63–70. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bailey CJ (1992) Biguanides and NIDDM . Diabetes Care 15 :755–772. [ PubMed ] [ Google Scholar ]
• Ben Nasr M, Tezza S, D’Addio F, Mameli C, Usuelli V, Maestroni A, Corradi D, Belletti S, Albarello L, Becchi G, et al. (2017) PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes . Sci Transl Med 9 :eaam7543. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bergmann NC, Lund A, Gasbjerg LS, Meessen ECE, Andersen MM, Bergmann S, Hartmann B, Holst JJ, Jessen L, Christensen MB, et al. (2019) Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study . Diabetologia 62 :665–675. [ PubMed ] [ Google Scholar ]
• Bernal-Mizrachi E, Kulkarni RN, Scott DK, Mauvais-Jarvis F, Stewart AF, Garcia-Ocaña A (2014) Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map . Diabetes 63 :819–831. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, Pagidipati NJ, Chan JC, Gustavson SM, Iqbal N, et al.; EXSCEL Study Group (2018) Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis . Lancet Diabetes Endocrinol 6 :105–113. [ PubMed ] [ Google Scholar ]
• Bliss M (1982) Banting’s, Best’s, and Collip’s accounts of the discovery of insulin . Bull Hist Med 56 :554–568. [ PubMed ] [ Google Scholar ]
• Bochenek MA, Veiseh O, Vegas AJ, McGarrigle JJ, Qi M, Marchese E, Omami M, Doloff JC, Mendoza-Elias J, Nourmohammadzadeh M, et al. (2018) Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques . Nat Biomed Eng 2 :810–821. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, et al. (2015) Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion . Nat Med 21 :512–517. [ PubMed ] [ Google Scholar ]
• Bonora E, Cigolini M, Bosello O, Zancanaro C, Capretti L, Zavaroni I, Coscelli C, Butturini U (1984) Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects . Curr Med Res Opin 9 :47–51. [ PubMed ] [ Google Scholar ]
• Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis . N Engl J Med 313 :353–360. [ PubMed ] [ Google Scholar ]
• Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF (2010) Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence . Popul Health Metr 8 :29. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Rodrigues B, Johnson JD, Parks JS, et al. (2007) Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment . Nat Med 13 :340–347. [ PubMed ] [ Google Scholar ]
• Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M (2016) The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies . Diabetes Care 39 :198–205. [ PubMed ] [ Google Scholar ]
• Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes . Diabetes Care 27 :2628–2635. [ PubMed ] [ Google Scholar ]
• Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD, Lin H, Jaffe JL, Coch RW, Haldeman JM, MacDonald PE, et al. (2019a) β Cell tone is defined by proglucagon peptides through cAMP signaling . JCI Insight 4 :e126742. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Capozzi ME, Wait JB, Koech J, Gordon AN, Coch RW, Svendsen B, Finan B, D’Alessio DA, Campbell JE (2019b) Glucagon lowers glycemia when β-cells are active . JCI Insight 5 :e129954. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Carboneau BA, Allan JA, Townsend SE, Kimple ME, Breyer RM, Gannon M (2017) Opposing effects of prostaglandin E 2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation . Mol Metab 6 :548–559. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chae H, Augustin R, Gatineau E, Mayoux E, Bensellam M, Antoine N, Khattab F, Lai BK, Brusa D, Stierstorfer B, et al. (2020) SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans . Mol Metab 42 :101071. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chamberlain CE, Scheel DW, McGlynn K, Kim H, Miyatsuka T, Wang J, Nguyen V, Zhao S, Mavropoulos A, Abraham AG, et al. (2014) Menin determines K-RAS proliferative outputs in endocrine cells . J Clin Invest 124 :4093–4101. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK (2011) PDGF signalling controls age-dependent proliferation in pancreatic β-cells . Nature 478 :349–355. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen H, Kleinberger JW, Takane KK, Salim F, Fiaschi-Taesch N, Pappas K, Parsons R, Jiang J, Zhang Y, Liu H, et al. (2015) Augmented Stat5 signaling bypasses multiple impediments to lactogen-mediated proliferation in human β-cells . Diabetes 64 :3784–3797. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen J, Cha-Molstad H, Szabo A, Shalev A (2009) Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein . Am J Physiol Endocrinol Metab 296 :E1133–E1139. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen J, Hui ST, Couto FM, Mungrue IN, Davis DB, Attie AD, Lusis AJ, Davis RA, Shalev A (2008a) Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes . FASEB J 22 :3581–3594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A (2008b) Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis . Diabetes 57 :938–944. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chou DH, Webber MJ, Tang BC, Lin AB, Thapa LS, Deng D, Truong JV, Cortinas AB, Langer R, Anderson DG (2015) Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates . Proc Natl Acad Sci USA 112 :2401–2406. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P (2017) Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic β cells . Mol Metab 6 :1024–1039. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR (2003) Oxyntomodulin suppresses appetite and reduces food intake in humans . J Clin Endocrinol Metab 88 :4696–4701. [ PubMed ] [ Google Scholar ]
• Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, et al. (2020) GDF15 mediates the effects of metformin on body weight and energy balance . Nature 578 :444–448. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Colli ML, Hill JLE, Marroquí L, Chaffey J, Dos Santos RS, Leete P, Coomans de Brachène A, Paula FMM, Op de Beeck A, Castela A, et al. (2018) PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction . EBioMedicine 36 :367–375. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• RISE Consortium (2019) Lack of durable improvements in β-cell function following withdrawal of pharmacological interventions in adults with impaired glucose tolerance or recently diagnosed type 2 diabetes . Diabetes Care 42 :1742–1751. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, et al. (2017) Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling . J Clin Invest 127 :3835–3844. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dai C, Kayton NS, Shostak A, Poffenberger G, Cyphert HA, Aramandla R, Thompson C, Papagiannis IG, Emfinger C, Shiota M, et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets . J Clin Invest 126 :1857–1870. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dai C, Walker JT, Shostak A, Bouchi Y, Poffenberger G, Hart NJ, Jacobson DA, Calcutt MW, Bottino R, Greiner DL, et al. (2020) Dapagliflozin does not directly affect human α or β cells . Endocrinology 161 :bqaa080. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, Bloom SR (2001) Oxyntomodulin inhibits food intake in the rat . Endocrinology 142 :4244–4250. [ PubMed ] [ Google Scholar ]
• Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR (2002) Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats . Am J Physiol Endocrinol Metab 283 :E1173–E1177. [ PubMed ] [ Google Scholar ]
• Defronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Gastaldelli A, Henry RR, Kitabchi AE, et al.; ACT NOW Study (2013) Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates . Diabetes 62 :3920–3926. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Delaunay F, Khan A, Cintra A, Davani B, Ling ZC, Andersson A, Ostenson CG, Gustafsson J, Efendic S, Okret S (1997) Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids . J Clin Invest 100 :2094–2098. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Desai T, Shea LD (2017) Advances in islet encapsulation technologies . Nat Rev Drug Discov 16 :338–350. [ PubMed ] [ Google Scholar ]
• Devaraj S, Venkatachalam A, Chen X (2016) Metformin and the gut microbiome in diabetes . Clin Chem 62 :1554–1555. [ PubMed ] [ Google Scholar ]
• Doloff JC, Veiseh O, Vegas AJ, Tam HH, Farah S, Ma M, Li J, Bader A, Chiu A, Sadraei A, et al. (2017) Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates . Nat Mater 16 :671–680. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Donath MY, Dinarello CA, Mandrup-Poulsen T (2019) Targeting innate immune mediators in type 1 and type 2 diabetes . Nat Rev Immunol 19 :734–746. [ PubMed ] [ Google Scholar ]
• Drucker DJ (2018) Mechanisms of action and therapeutic application of glucagon-like peptide-1 . Cell Metab 27 :740–756. [ PubMed ] [ Google Scholar ]
• Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF (1987) Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line . Proc Natl Acad Sci USA 84 :3434–3438. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Duca FA, Côté CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, Lam TK (2015) Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats . Nat Med 21 :506–511. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Eguchi K, Nagai R (2017) Islet inflammation in type 2 diabetes and physiology . J Clin Invest 127 :14–23. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• El Khatib MM, Sakuma T, Tonne JM, Mohamed MS, Holditch SJ, Lu B, Kudva YC, Ikeda Y (2015) β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection . Gene Ther 22 :430–438. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• El-Khatib FH, Balliro C, Hillard MA, Magyar KL, Ekhlaspour L, Sinha M, Mondesir D, Esmaeili A, Hartigan C, Thompson MJ, et al. (2017) Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial . Lancet 389 :369–380. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• El-Mir MY, Detaille D, R-Villanueva G, Delgado-Esteban M, Guigas B, Attia S, Fontaine E, Almeida A, Leverve X (2008) Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons . J Mol Neurosci 34 :77–87. [ PubMed ] [ Google Scholar ]
• El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I . J Biol Chem 275 :223–228. [ PubMed ] [ Google Scholar ]
• Elrick H, Stimmler L, Hlad CJ Jr, Arai Y (1964) Plasma Insulin Response to Oral and Intravenous Glucose Administration . J Clin Endocrinol Metab 24 :1076–1082. [ PubMed ] [ Google Scholar ]
• Engin F, Yermalovich A, Nguyen T, Hummasti S, Fu W, Eizirik DL, Mathis D, Hotamisligil GS (2013) Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes [published correction appears in Sci Transl Med (2013) 5 :214er11] . Sci Transl Med 5 :211ra156. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients . BMJ 330 :1304–1305. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Evans-Molina C, Robbins RD, Kono T, Tersey SA, Vestermark GL, Nunemaker CS, Garmey JC, Deering TG, Keller SR, Maier B, et al. (2009) Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure . Mol Cell Biol 29 :2053–2067. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Fernández-Real JM, López-Bermejo A, Ropero AB, Piquer S, Nadal A, Bassols J, Casamitjana R, Gomis R, Arnaiz E, Pérez I, et al. (2008) Salicylates increase insulin secretion in healthy obese subjects . J Clin Endocrinol Metab 93 :2523–2530. [ PubMed ] [ Google Scholar ]
• Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B (2014) Metformin: from mechanisms of action to therapies . Cell Metab 20 :953–966. [ PubMed ] [ Google Scholar ]
• Foretz M, Guigas B, Viollet B (2019) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus . Nat Rev Endocrinol 15 :569–589. [ PubMed ] [ Google Scholar ]
• Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state . J Clin Invest 120 :2355–2369. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Frias JPBastyr EJ 3rd, Vignati L, Tschöp MH, Schmitt C, Owen K, Christensen RHDiMarchi RD (2017) The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes . Cell Metab 26 :343–352.e2. [ PubMed ] [ Google Scholar ]
• Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA (2020) Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens . Diabetes Obes Metab 22 :938–946. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, et al. (2018) Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial . Lancet 392 :2180–2193. [ PubMed ] [ Google Scholar ]
• Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O’Neill HM, Ford RJ, Palanivel R, O’Brien M, et al. (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin . Nat Med 19 :1649–1654. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, et al.; REWIND Investigators (2019) Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial . Lancet 394 :121–130. [ PubMed ] [ Google Scholar ]
• Giugliano D, Ceriello A, Saccomanno F, Quatraro A, Paolisso G, D’Onofrio F (1985) Effects of salicylate, tolbutamide, and prostaglandin E2 on insulin responses to glucose in noninsulin-dependent diabetes mellitus . J Clin Endocrinol Metab 61 :160–166. [ PubMed ] [ Google Scholar ]
• Goudy KS, Tisch R (2005) Immunotherapy for the prevention and treatment of type 1 diabetes . Int Rev Immunol 24 :307–326. [ PubMed ] [ Google Scholar ]
• Gregg BE, Moore PC, Demozay D, Hall BA, Li M, Husain A, Wright AJ, Atkinson MA, Rhodes CJ (2012) Formation of a human β-cell population within pancreatic islets is set early in life . J Clin Endocrinol Metab 97 :3197–3206. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P (2012) Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors . Diabetes Obes Metab 14 :83–90. [ PubMed ] [ Google Scholar ]
• Harlan DM (2016) Islet transplantation for hypoglycemia unawareness/severe hypoglycemia: caveat emptor . Diabetes Care 39 :1072–1074. [ PubMed ] [ Google Scholar ]
• Harrower AD (1991) Efficacy of gliclazide in comparison with other sulphonylureas in the treatment of NIDDM . Diabetes Res Clin Pract 14 ( Suppl 2 ):S65–S67. [ PubMed ] [ Google Scholar ]
• He L, Wondisford FE (2015) Metformin action: concentrations matter . Cell Metab 21 :159–162. [ PubMed ] [ Google Scholar ]
• Hedrington MS, Davis SN (2019) Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes . Expert Opin Pharmacother 20 :2229–2235. [ PubMed ] [ Google Scholar ]
• Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, et al.; Clinical Islet Transplantation Consortium (2016) Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia . Diabetes Care 39 :1230–1240. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, Matsumoto I, Ihm SH, Zhang HJ, Parkey J, et al. (2005) Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes . JAMA 293 :830–835. [ PubMed ] [ Google Scholar ]
• Hernandez AFGreen JBJanmohamed SD’Agostino RB Sr , Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MCet al.; Harmony Outcomes committees and investigators (2018) Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial . Lancet 392 :1519–1529. [ PubMed ] [ Google Scholar ]
• Hiatt WR, Kaul S, Smith RJ (2013) The cardiovascular safety of diabetes drugs--insights from the rosiglitazone experience . N Engl J Med 369 :1285–1287. [ PubMed ] [ Google Scholar ]
• Hirshberg B, Preston EH, Xu H, Tal MG, Neeman Z, Bunnell D, Soleimanpour S, Hale DA, Kirk AD, Harlan DM (2003) Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model . Transplantation 76 :55–60. [ PubMed ] [ Google Scholar ]
• Hu W, Jiang C, Guan D, Dierickx P, Zhang R, Moscati A, Nadkarni GN, Steger DJ, Loos RJF, Hu C, et al. (2019) Patient adipose stem cell-derived adipocytes reveal genetic variation that predicts antidiabetic drug response . Cell Stem Cell 24 :299–308.e6. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, et al.; PIONEER 6 Investigators (2019) Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes . N Engl J Med 381 :841–851. [ PubMed ] [ Google Scholar ]
• Imamura M, Nakanishi K, Suzuki T, Ikegai K, Shiraki R, Ogiyama T, Murakami T, Kurosaki E, Noda A, Kobayashi Y, et al. (2012) Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus . Bioorg Med Chem 20 :3263–3279. [ PubMed ] [ Google Scholar ]
• Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, et al.; ADOPT Study Group (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy . N Engl J Med 355 :2427–2443. [ PubMed ] [ Google Scholar ]
• Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, Kravitz BG, Herman WH, Viberti G, Holman RR; ADOPT Study Group (2011) Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT . Diabetes 60 :1552–1560. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, et al. (2010) Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women . Diabetes 59 :1899–1905. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kemp CB, Knight MJ, Scharp DW, Lacy PE, Ballinger WF (1973) Transplantation of isolated pancreatic islets into the portal vein of diabetic rats . Nature 244 :447. [ PubMed ] [ Google Scholar ]
• Kim HI, Cha JY, Kim SY, Kim JW, Roh KJ, Seong JK, Lee NT, Choi KY, Kim KS, Ahn YH (2002) Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells . Diabetes 51 :676–685. [ PubMed ] [ Google Scholar ]
• Kim HI, Kim JW, Kim SH, Cha JY, Kim KS, Ahn YH (2000) Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter . Diabetes 49 :1517–1524. [ PubMed ] [ Google Scholar ]
• Kim SH, Liu A, Ariel D, Abbasi F, Lamendola C, Grove K, Tomasso V, Ochoa H, Reaven G (2014) Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study . Diabetes Care 37 :1944–1950. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Koffert JP, Mikkola K, Virtanen KA, Andersson AD, Faxius L, Hällsten K, Heglind M, Guiducci L, Pham T, Silvola JMU, et al. (2017) Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial . Diabetes Res Clin Pract 131 :208–216. [ PubMed ] [ Google Scholar ]
• Koh A, Mannerås-Holm L, Yunn NO, Nilsson PM, Ryu SH, Molinaro A, Perkins R, Smith JG, Bäckhed F (2020) Microbial imidazole propionate affects responses to metformin through p38γ-dependent inhibitory AMPK phosphorylation . Cell Metab 32 :643–653.e4. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kreymann B, Williams G, Ghatei MA, Bloom SR (1987) Glucagon-like peptide-1 7-36: a physiological incretin in man . Lancet 2 :1300–1304. [ PubMed ] [ Google Scholar ]
• Kuhre RE, Ghiasi SM, Adriaenssens AE, Wewer Albrechtsen NJ, Andersen DB, Aivazidis A, Chen L, Mandrup-Poulsen T, Ørskov C, Gribble FM, et al. (2019) No direct effect of SGLT2 activity on glucagon secretion . Diabetologia 62 :1011–1023. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kulkarni RN, Mizrachi EB, Ocana AG, Stewart AF (2012) Human β-cell proliferation and intracellular signaling: driving in the dark without a road map . Diabetes 61 :2205–2213. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kurosaki E, Ogasawara H (2013) Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data . Pharmacol Ther 139 :51–59. [ PubMed ] [ Google Scholar ]
• Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, Trüb T (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use . Diabetes 49 :999–1005. [ PubMed ] [ Google Scholar ]
• Lambeir AM, Scharpé S, De Meester I (2008) DPP4 inhibitors for diabetes--what next? Biochem Pharmacol 76 :1637–1643. [ PubMed ] [ Google Scholar ]
• Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes . Diabetologia 50 :752–763. [ PubMed ] [ Google Scholar ]
• Lebovitz HE (2019) Thiazolidinediones: the forgotten diabetes medications . Curr Diab Rep 19 :151. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, Ehrlich SF, Mamtani R, Bilker W, Vaughn DJ, et al. (2015) Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes . JAMA 314 :265–277. [ PubMed ] [ Google Scholar ]
• Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, Zhang L, Shen J, Bala MM, Sohani ZN, et al. (2016) Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies . BMJ 352 :i610. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Link JT (2003) Pharmacological regulation of hepatic glucose production . Curr Opin Investig Drugs 4 :421–429. [ PubMed ] [ Google Scholar ]
• Luippold G, Klein T, Mark M, Grempler R (2012) Empagliflozin, a novel potent and selective SGLT-2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin-induced diabetic rats, a model of type 1 diabetes mellitus . Diabetes Obes Metab 14 :601–607. [ PubMed ] [ Google Scholar ]
• Maganti AV, Tersey SA, Syed F, Nelson JB, Colvin SC, Maier B, Mirmira RG (2016) Peroxisome proliferator-activated receptor-γ activation augments the β-cell unfolded protein response and rescues early glycemic deterioration and β cell death in non-obese diabetic mice . J Biol Chem 291 :22524–22533. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Makrilakis K (2019) The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expect . Int J Environ Res Public Health 16 :2720. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M (2007) The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients . Diabetologia 50 :2486–2494. [ PubMed ] [ Google Scholar ]
• Marhfour I, Lopez XM, Lefkaditis D, Salmon I, Allagnat F, Richardson SJ, Morgan NG, Eizirik DL (2012) Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes . Diabetologia 55 :2417–2420. [ PubMed ] [ Google Scholar ]
• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, et al.; SUSTAIN-6 Investigators (2016a) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes . N Engl J Med 375 :1834–1844. [ PubMed ] [ Google Scholar ]
• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al.; LEADER Steering Committee; LEADER Trial Investigators (2016b) Liraglutide and cardiovascular outcomes in type 2 diabetes . N Engl J Med 375 :311–322. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Massollo M, Marini C, Brignone M, Emionite L, Salani B, Riondato M, Capitanio S, Fiz F, Democrito A, Amaro A, et al. (2013) Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice . J Nucl Med 54 :259–266. [ PubMed ] [ Google Scholar ]
• McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract . Diabetologia 59 :426–435. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• McIntyre N, Holdsworth CD, Turner DS (1964) New interpretation of oral glucose tolerance . Lancet 2 :20–21. [ PubMed ] [ Google Scholar ]
• McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, et al.; DAPA-HF Trial Committees and Investigators (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction . N Engl J Med 381 :1995–2008. [ PubMed ] [ Google Scholar ]
• Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans . Diabetes 57 :1584–1594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, et al. (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes . J Med Chem 51 :1145–1149. [ PubMed ] [ Google Scholar ]
• Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Záková L, Kletvíková E, Jiráček J, et al. (2013) How insulin engages its primary binding site on the insulin receptor . Nature 493 :241–245. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP . Nature 494 :256–260. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Minkowski O (1892) Weitere Mitteilungen über den Diabetes mellitus nach Extirpation des Pankreas . Berliner Klinische Wochenschrift 29 :90–93. [ Google Scholar ]
• Misbin RI (2004) The phantom of lactic acidosis due to metformin in patients with diabetes . Diabetes Care 27 :1791–1793. [ PubMed ] [ Google Scholar ]
• Mudaliar S, Armstrong DA, Mavian AA, O’Connor-Semmes R, Mydlow PK, Ye J, Hussey EK, Nunez DJ, Henry RR, Dobbins RL (2012) Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2, improves serum glucose profiles in type 1 diabetes . Diabetes Care 35 :2198–2200. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL (2011) Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell . Endocrinology 152 :4610–4619. [ PubMed ] [ Google Scholar ]
• Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, et al. (2019) Glucagon-like peptide 1 (GLP-1) . Mol Metab 30 :72–130. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Munir KM, Lamos EM (2017) Diabetes type 2 management: what are the differences between DPP-4 inhibitors and how do you choose? Expert Opin Pharmacother 18 :839–841. [ PubMed ] [ Google Scholar ]
• Naftanel MA, Harlan DM (2004) Pancreatic islet transplantation . PLoS Med 1 :e58. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Nauck M, Stöckmann F, Ebert R, Creutzfeldt W (1986a) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes . Diabetologia 29 :46–52. [ PubMed ] [ Google Scholar ]
• Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W (1986b) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses . J Clin Endocrinol Metab 63 :492–498. [ PubMed ] [ Google Scholar ]
• Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, et al.; Wellcome Trust Case Control Consortium (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A . Nature 450 :887–892. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism . Nature 440 :470–476. [ PubMed ] [ Google Scholar ]
• Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, et al. (2010) Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus . J Med Chem 53 :6355–6360. [ PubMed ] [ Google Scholar ]
• Ohnishi ST, Endo M, editors. (1981) The Mechanism of Gated Calcium Transport Across Biological Membranes , Academic Press, New York. [ Google Scholar ]
• Osipovich AB, Stancill JS, Cartailler JP, Dudek KD, Magnuson MA (2020) Excitotoxicity and overnutrition additively impair metabolic function and identity of pancreatic β-cells . Diabetes 69 :1476–1491. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Osum KC, Burrack AL, Martinov T, Sahli NL, Mitchell JS, Tucker CG, Pauken KE, Papas K, Appakalai B, Spanier JA, et al. (2018) Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes . Sci Rep 8 :8295. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain . Biochem J 348 :607–614. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ozanne SE, Guest PC, Hutton JC, Hales CN (1995) Intracellular localization and molecular heterogeneity of the sulphonylurea receptor in insulin-secreting cells . Diabetologia 38 :277–282. [ PubMed ] [ Google Scholar ]
• Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes . Science 313 :1137–1140. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Paty BW, Harmon JS, Marsh CL, Robertson RP (2002) Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets . Transplantation 73 :353–357. [ PubMed ] [ Google Scholar ]
• Penesova A, Koska J, Ortega E, Bunt JC, Bogardus C, de Courten B (2015) Salsalate has no effect on insulin secretion but decreases insulin clearance: a randomized, placebo-controlled trial in subjects without diabetes . Diabetes Obes Metab 17 :608–612. [ PubMed ] [ Google Scholar ]
• Perdigoto AL, Quandt Z, Anderson M, Herold KC (2019) Checkpoint inhibitor-induced insulin-dependent diabetes: an emerging syndrome . Lancet Diabetes Endocrinol 7 :421–423. [ PubMed ] [ Google Scholar ]
• Perley MJ, Kipnis DM (1967) Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects . J Clin Invest 46 :1954–1962. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Pernicova I, Korbonits M (2014) Metformin--mode of action and clinical implications for diabetes and cancer . Nat Rev Endocrinol 10 :143–156. [ PubMed ] [ Google Scholar ]
• Preiss D, Dawed A, Welsh P, Heggie A, Jones AG, Dekker J, Koivula R, Hansen TH, Stewart C, Holman RR, et al.; DIRECT consortium group (2017) Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes . Diabetes Obes Metab 19 :356–363. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes . J Clin Invest 116 :1802–1812. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Pueyo ME, Darquy S, Capron F, Reach G (1993) In vitro activation of human macrophages by alginate-polylysine microcapsules . J Biomater Sci Polym Ed 5 :197–203. [ PubMed ] [ Google Scholar ]
• Pybus F (1924) Notes on suprarenal and pancreatic grafting . Lancet 204 :550–551. [ Google Scholar ]
• Quattrin T, Haller MJ, Steck AK, Felner EI, Li Y, Xia Y, Leu JH, Zoka R, Hedrick JA, Rigby MR, et al.; T1GER Study Investigators (2020) Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes . N Engl J Med 383 :2007–2017. [ PubMed ] [ Google Scholar ]
• Rachdi L, Kariyawasam D, Aïello V, Herault Y, Janel N, Delabar JM, Polak M, Scharfmann R (2014a) Dyrk1A induces pancreatic β cell mass expansion and improves glucose tolerance . Cell Cycle 13 :2221–2229. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rachdi L, Kariyawasam D, Guez F, Aïello V, Arbonés ML, Janel N, Delabar JM, Polak M, Scharfmann R (2014b) Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass . Diabetologia 57 :960–969. [ PubMed ] [ Google Scholar ]
• Rege NK, Phillips NFB, Weiss MA (2017) Development of glucose-responsive ‘smart’ insulin systems . Curr Opin Endocrinol Diabetes Obes 24 :267–278. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin . Diabetologia 60 :1577–1585. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rewers M, Gottlieb P (2009) Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future . Diabetes Care 32 :1769–1782. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA, Zeissler M, Leete P, Krogvold L, Dahl-Jørgensen K, et al. (2016) Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes . Diabetologia 59 :2448–2458. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rickels MR, Liu C, Shlansky-Goldberg RD, Soleimanpour SA, Vivek K, Kamoun M, Min Z, Markmann E, Palangian M, Dalton-Bakes C, et al. (2013) Improvement in β-cell secretory capacity after human islet transplantation according to the c7 protocol . Diabetes 62 :2890–2897. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rickels MR, Robertson RP (2019) Pancreatic islet transplantation in humans: recent progress and future directions . Endocr Rev 40 :631–668. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rodriguez-Calvo T, Suwandi JS, Amirian N, Zapardiel-Gonzalo J, Anquetil F, Sabouri S, von Herrath MG (2015) Heterogeneity and lobularity of pancreatic pathology in type 1 diabetes during the prediabetic phase . J Histochem Cytochem 63 :626–636. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rojas LB, Gomes MB (2013) Metformin: an old but still the best treatment for type 2 diabetes . Diabetol Metab Syndr 5 :6. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rosen ED, Kulkarni RN, Sarraf P, Ozcan U, Okada T, Hsu CH, Eisenman D, Magnuson MA, Gonzalez FJ, Kahn CR, et al. (2003) Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis . Mol Cell Biol 23 :7222–7229. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N, Hale PM; Repaglinide Versus Nateglinide Comparison Study Group (2004) Repaglinide versus nateglinide monotherapy: a randomized, multicenter study . Diabetes Care 27 :1265–1270. [ PubMed ] [ Google Scholar ]
• Sampaio MS, Kuo HT, Bunnapradist S (2011) Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients . Clin J Am Soc Nephrol 6 :1198–1206. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Saponaro C, Gmyr V, Thévenet J, Moerman E, Delalleau N, Pasquetti G, Coddeville A, Quenon A, Daoudi M, Hubert T, et al. (2019) The GLP1R agonist liraglutide reduces hyperglucagonemia induced by the SGLT2 inhibitor dapagliflozin via somatostatin release . Cell Rep 28 :1447–1454.e4. [ PubMed ] [ Google Scholar ]
• Saponaro C, Mühlemann M, Acosta-Montalvo A, Piron A, Gmyr V, Delalleau N, Moerman E, Thévenet J, Pasquetti G, Coddeville A, et al. (2020) Interindividual heterogeneity of SGLT2 expression and function in human pancreatic islets . Diabetes 69 :902–914. [ PubMed ] [ Google Scholar ]
• Satin LS, Tavalin SJ, Kinard TA, Teague J (1995) Contribution of L- and non-L-type calcium channels to voltage-gated calcium current and glucose-dependent insulin secretion in HIT-T15 cells . Endocrinology 136 :4589–4601. [ PubMed ] [ Google Scholar ]
• Schwartz AV, Chen H, Ambrosius WT, Sood A, Josse RG, Bonds DE, Schnall AM, Vittinghoff E, Bauer DC, Banerji MA, et al. (2015) Effects of TZD use and discontinuation on fracture rates in ACCORD Bone Study . J Clin Endocrinol Metab 100 :4059–4066. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Shalev A, Pise-Masison CA, Radonovich M, Hoffmann SC, Hirshberg B, Brady JN, Harlan DM (2002) Oligonucleotide microarray analysis of intact human pancreatic islets: identification of glucose-responsive genes and a highly regulated TGFbeta signaling pathway . Endocrinology 143 :3695–3698. [ PubMed ] [ Google Scholar ]
• Shankar SS, Shankar RR, Mixson LA, Miller DL, Pramanik B, O’Dowd AK, Williams DM, Frederick CB, Beals CR, Stoch SA, et al. (2018) Native oxyntomodulin has significant glucoregulatory effects independent of weight loss in obese humans with and without type 2 diabetes . Diabetes 67 :1105–1112. [ PubMed ] [ Google Scholar ]
• Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen . N Engl J Med 343 :230–238. [ PubMed ] [ Google Scholar ]
• Sharma RB, O’Donnell AC, Stamateris RE, Ha B, McCloskey KM, Reynolds PR, Arvan P, Alonso LC (2015) Insulin demand regulates β cell number via the unfolded protein response . J Clin Invest 125 :3831–3846. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sims EK, Mirmira RG, Evans-Molina C (2020) The role of beta-cell dysfunction in early type 1 diabetes . Curr Opin Endocrinol Diabetes Obes 27 :215–224. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soccio RE, Chen ER, Rajapurkar SR, Safabakhsh P, Marinis JM, Dispirito JR, Emmett MJ, Briggs ER, Fang B, Everett LJ, et al. (2015) Genetic variation determines PPARγ function and anti-diabetic drug response in vivo . Cell 162 :33–44. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soleimanpour SA, Crutchlow MF, Ferrari AM, Raum JC, Groff DN, Rankin MM, Liu C, De León DD, Naji A, Kushner JA, et al. (2010) Calcineurin signaling regulates human islet beta-cell survival . J Biol Chem 285 :40050–40059. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soleimanpour SA, Hirshberg B, Bunnell DJ, Sumner AE, Ader M, Remaley AT, Rother KI, Rickels MR, Harlan DM (2012) Metabolic function of a suboptimal transplanted islet mass in nonhuman primates on rapamycin monotherapy . Cell Transplant 21 :1297–1304. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soleimanpour SA, Stoffers DA (2013) The pancreatic β cell and type 1 diabetes: innocent bystander or active participant? Trends Endocrinol Metab 24 :324–331. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, et al. (2018) Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors . Diabetes 67 :1471–1480. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stancill JS, Cartailler JP, Clayton HW, O’Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA (2017) Chronic β-cell depolarization impairs β-cell identity by disrupting a network of Ca 2+ -regulated genes . Diabetes 66 :2175–2187. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stewart AF, Hussain MA, García-Ocaña A, Vasavada RC, Bhushan A, Bernal-Mizrachi E, Kulkarni RN (2015) Human β-cell proliferation and intracellular signaling: part 3 . Diabetes 64 :1872–1885. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stojanovic I, Dimitrijevic M, Vives-Pi M, Mansilla MJ, Pujol-Autonell I, Rodríguez-Fernandez S, Palova-Jelínkova L, Funda DP, Gruden-Movsesijan A, Sofronic-Milosavljevic L, et al. (2017) Cell-based tolerogenic therapy, experience from animal models of multiple sclerosis, type 1 diabetes and rheumatoid arthritis . Curr Pharm Des 23 :2623–2643. [ PubMed ] [ Google Scholar ]
• Sturek JM, Castle JD, Trace AP, Page LC, Castle AM, Evans-Molina C, Parks JS, Mirmira RG, Hedrick CC (2010) An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells . J Clin Invest 120 :2575–2589. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Suga T, Kikuchi O, Kobayashi M, Matsui S, Yokota-Hashimoto H, Wada E, Kohno D, Sasaki T, Takeuchi K, Kakizaki S, et al. (2019) SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels . Mol Metab 19 :1–12. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, Liu J, Deng Y, Xia J, Chen B, et al. (2018) Gut microbiota and intestinal FXR mediate the clinical benefits of metformin . Nat Med 24 :1919–1929. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sutherland DE, Matas AJ, Najarian JS (1978) Pancreatic islet cell transplantation . Surg Clin North Am 58 :365–382. [ PubMed ] [ Google Scholar ]
• Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC, Evans-Molina C, Rickus JL, Maier B, Mirmira RG (2012) Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model . Diabetes 61 :818–827. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Thielen LA, Chen J, Jing G, Moukha-Chafiq O, Xu G, Jo S, Grayson TB, Lu B, Li P, Augelli-Szafran CE, et al. (2020) Identification of an anti-diabetic, orally available small molecule that regulates TXNIP expression and glucagon action . Cell Metab 32 :353–365.e8. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, Keil S, Haack T, Wagner M, Bossart M, et al. (2019) A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials . Diabetes Obes Metab 21 :120–128. [ PubMed ] [ Google Scholar ]
• Vallon V (2015) The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus . Annu Rev Med 66 :255–270. [ PubMed ] [ Google Scholar ]
• Vasseur M, Debuyser A, Joffre M (1987) Sensitivity of pancreatic beta cell to calcium channel blockers. An electrophysiologic study of verapamil and nifedipine . Fundam Clin Pharmacol 1 :95–113. [ PubMed ] [ Google Scholar ]
• Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K, et al. (2016) Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates . Nat Biotechnol 34 :345–352. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Vergari E, Knudsen JG, Ramracheya R, Salehi A, Zhang Q, Adam J, Asterholm IW, Benrick A, Briant LJB, Chibalina MV, et al. (2019) Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion . Nat Commun 10 :139. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wallner K, Shapiro AM, Senior PA, McCabe C (2016) Cost effectiveness and value of information analyses of islet cell transplantation in the management of ‘unstable’ type 1 diabetes mellitus . BMC Endocr Disord 16 :17. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wang H, Bender A, Wang P, Karakose E, Inabnet WB, Libutti SK, Arnold A, Lambertini L, Stang M, Chen H, et al. (2017) Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas . Nat Commun 8 :767. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wang Y, An H, Liu T, Qin C, Sesaki H, Guo S, Radovick S, Hussain M, Maheshwari A, Wondisford FE, O’Rourke B, He L (2019) Metformin improves mitochondrial respiratory activity through activation of AMPK . Cell Rep 29 :1511–1523.e5. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Westerman J, Wirtz KW, Berkhout T, van Deenen LL, Radhakrishnan R, Khorana HG (1983) Identification of the lipid-binding site of phosphatidylcholine-transfer protein with phosphatidylcholine analogs containing photoactivable carbene precursors . Eur J Biochem 132 :441–449. [ PubMed ] [ Google Scholar ]
• World Health Organization (2020) World Health Organization Diabetes Fact Sheet . [ Google Scholar ]
• Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, Capozzi ME, van der Velden WJ, Stutsman C, Cardona GR, et al. (2020) Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist . JCI Insight 5 :e140532. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Williams P (1894) Notes on diabetes treated with extract and by grafts of sheep’s pancreas . BMJ 2 :1303–1304. [ Google Scholar ]
• Williamson RT (1901) On the treatment of glycosuria and diabetes mellitus with sodium salicylate . BMJ 1 :760–762. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Witters LA (2001) The blooming of the French lilac . J Clin Invest 108 :1105–1107. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al.; DECLARE–TIMI 58 Investigators (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes . N Engl J Med 380 :347–357. [ PubMed ] [ Google Scholar ]
• Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, et al. (2017) Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug . Nat Med 23 :850–858. [ PubMed ] [ Google Scholar ]
• Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA, et al. (2005) Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial . Diabetes 54 :2390–2395. [ PubMed ] [ Google Scholar ]
• Xu G, Chen J, Jing G, Shalev A (2012) Preventing β-cell loss and diabetes with calcium channel blockers . Diabetes 61 :848–856. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Yang JF, Gong X, Bakh NA, Carr K, Phillips NFB, Ismail-Beigi F, Weiss MA, Strano MS (2020) Connecting rodent and human pharmacokinetic models for the design and translation of glucose-responsive insulin . Diabetes 69 :1815–1826. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Yu O, Azoulay L, Yin H, Filion KB, Suissa S (2018) Sulfonylureas as initial treatment for type 2 diabetes and the risk of severe hypoglycemia . Am J Med 131 :317.e11–317.e22. [ PubMed ] [ Google Scholar ]
• Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action . J Clin Invest 108 :1167–1174. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al.; EMPA-REG OUTCOME Investigators (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes . N Engl J Med 373 :2117–2128. [ PubMed ] [ Google Scholar ]

About the Journal

"[T]he simple word Care may suffice to express [the journal’s] philosophical mission", "to promote better patient care by serving the expanded needs of all health professionals committed to the care of patients with diabetes."  More .

Editor-in-Chief

Steven E. Kahn, MB, ChB

Editorial Board

2022 JCR Metrics Impact Factor 16.2 (6th) Total Citations 83,788 (2nd) Eigenfactor 0.07696 (1st) Learn More

Diabetes Care "On Air"

Join co-hosts Alice Cheng, MD, FRCPC, and Michael Rickels, MD, MS, as they interview authors and discuss the latest high-impact research published in each monthly issue of  Diabetes Care . Available from most podcasting platforms.

Listen and follow today on  Apple Podcasts   |   Google Play   |   Amazon Music   |   Spotify

January Issue Highlights

Reports from the grade study, current issue highlights.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial

Comparative Effects of Randomized Second-line Therapy for Type 2 Diabetes on a Composite Outcome Incorporating Glycemic Control, Body Weight, and Hypoglycemia: An Analysis of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Association of Diabetic Ketoacidosis in Childhood New-Onset Type 1 Diabetes With Day of Presentation in Germany

Access the complete  Table of Contents .

Submit your artwork for the cover of Diabetes Care   

Calling all artists impacted by diabetes! Please consider submitting your original artwork for publication on the cover of an issue of Diabetes Care . Any subject or medium is welcome.  Learn more .

Follow Diabetes Care on X  

Join us on X @DiabetesCareADA to learn about recently published articles, along with your diabetes research community, and share ideas with fellow professionals. Find the newest published articles, information on related ADA podcasts, new professional book titles, and up-to-date diabetes news items. You can also follow ADA Publications on Facebook @adaPublications .

Article Collection: Reports from the GRADE Study

GRADE compared several classes of glucose-lowering agents for people with type 2 diabetes already being treated with lifestyle intervention and metformin. It assessed outcomes, side effects, and psychosocial measures to inform personalized treatment decisions in clinical practice.

ADA Releases Updated Clinical Practice Guidelines for 2024

The Standards of Care includes vital new and updated recommendations for the care of all people with diabetes or prediabetes. In this update, key themes include cardiovascular disease reduction, obesity treatment, type 1 diabetes diagnosis, bone health, behavioral and lifestyle considerations, and diabetes technology. 

Diabetes Care  "On Air" podcast

Listen here and follow on most podcast platforms.

• Online ISSN 1935-5548
• Print ISSN 0149-5992
• Diabetes Care
• Clinical Diabetes
• Diabetes Spectrum
• Standards of Medical Care in Diabetes
• Scientific Sessions Abstracts
• BMJ Open Diabetes Research & Care
• ShopDiabetes.org
• ADA Professional Books

Clinical Compendia

• Clinical Compendia Home
• Latest News
• DiabetesPro SmartBrief
• Special Collections
• DiabetesPro®
• Diabetes Food Hub™
• Insulin Affordability
• Know Diabetes By Heart™
• About the ADA
• Journal Policies
• For Reviewers
• Advertising in ADA Journals
• Reprints and Permission for Reuse
• Copyright Notice/Public Access Policy
• ADA Professional Membership
• ADA Member Directory
• Diabetes.org
• X (Twitter)
• Cookie Policy
• Accessibility
• Terms & Conditions
• Get Adobe Acrobat Reader
• © Copyright American Diabetes Association

This Feature Is Available To Subscribers Only

Sign In or Create an Account

American Diabetes Association Releases 2023 Standards of Care in Diabetes to Guide Prevention, Diagnosis, and Treatment for People Living with Diabetes

New guidelines include updates to recommendations around obesity, hypertension, heart failure medication, social determinants of health, and lipid management Today, the American Diabetes Association ® (ADA) published Standards of Care in Diabetes—2023 (Standards of Care) , comprehensive, evidence-based guidelines for the prevention, diagnosis, and treatment of diabetes. Based on the latest scientific research and clinical trials, the Standards of Care includes vital new and updated practice guidelines to care for people with diabetes and prediabetes, including for the diagnosis and treatment of youth and adults with type 1, type 2, or gestational diabetes; strategies for the prevention or delay of type 2 diabetes and associated comorbidities; and therapeutic approaches that can reduce complications, mitigate cardiovascular and renal risk, and improve health outcomes. “ADA’s mission is to prevent and cure diabetes, a chronic illness that requires continuous medical care, and the release of ADA’s Standards of Care is a critical part of that mission,” said Chuck Henderson, chief executive officer for the ADA. “This year’s annual report provides necessary guidance that considers the role health inequities play in the development of diabetes, particularly for vulnerable communities and communities of color disproportionately impacted by the disease. This guidance will ensure health care teams, clinicians and researchers treat the whole person.” Notable updates to the Standards of Care in Diabetes─2023 include:

•     Emphasis on supporting higher weight loss (up to 15%) based on the efficacy of and access to newer medications when appropriate
•     New recommendations related to sleep health and physical activity in people with diabetes
•     Broad consideration of social determinants of health in guiding the design and delivery of care
•     New hypertension diagnosis cut-offs (hypertension is now defined as a systolic blood pressure ≥130 mmHg or a diastolic blood pressure ≥80 mmHg)
•     The expanded role of SGLT2 inhibitor use in preserved and reduced heart failure ejection fraction
•     The role of finerenone in individuals with diabetes and chronic kidney disease with albuminuria
•     New lipid management recommendations suggesting lower LDL goals for high-risk individuals

“Evidence-based recommendations drive better care for all people with diabetes, including vulnerable communities and those at high risk. ADA’s Standards of Care are the gold standard for diabetes care and prevention that allows clinicians around the world to remain abreast of the rapidly changing healthcare landscape,” said Dr. Robert Gabbay, chief scientific and medical officer for the ADA.  Other noteworthy changes to the 2023 Standards of Care include:

•     Details on digital health, telehealth , and telemedicine and the benefits of these modalities of care delivery
•     The utility of point-of-care A1C testing for diabetes screening and diagnosis
•     An expanded “ Nonalcoholic Fatty Liver Disease ” (NAFLD) subsection
•     Screening for food insecurity by any member of the diabetes healthcare team
•     Updates in alignment with the Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
•     The use of technology in older adults with diabetes
•     The use of person-first and inclusive language
•     Updates in vaccination for people with diabetes 
•     Updates in COVID-19 and diabetes

The Standards of Care are reviewed and updated annually by the ADA’s Professional Practice Committee (PPC). “The field of diabetes is changing fast. ADA’s Standards of Care strives to provide up-to-date guidance using the best available evidence rigorously and comprehensively,” said Nuha ElSayed, MD, MMSc, PPC chair.  The committee is a multidisciplinary team of 20 leading U.S. experts in the field of diabetes care and includes physicians, nurse practitioners, certified diabetes care and education specialists, registered dietitians, pharmacists, methodologists, and others with experience in adult and pediatric endocrinology, epidemiology, public health, cardiovascular risk management, microvascular complications, preconception and pregnancy care, weight management, diabetes prevention, behavioral and mental health, inpatient care, and use of technology in diabetes management. Two designated representatives of the American College of Cardiology (ACC) participated in the subcommittee on the "Cardiovascular Disease and Risk Management" section. This section received endorsement from the ACC for the sixth consecutive year. New this year, the ADA garnered the expertise of specialized subject matter experts by adding them as committee members to the subsections on neuropathy, retinopathy, foot care, and non-alcoholic fatty liver disease.  Today, the Standards of Care in Diabetes—2023 is available online and is published as a supplement to the January 2023 issue of Diabetes Care ® . The online version will be annotated in real-time with necessary updates if new evidence or regulatory changes merit immediate incorporation through the “living” Standards of Care process. The ADA fosters broad dissemination through a shortened version of the guidelines, known as the Abridged Standards of Care , for primary care providers in its journal Clinical Diabetes ® and offers a convenient Standards of Care   app as well as a Standards of Care pocket chart. Other Standards of Care resources, including a webcast with continuing education credit and a full slide deck, can be found on the ADA’s professional website, DiabetesPro ® .

# # #  

About the American Diabetes Association The American Diabetes Association (ADA) is the nation’s leading voluntary health organization fighting to bend the curve on the diabetes epidemic and help people living with diabetes thrive. For 82 years, the ADA has driven discovery and research to treat, manage, and prevent diabetes while working relentlessly for a cure. Through advocacy, program development, and education we aim to improve the quality of life for the over 133 million Americans living with diabetes or prediabetes. Diabetes has brought us together. What we do next will make us Connected for Life. To learn more or to get involved, visit us at diabetes.org  or call 1-800-DIABETES (1-800-342-2383). Join the fight with us on Facebook ( American Diabetes Association ), Spanish Facebook ( Asociación Americana de la Diabetes ), LinkedIn ( American Diabetes Association ), Twitter ( @AmDiabetesAssn ), and Instagram ( @AmDiabetesAssn ).

Contact Virginia Cramer for press-related questions.

New Aspects of Diabetes Research and Therapeutic Development

Affiliations.

• 1 Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) [email protected]; [email protected]; [email protected].
• 2 Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.).
• PMID: 34193595
• PMCID: PMC8274312
• DOI: 10.1124/pharmrev.120.000160

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.

Trial registration: ClinicalTrials.gov NCT02239354 .

U.S. Government work not protected by U.S. copyright.

Publication types

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't
• Research Support, U.S. Gov't, Non-P.H.S.
• Diabetes Mellitus, Type 1*
• Diabetes Mellitus, Type 2* / drug therapy
• Hypoglycemic Agents / therapeutic use
• Hypoglycemic Agents

Associated data

• ClinicalTrials.gov/NCT02239354

Grants and funding

• R01 DK108921/DK/NIDDK NIH HHS/United States
• P30 DK020572/DK/NIDDK NIH HHS/United States
• U01 DK127747/DK/NIDDK NIH HHS/United States
• I01 BX004444/BX/BLRD VA/United States
• R01 DK046409/DK/NIDDK NIH HHS/United States

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• SPONSOR FEATURE Sponsor retains sole responsibility for the content of this article

Diabetes: Following the science in the search for a cure

Produced by

Diabetes is one of the priority cardiovascular, renal and metabolic diseases for which AstraZeneca is developing novel therapies. The global number of people living with diabetes is expected to rise to 700 million by 2045 1 . AstraZeneca’s ambition is not just to reduce the raised blood glucose typical of the disease, it is to tackle the underlying pathophysiological drivers in order to instigate diabetes remission, prevent diabetic complications and deaths and, ultimately, to deliver a cure.

“AstraZeneca recognises that diabetes is more than a disease of the pancreas, and our research is focused on the underlying mechanisms that link diabetes to comorbidities, especially the main causes of death from the disease, including myocardial infarction and stroke, as well as heart and kidney failure,” says David Baker, Head of Metabolism Bioscience, Biopharmaceuticals R&D.

Induce remission

New approaches for the treatment of type 2 diabetes aim to induce remission as soon as possible after diagnosis by achieving durable responses to novel medicines designed to target the causes of type 2 diabetes and its related complications.

Obesity and insulin resistance are two key drivers in the development of type 2 diabetes, and are also connected to the development of diseases of the heart and circulation, liver and kidneys.

In people with obesity, bariatric surgery can cause remission of type 2 diabetes, and therapeutic alternatives are being sought to achieve levels of weight loss comparable to surgery 2 . Insulin resistance (reduced cell response to the glucose-lowering pancreatic hormone, insulin) has been a target for anti-diabetic medicines for many years. However, growing understanding of its central role in the development of blood vessel, kidney and liver diseases, has made it a research priority for addressing a key gap in the therapeutic armoury available to doctors and patients.

Precision medicine

There is no single gene for type 2 diabetes but identification of the genomic drivers of the multiple biological mechanisms that lead to diabetes holds considerable promise. It is expected that new genomic understanding, linked to clinical phenotypes, will help to differentiate sub-groups of patients according to their risk of developing diabetes and progressing to diabetic complications. This segmentation of type 2 diabetes could also indicate opportunities for targeted therapies to intervene early in the disease.

Novel therapeutics

Advancing our understanding of disease biology enables us to uncover potential novel approaches for future diabetes treatments. At AstraZeneca, our toolbox of drug modalities enables us to address almost any drug target in diabetes using a range of therapeutics from classical small drug molecules to novel agents such as oligonucleotide and mRNA therapies. Approaches are being developed that can repair or modify a cell’s blueprint for making key proteins that can be applied to type 2 diabetes and its complications.

Antisense oligonucleotides are short, synthetic, chemically modified pieces of RNA that can be used to ‘silence’ genes and prevent detrimental proteins from being made. Antisense oligonucleotides have been designed for delivery specifically into the insulin-producing beta-cells of the pancreas whose dysfunction can lead to diabetes 2 . This has opened the door to antisense oligonucleotide therapy aimed at restoring beta-cell function in diabetes and potentially ‘knocking out’ other genes in a way that could support long-term remission or even cure ( Fig. 1 ).

Figure 1. Pancreactic beta cells at different stages of regeneration.

Messenger RNA (mRNA) has also been investigated for its potential in treating the small blood vessel damage, which commonly occurs with diabetes and can lead to organ failure. Encouraging results were obtained with injections of modified mRNA encoding for vascular endothelial growth factor A (VEGF-A), a protein involved in blood vessel formation. Local expression of VEGF-A was accompanied by improved blood flow in the skin of men with type 2 diabetes 3 .

Making insulin-resistant cells more sensitive to insulin is another goal of novel therapeutics for diabetes. In preclinical research, insulin sensitivity has been improved with gene therapy, antisense oligonucleotides and novel biologic approaches to decrease ectopic fat, particularly in the liver, which in turn alleviates insulin resistance and rejuvenates beta-cell function, leading to diabetes remission.

From remission to cure

If we want to change the trajectory of rising diabetes cases, we need to use novel approaches that target the drivers of diseases.At AstraZeneca, we are using our genomics expertise and state-of-the-art drug discovery technologies to build on strong science to develop potential medicines aimed at treating – and ultimately curing – diabetes.

Christopher Rhodes 1 , David Baker 2 & Regina Danielson Fritsche 3 .

1. One MedImmune Way, Gaithersburg, Maryland 20878, US.

2. Granta Park, Great Abington, Cambridge, CB21 6GH, UK.

3. Pepparedsleden 1, Mölndal, SE-431 83, Sweden.

International Diabetes Federation. Diabetes Atlas (2019).

Ämmälä, C., et al. Sci. Adv. 4 , eaat3386 (2018).

Article   PubMed   Google Scholar  

Gan, L.-M., et al. Nat Commun 10 , 871 (2019).

Download references

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies