Q&A: insulin secretion and type 2 diabetes: why do β-cells fail?
© Cantley and Ashcroft; licensee BioMed Central. 2015
Received: 15 April 2015
Accepted: 17 April 2015
Published: 16 May 2015
What is type 2 diabetes?
Diabetes mellitus is a term that covers a multitude of problems with many etiologies, unified by one common feature: the pathological elevation of blood glucose. Sustained hyperglycemia leads to tissue damage in susceptible organs and eventually results in secondary complications including retinopathy, nephropathy, peripheral neuropathy, cardiovascular disease and stroke [1-3]. Diabetes currently affects 387 million people worldwide, and this number is predicted to increase to 592 million by 2035 . The dramatic rise in the disease in recent years not only causes individual misery, but also places an enormous and increasing burden on healthcare systems and the global economy [5,6]. Indeed, many countries spend as much as 10 % of their healthcare budget on treating diabetes and its complications.
Type 1 diabetes (T1D) is much less common than T2D, accounting for <10 % of cases. It is precipitated by an autoimmune attack on the β-cells that results in an insulin deficient state, although a small number of functioning β-cells may remain . Typically, T1D presents in childhood or young adulthood.
In addition, there are rare inherited monogenic forms of diabetes that usually present in early life, and account for only 1 to 2 % of all diabetes cases. Unlike T2D, where it is believed multiple genes predispose to the disease, monogenic diabetes is caused by mutations in a single gene. Many of these genes encode transcriptional regulators, metabolic enzymes and ion channels that regulate β-cell stimulus-secretion coupling, or they may affect the development of the pancreas. Interestingly, common genetic variants in many of the genes known to cause monogenic diabetes enhance T2D risk; thus, their study may help elucidate the etiology of T2D.
T1D must be treated by insulin injections, due to the lack of β-cells. Therapy for T2D consists initially of dietary control and lifestyle modifications, followed by oral hypoglycemic agents, which may increase insulin secretion (for example, sulfonylureas) or reduce insulin resistance or hepatic glucose output (for example, metformin). If these fail to control hyperglycemia, then insulin is given. Monogenic diabetes is treated in different ways according to the gene involved.
Why are there no other hormones that can substitute for insulin?
Most control systems, including physiological ones, have built-in redundancy, which ensures that when one system fails another takes over. For example, several hormones can elevate blood glucose. However, only insulin can reduce blood glucose. At first this might seem surprising, but it is worth remembering that too much insulin has far more immediate and devastating effects than too little insulin. If blood glucose falls below 2 mmol/l for as little as 5 minutes, it can cause lethal brain damage. By contrast, it is only when blood glucose is chronically elevated over many weeks and months, due to a sustained lack of insulin, that the complications of diabetes are produced. Thus, insulin is a ‘Goldilocks’ hormone in that both too much and too little are dangerous. But although lack of insulin, and the consequent diabetes, receives much attention, an acute excess of insulin is far more damaging.
Insulin’s other function - its ability to enhance growth - is mirrored by several hormones, such as insulin-like growth factor 1 and 2. It is only the role of insulin in glucose homeostasis that is unique. We therefore speculate that the danger of hypoglycemia is the reason for the unique ability of insulin, acting via a single receptor, to lower blood glucose. In our evolutionary history, when humans battled with inadequate food and unplanned exercise (escaping predators) hypoglycemia was more likely than hyperglycemia. In this situation, a single means of lowering blood glucose is advantageous as there is less chance of inadvertent hypoglycemia. By contrast, the presence of numerous feedback systems to bolster blood sugar is beneficial. Although T2D is an increasing problem in societies today, in evolutionary terms it is of little significance because it generally presents after an individual’s reproductive age. Furthermore, it is only in very recent times that we have been exposed to the plentiful availability of high calorie diets and sedentary lifestyles that drive obesity and T2D.
How do β-cells avoid inappropriate insulin secretion?
Second, a number of metabolic genes that are widely expressed in other tissues are not expressed in pancreatic β-cells [9-11]. Such ‘disallowed’ genes include those encoding lactate dehydrogenase (LDHA) and the monocarboxylate transporter 1 (MCT1/SLC16A1), which are involved in the metabolism of lactate and pyruvate. This prevents insulin secretion in response to circulating lactate and pyruvate during exercise. Mutations in the SLC16A1 gene that result in its aberrant expression in β-cells provoke exercise-induced hypoglycemia by enabling pyruvate-induced insulin secretion [12,13]. In early humans, exercise-induced hypoglycemia could be lethal as it would impede escape from a predator; the absence of MCT1 ensures insulin secretion remains switched off during exercise. Similarly, adrenaline inhibits insulin secretion, ensuring blood glucose levels do not drop during exercise or the ‘fight-or-flight’ response.
What causes the insulin deficiency in type 2 diabetes?
The impaired insulin secretion found in T2D could be due to a decline in the cellular secretory rate (that is, in individual β-cell function), or to a decrease in β-cell mass (the product of β-cell size and number), or both. While there has been much debate about the relative contributions of secretory dysfunction and loss of β-cell mass to impaired insulin secretion in T2D, a consensus view is still lacking. This may, in part, be due to the difficulty in obtaining human islets (especially from T2D donors) of sufficient quality and quantity for functional studies, as islet isolation programs primarily operate to provide islets from healthy donors for transplantation therapy . Furthermore, there are several factors that may vary between human islet preparations, thereby confounding the comparison of control and T2D islet function: donors may have been maintained on different cocktails of drugs prior to death, genetic background and environmental factors may be poorly controlled, and variations in the cold ischemic time to which the islets are exposed during pancreas transport and islet isolation may alter islet gene expression and function . However, when many of the above variables are controlled for, studies with modest sample sizes (n = 5 to 17 cases) have clearly shown that glucose-stimulated insulin secretion (GSIS) is defective in islets from T2D donors, relative to non-diabetic donors [16-18]. In two of these studies, islets from T2D donors responded normally to non-glucose stimuli, suggesting defective GSIS in these cohorts is likely due to impaired glucose-sensing (stimulus-secretion coupling) rather than a loss of insulin content or a constitutive defect in insulin exocytosis [16,18]. Nevertheless, more work is needed, both to increase the numbers of cases studied and to investigate the nature of the defective GSIS response in detail.
Histological studies of β-cell mass are more straightforward because they can be conducted on fixed tissues. Several studies have reported a decrease in β-cell mass in T2D [19-21]. However, an important caveat with these experiments is that β-cells are usually identified by insulin staining. This means that the insulin content must be high enough for it to be detected histologically - β-cells with greatly reduced insulin content will not be counted and β-cell mass thus underestimated. Recent studies indicate that T2D islets contain many β-cells that can be identified as such using electron microscopy by their characteristic ‘poached-egg’ insulin granules, but where the granules are strikingly few and insulin is undetectable by immunostaining . Hyperglycemia produces similar effects in a mouse model of diabetes . Thus, the extent to which β-cell mass is reduced in T2D remains unclear. While there is good evidence that islet insulin staining (aka content) decreases with time, the relative contributions of decreased insulin content, fewer β-cells and impaired stimulus-secretion coupling to reduced insulin secretion in T2D is still uncertain. Notwithstanding this, in the 5 year period following diagnosis, patients with T2D show a 25 % reduction in the mass of insulin-positive cells, relative to non-diabetic controls, whereas in individuals with longstanding T2D (>15 years), β-cell mass is reduced by over 50 % . This progressive loss of β-cell mass during disease progression places an ever-greater secretory burden on the β-cells that remain functional. Their resilience is likely determined by a complex interplay between environmental, genetic and epigenetic factors.
Do changes in β-cell identity contribute to type 2 diabetes?
It is clear that multiple mechanisms are involved in the development of T2D. However, recent evidence suggests that β-cell identity may not be fixed, and changes in β-cell identity may contribute to defective insulin secretion in T2D.
It is well established that hyperglycemia in mice results in altered expression of β-cell transcription factors and defective insulin secretion, a situation described as β-cell dedifferentiation . Recent elegant studies have shown that deletion of certain transcription factors in mice, such as FOXO1 , leads to dedifferentiation of pancreatic β-cells, which lose their insulin content and revert to islet progenitor-like cells. Similarly, expression of the progenitor cell marker Ngn3 has been reported in a mouse model of diabetes . Whether this is the case for human β-cells in T2D is as yet unclear . However, marked changes in β-cell transcription factors are observed in humans with T2D  and in non-human primates with diet-induced pre-diabetes .
It is well established that the loss of insulin immunostaining seen in many mouse models of diabetes is paralleled by an increase in glucagon immunostaining. These changes appear to be driven by hyperglycemia. In one of these mouse models, lineage tracing revealed that a small number of β-cells start to express glucagon . However, it remains unclear if these β-cells fully convert to α-cells, or if they represent an intermediate cell type that expresses glucagon as well as many β-cell proteins (except for insulin). In contrast, lineage tracing has also shown that both α-cells  and δ-cells  can convert to fully functioning β-cells, highlighting the potential plasticity of islet cells.
Thus, much of the current research in this area is focused on how to differentiate β-cells from progenitor cells or other islet cell types. Interestingly, the effects of hyperglycemia on β-cell dedifferentiation, loss of insulin content and glucagon expression can be reversed by tight control of blood glucose [22,25].
Is obesity a driver of β-cell failure?
The current global epidemics of obesity and T2D show remarkably similar trends and geographic distribution, and there is good evidence that the risk of T2D is increased by obesity . However, obesity appears to exert its effect primarily on insulin resistance rather than on β-cell function, and only a minority of obese individuals will develop T2D , while many non-obese individuals will do so . Furthermore, obesity is associated with an enhanced insulin response to glucose in non-diabetic individuals [33,34], and recent histological studies have revealed obesity is associated with a 50 % increase in β-cell mass . Thus, it appears that far from obesity causing β-cell failure, the inherent ability for β-cell function to adapt to obesity fails in some individuals, resulting in T2D .
To what extent is type 2 diabetes a genetic disease?
An individual’s risk of developing T2D is determined by a complex interplay between genetic and environmental/lifestyle factors. Genotype clearly plays an important role: prospective studies of monozygotic twins have shown a 76 % concordance rate for T2D, and a 96 % concordance rate for impaired glucose tolerance . Furthermore, a family history of T2D more than doubles an individual’s risk of developing the disease . But at the same time the epidemiological evidence shows a dramatic rise in T2D rates over the past 60 years that clearly cannot be due to genetic change, but is associated with alterations in diet and behavior, including a more sedentary lifestyle and increased consumption of calorie-dense foods .
T2D risk may also be influenced by epigenetic changes, which are heritable alterations affecting cell function which do not involve changes in the DNA sequence. These are largely determined by environmental factors, such as parental nutrition. Recent evidence suggests that β-cells from T2D patients show altered DNA methylation (a common epigenetic mark) with changes in gene expression profiles . Rodent studies have shown that suboptimal maternal or paternal nutrition can influence chromatin modifications and gene expression in β-cells of subsequent offspring, consistent with epigenetic transmission [39,40]. In humans maternal and early-life nutrition is known to influence the risk of T2D in offspring [41,42]. Further studies will be needed to clarify the emerging role of epigenetics in the etiology of T2D.
Are specific gene variants associated with type 2 diabetes?
This is not a straightforward question to answer.
T2D is a polygenic disease, and current evidence favors the idea that in most individuals, the risk of developing the disease is determined by the combination of at-risk variants at many gene loci, each of which alone confers only a small increase in disease risk . This makes T2D distinct from the much rarer monogenic forms of diabetes, such as maturity onset diabetes of the young (MODY) and neonatal diabetes . It also indicates that T2D is not a single entity, as hyperglycemia may be produced by different combinations of genes in different individuals, which may also result in phenotypic variations.
Currently, the best method for identifying genes contributing to polygenic diseases are genome-wide association studies (GWAS). These are based on the association of common genetic variants - single-nucleotide polymorphisms - with a given phenotype, such as hyperglycemia. To date, more than 70 gene loci have been found to be associated with T2D in large-cohort studies , with the majority of these loci being implicated in β-cell function.
One problem with GWAS studies is the size of the cohorts that must be studied (sometimes >100,000 people) to generate sufficient statistical power. Such large cohorts are difficult to phenotype in sufficient depth to reveal the complex physiology underlying T2D. Thus, most studies inevitably rely on relatively simple phenotyping procedures, such as measurement of fasting blood glucose, which do not adequately reveal the underlying etiology. Therefore, efforts to improve disease phenotyping are important. A recent study analyzed the association of 37 hyperglycemia susceptibility loci with three key traits that influence blood glucose: insulin sensitivity, β-cell insulin processing and insulin secretion . This revealed that risk loci were clustered into three distinct groups, each associated with only one of the three phenotypic measurements. This study highlights both the marked physiological heterogeneity underlying glycemic traits, and the need for stratification of diabetes phenotypes to enhance the power of GWAS.
New approaches to studying genotype-phenotype interactions in β-cells are urgently needed. Some progress towards this goal was made in a recent study, which analyzed islets isolated from human donors with differing at-risk genotypes. This painstaking approach revealed the direct influence of a subset of diabetes risk loci on impaired insulin secretion ex vivo , and provided mechanistic insights into the role of these genetic variants.
Is a personalized treatment for type 2 diabetes, based on genotype, possible?
In some diseases, such as breast cancer, genotyping is routinely used to predict whether a patient will benefit from a particular drug . Genotyping has also revolutionized therapy in some types of monogenic diabetes . The potential for genotype-specific therapy in T2D is less clear, principally because each gene variant only explains a small degree of disease risk. However, a recent study revealed that in T2D patients carrying an alpha-2A-adrenergic receptor mutation, treatment with a drug targeted to this receptor restored insulin secretion . This raises the tantalizing possibility of mining GWAS data for new drug targets to develop personalized treatments for groups of individuals with specific subtypes of T2D.
Are other islet cell types involved in the pathogenesis of type 2 diabetes?
It is now well established that T2D is not caused simply by lack of insulin and that impaired glucagon secretion from pancreatic α-cells also plays a pivotal role. Glucagon elevates blood glucose by stimulating gluconeogenesis and glucose output from liver hepatocytes. In T2D there is a marked increase in glucagon secretion at high glucose, which exacerbates the hyperglycemic effects of insulinopenia . There is also too little glucagon secretion at low glucose, which may precipitate fatal hypoglycemia .
Glucagon, a long-neglected player in glucose homeostasis and T2D, has recently taken center stage. The spectacular finding that the complete destruction of the β-cells by streptozotocin does not result in hyperglycemia in mice in which the glucagon receptor has been genetically ablated , whereas wild-type mice are severely diabetic following β-cell ablation, underscores the importance of glucagon in glucose homeostasis. Because expression of the glucagon receptor in the liver alone is sufficient to produce severe diabetes in glucagon receptor-null mice lacking functional β-cells , suppression of glucagon-induced hepatic glucose output would appear to be a good target for T2D therapy.
Metformin, widely used to treat T2D (especially in the obese), has been proposed to lower blood glucose by antagonizing glucagon action . This appears to be mediated via reduced cellular metabolism, which leads to inhibition of adenylyl cyclase and cyclic AMP production, and so lowers hepatic gluconeogenesis. Other strategies for reducing glucagon action include reducing glucagon release from pancreatic α-cells  and blocking glucagon stimulation of hepatic glucose output . Indeed, glucagon receptor antagonists improve glycemia in T2D , and glucagon-like peptide 1 (GLP1) mimetics and inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme that inactivates GLP-1) are thought to improve glucose homeostasis, at least in part, by reducing plasma glucagon levels . Reduced hepatic glucose output may also be part of the reason why excellent diabetes control can be rapidly achieved (prior to substantial weight loss) by a very low calorie diet . A better understanding of the mechanisms regulating glucagon secretion and action, both in health and disease, and of how these may be targeted therapeutically in T2D is therefore urgently required.
Can β-cell dysfunction in type 2 diabetes be reversed?
The UK Prospective Diabetes Study Group (UKPDS) demonstrated that there is an inexorable decline in β-cell function with time, whether with diet-control, insulin or sulfonylurea therapies . A key question is what causes this decline and whether it can be reversed.
Improvement in insulin secretion after intensive insulin treatment has been reported [56,57], and a very low-calorie diet can improve insulin action, β-cell function and glucose homeostasis in T2D patients . Thus, some reversal of impaired β-cell function in T2D appears possible, at least in the short term.
Current pharmacological therapies also improve glycemic control in T2D by increasing insulin secretion. These include the sulfonylurea drugs, which act by closing KATP channels. Drugs that mimic or amplify the action of gut hormones - known as incretins - also enhance insulin secretion. Glucagon-like peptide-1 (GLP-1), for example, is released from intestinal L-cells in response to the presence of food in the gut, and like other incretins, it potentiates insulin secretion at stimulatory glucose concentrations, but not at low glucose . This makes GLP-1 an attractive therapeutic target, because it enhances insulin secretion only in response to a meal, when it is needed, and not during inter-meal intervals when it could increase the risk of hypoglycemia. Thus, GLP-1 mimetics and DPP4 inhibitors are now widely used. They are highly effective at boosting insulin secretion and maintaining glucose homeostasis in T2D patients , and they do not cause the weight gain and hypoglycemia risk associated with insulin and sulfonylurea therapies . However, questions have been raised over the long-term safety of incretin-based therapies: in particular, an off-target effect on ductal cells of the exocrine pancreas may increase the incidence of pancreatitis, potentially leading to pancreatic cancer [60,61]. There is debate about whether the potential risk is justified by the profound benefits of incretin-based medications.
Recent studies have revealed that gastric bypass surgery rapidly restores glucose homeostasis in T2D patients, prior to the substantial weight loss associated with this procedure . One explanation for this remarkable finding is that surgery results in an increase in GLP1 secretion and an associated rise in insulin release . Therefore, gastric bypass surgery may be a viable surgical therapy for treating T2D.
Where can we expect progress in our understanding of β-cell failure in type 2 diabetes?
As ever, research on T2D is a vibrant field and much energy is directed towards understanding the changes in β-cell function associated with diabetes. The root cause of defective stimulus-secretion coupling during T2D remains elusive, and more functional studies using islets isolated from humans with T2D are clearly needed. Currently, there is a renewed focus on β-cell dedifferentiation using mouse models, and how this may be prevented or reversed, and on the extent to which other islet cells can be induced to differentiate into β-cells. The role of glucagon in T2D is also receiving considerable attention, and there is an emphasis on efforts towards better stratification of disease phenotypes in genetic studies. Recent therapeutic developments also hint at the possibility of restoring endogenous β-cell function, although the long-term stability, safety and efficacy of these approaches is not yet known. We look forward to the results of all of these studies.
We apologize to colleagues whose work we were unable to include due to space reasons, or which we may have overlooked. It is impossible to cover all areas in depth in a short review. We thank our many colleagues and students for stimulating discussion and the Wellcome Trust, the Royal Society and Diabetes UK for financial support.
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.View ArticleGoogle Scholar
- Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.View ArticlePubMedGoogle Scholar
- Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiological Reviews, Volume 93. 2013;1:137–88.View ArticleGoogle Scholar
- International Diabetes Federation. IDF Diabetes Atlas. 6th edition. 2013.Google Scholar
- Ray JA, Valentine WJ, Secnik K, Oglesby AK, Cordony A, Gordois A, et al. Review of the cost of diabetes complications in Australia, Canada, France, Germany, Italy and Spain. Curr Med Res Opin. 2005;21:1617–29.View ArticlePubMedGoogle Scholar
- Scully T. Diabetes in numbers. Nature. 2012;485:S2–3.View ArticlePubMedGoogle Scholar
- Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 2003;46:3–19.View ArticlePubMedGoogle Scholar
- Oram R, Jones A, Besser RJ, Knight B, Shields B, Brown R, et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia. 2014;57:187–91.View ArticlePubMed CentralPubMedGoogle Scholar
- Quintens R, Hendrickx N, Lemaire K, Schuit F. Why expression of some genes is disallowed in beta-cells. Biochem Soc Trans. 2008;36:300–5.View ArticlePubMedGoogle Scholar
- Pullen TJ, Khan AM, Barton G, Butcher SA, Sun G, Rutter GA. Identification of genes selectively disallowed in the pancreatic islet. Islets. 2010;2:89–95.View ArticlePubMedGoogle Scholar
- Schuit F, Van Lommel L, Granvik M, Goyvaerts L, de Faudeur G, Schraenen A, et al. β-cell-specific gene repression: a mechanism to protect against inappropriate or maladjusted insulin secretion? Diabetes. 2012;61:969–75.View ArticlePubMed CentralPubMedGoogle Scholar
- Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, et al. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet. 2007;81:467–74.View ArticlePubMed CentralPubMedGoogle Scholar
- Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA. Overexpression of monocarboxylate transporter-1 (Slc16a1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise. Diabetes. 2012;61:1719–25.View ArticlePubMed CentralPubMedGoogle Scholar
- Kulkarni RN, Stewart AF. Summary of the Keystone Islet Workshop (April. 2014): the increasing demand for human islet availability in diabetes research. Diabetes. 2014;63:3979–81.View ArticlePubMedGoogle Scholar
- Cantley J, Walters SN, Jung MH, Weinberg A, Cowley MJ, Whitworth TP, et al. A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis. Cell Transplant. 2013;22:2147–59.View ArticlePubMedGoogle Scholar
- Deng S, Vatamaniuk M, Huang X, Doliba N, Lian M-M, Frank A, et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 2004;53:624–32.View ArticlePubMedGoogle Scholar
- Marselli L, Suleiman M, Masini M, Campani D, Bugliani M, Syed F, et al. Are we overestimating the loss of beta cells in type 2 diabetes? Diabetologia. 2014;57:362–5.View ArticlePubMedGoogle Scholar
- Rosengren AH, Braun M, Mahdi T, Andersson SA, Travers ME, Shigeto M, et al. Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type 2 diabetes. Diabetes. 2012;61:1726–33.View ArticlePubMed CentralPubMedGoogle Scholar
- Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.View ArticlePubMedGoogle Scholar
- Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, et al. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 2003;88:2300–8.View ArticlePubMedGoogle Scholar
- Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic β-cell mass in European subjects with type 2 diabetes. Diabetes Obesity Metab. 2008;10:32–42.View ArticleGoogle Scholar
- Brereton MF, Iberl M, Shimomura K, Zhang Q, Adriaenssens AE, Proks P, et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat Commun. 2014;5:4639.View ArticlePubMed CentralPubMedGoogle Scholar
- Weir GC, Aguayo-Mazzucato C, Bonner-Weir S. Beta-cell dedifferentiation in diabetes is important, but what is it? Islets. 2013;5:233–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Talchai C, Xuan S, Lin Hua V, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150:1223–34.View ArticlePubMed CentralPubMedGoogle Scholar
- Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic beta cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 2014;19:872–82.View ArticlePubMed CentralPubMedGoogle Scholar
- Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, et al. Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Investig. 2013;123:3305–16.View ArticlePubMed CentralPubMedGoogle Scholar
- Fiori JL, Shin Y-K, Kim W, Krzysik-Walker SM, González-Mariscal I, Carlson OD, et al. Resveratrol prevents β-cell dedifferentiation in nonhuman primates given a high-fat/high-sugar diet. Diabetes. 2013;62:3500–13.View ArticlePubMed CentralPubMedGoogle Scholar
- Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464:1149–54.View ArticlePubMed CentralPubMedGoogle Scholar
- Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, et al. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature. 2014;514:503–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Yach D, Stuckler D, Brownell KD. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat Med. 2006;12:62–6.View ArticlePubMedGoogle Scholar
- Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–6.View ArticlePubMedGoogle Scholar
- Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care. 2011;34:1249–57.View ArticlePubMed CentralPubMedGoogle Scholar
- Perley M, Kipnis DM. Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects. Diabetes. 1966;15:867–74.View ArticlePubMedGoogle Scholar
- Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Investig. 1988;81:442–8.View ArticlePubMed CentralPubMedGoogle Scholar
- Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36:111–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Medici F, Hawa M, Ianari A, Pyke DA, Leslie RDG. Concordance rate for Type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia. 1999;42:146–50.View ArticlePubMedGoogle Scholar
- Lyssenko V, Almgren P, Anevski D, Perfekt R, Lahti K, Nissén M, et al. Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes. 2005;54:166–74.View ArticlePubMedGoogle Scholar
- Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R, et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J. 2012;31:1405–26.View ArticlePubMed CentralPubMedGoogle Scholar
- Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A. 2011;108:5449–54.View ArticlePubMed CentralPubMedGoogle Scholar
- Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010;467:963–6.View ArticlePubMedGoogle Scholar
- Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav. 2006;88:234–43.View ArticlePubMedGoogle Scholar
- Dabelea D, Crume T. Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes. 2011;60:1849–55.View ArticlePubMed CentralPubMedGoogle Scholar
- Lyssenko V, Laakso M. Genetic screening for the risk of type 2 diabetes: worthless or valuable? Diabetes Care. 2013;36:S120–6.View ArticlePubMed CentralPubMedGoogle Scholar
- Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–49.View ArticlePubMedGoogle Scholar
- Mahajan A, Go MJ, Zhang W, Below JE, Gaulton KJ, Ferreira T, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014;46:234–44.View ArticlePubMedGoogle Scholar
- Dimas AS, Lagou V, Barker A, Knowles JW, Mägi R, Hivert M-F, et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes. 2014;63:2158–71.View ArticlePubMedGoogle Scholar
- Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science. 2014;343:1466–70.View ArticlePubMed CentralPubMedGoogle Scholar
- Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467–77.View ArticlePubMedGoogle Scholar
- Tang Y, Axelsson AS, Spegel P, Andersson LE, Mulder H, Groop LC, et al. Genotype-based treatment of type 2 diabetes with an alpha2A-adrenergic receptor antagonist. Sci Transl Med. 2014;6:257ra139.View ArticlePubMedGoogle Scholar
- Ashcroft FM, Rorsman P. K(ATP) channels and islet hormone secretion: new insights and controversies. Nat Rev Endocrinol. 2013;9:660–9.View ArticlePubMedGoogle Scholar
- Lee Y, Berglund ED, Wang MY, Fu X, Yu X, Charron MJ, et al. Metabolic manifestations of insulin deficiency do not occur without glucagon action. Proc Natl Acad Sci U S A. 2012;109:14972–6.View ArticlePubMed CentralPubMedGoogle Scholar
- Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:256–60.View ArticlePubMed CentralPubMedGoogle Scholar
- Prince MJ, Garhyan P, Abu-Raddad EJ, Fu H, Lim CN, Pinaire JA, et al. Short-term treatment with glucagon receptor antagonist LY2409021 effectively reduces fasting blood glucose (FBG) and HbA1c in patients with type 2 diabetes mellitus. Diabetologia. 2011;54:S86.Google Scholar
- Nauck MA, Vilsbøll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies: viewpoints on the way to consensus. Diabetes Care. 2009;32:S223–31.View ArticlePubMed CentralPubMedGoogle Scholar
- Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54:2506–14.View ArticlePubMed CentralPubMedGoogle Scholar
- Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753–60.View ArticlePubMedGoogle Scholar
- Kramer CK, Choi H, Zinman B, Retnakaran R. Determinants of reversibility of beta-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes. Am J Physiol Endocrinol Metab. 2013;305:E1398–407.View ArticlePubMedGoogle Scholar
- Parkes DG, Pittner R, Jodka C, Smith P, Young A. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism. 2001;50:583–9.View ArticlePubMedGoogle Scholar
- Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care. 2013;36:2126–32.View ArticlePubMed CentralPubMedGoogle Scholar
- Gale EA. GLP-1 based agents and acute pancreatitis: drug safety falls victim to the three monkey paradigm. BMJ. 2013;346:f1263.View ArticlePubMedGoogle Scholar
- Butler PC, Elashoff M, Elashoff R, Gale EAM. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 2013;36:2118–25.View ArticlePubMed CentralPubMedGoogle Scholar
- Chandarana K, Batterham RL. Shedding pounds after going under the knife: metabolic insights from cutting the gut. Nat Med. 2012;18:668–9.View ArticlePubMedGoogle Scholar
- Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson-Perez HE, Stefater MA, et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology. 2011;141:950–8.View ArticlePubMed CentralPubMedGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.