Insulin Secretory Dysfunction Research Articles

β-Hydroxypyruvate: a new diabetogenic factor?

The incidence of type 2 diabetes mellitus (T2DM) is increasing at an alarming rate. Insulin secretory dysfunction and insulin resistance are characteristic features of T2DM. However, their relative contributions to the progression from normal glucose tolerance to impaired glucose tolerance (IGT) to T2DM remain unknown. This limits the capacity of researchers to establish therapeutic interventions for T2DM. Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are the two primary incretin hormones secreted by intestinal K and L cells, respectively. Secretion of these incretins increases postprandially and they potentiate glucose-stimulated insulin secretion (GSIS). Despite blunted incretin responses in patients with T2DM, insulinotropic responses to exogenously administered GLP-1 remain active in these patients (1). Although controversy exists, a recent study demonstrated that insulin secretory responses to GIP were retained in patients with T2DM (1,2). Additionally, incretin response to GIP is improved by reducing blood glucose levels in patients with T2DM (3). These findings support the rationale for use of incretin-based pharmacotherapies in the treatment and management of T2DM. However, identification of the mechanism by which the function of K cells contributes to the development of T2DM is still elusive and requires a good model of study. To determine the role of K cells in the regulation of metabolism, K cells were eliminated from mice by expressing the diphtheria toxin A-chain gene in GIP-producing cells (DT mice). Despite a severely impaired …

Sesamin suppresses STZ induced INS-1 cell apoptosis through inhibition of NF-κB activation and regulation of Bcl-2 family protein expression

Diverse risk factors for diabetes can induce oxidative stress, leading to pancreatic beta cell damage and insulin secretion dysfunction. In the present study, we evaluated the effect of sesamin on streptozotocin (STZ) induced apoptosis in INS-1 cells and the possible mechanisms implicated. After preincubation with indicated concentrations of sesamin (0.1, 1.0 and 10.0μmol/l) for 24h, INS-1 cells were exposed to STZ (3mmol/l) for 12h. Sesamin effectively improved STZ induced cell damage as determined by MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] assay and insulin secretion capacity, and suppressed STZ induced cell apoptosis as evaluated by flow cytometry using annexin V and propidium iodide double staining. Western blot analysis demonstrated that sesamin markedly suppressed STZ induced nuclear factor kappa B (NF-κB) activation, with Bax protein down-regulated and Bcl-2 protein up-regulated significantly. Preincubation with sesamin resulted in an evident enhancement of total antioxidant capacity in INS-1 cells, accompanied by a significant reduction of intracellular reactive oxygen species and malondialdehyde, an end product of lipid peroxidation. Taken together, these findings suggested that sesamin was capable of suppressing STZ induced INS-1 cell apoptosis, which might be ascribed, at least partly, to the inhibition of NF-κB activation and subsequent regulation of Bcl-2 family protein expression. This study would provide a potential target for treatment of diabetes with sesamin as well as other antioxidants.

Cross-sectional and Longitudinal Analyses of Factors Contributing to the Progressive Loss of the β-cell Function in Type 2 Diabetes.

Type 2 diabetes is a progressive disease characterized by insulin resistance and insulin secretory dysfunction. In this study, we assessed the factors contributing to an insulin secretory defect in type 2 diabetes patients. The subjects consisted of 382 patients with type 2 diabetes, aged 57±13 years. We estimated the β-cell function using 6-min post-glucagon increments in C-peptide (ΔCPR). A significant inverse correlation was observed between the time since the diagnosis of diabetes and ΔCPR. A simple liner regression analysis showed that ΔCPR decreases at a rate of 0.056 ng/mL/year. According to a multiple regression model, body mass index (BMI) and log (triglyceride) were positively correlated with ΔCPR. Time since the diagnosis of diabetes, diabetes in 1st degree relatives, the presence of diabetic retinopathy, and HbA1c were inversely correlated with ΔCPR. In 50 patients who underwent the glucagon stimulation test twice, the ΔCPR decreased from 2.27±1.47 to 1.72±1.08 ng/mL over a period of 6.5±0.9 years. A multiple regression analysis revealed the BMI and fasting plasma glucose level to be significant contributing factors to the decline in ΔCPR. The duration of diabetes, a low BMI, genetic factors, and the presence of microangiopathy may be associated with β-cell dysfunction in diabetic patients. The observations in this study suggest that obese subjects showed a rapid decline in the β-cell function despite an initial high CPR response. Environmental factors causing insulin resistance and glucotoxicity may therefore be involved in progressive β-cell failure.

Fenugreek lactone attenuates palmitate-induced apoptosis and dysfunction in pancreatic β-cells.

To investigate the effect of fenugreek lactone (FL) on palmitate (PA)-induced apoptosis and dysfunction in insulin secretion in pancreatic NIT-1 β-cells. Cells were cultured in the presence or absence of FL and PA (0.25 mmol/L) for 48 h. Then, lipid droplets in NIT-1 cells were observed by oil red O staining, and the intracellular triglyceride content was measured by colorimetric assay. The insulin content in the supernatant was determined using an insulin radio-immunoassay. Oxidative stress-associated parameters, including total superoxide dismutase, glutathione peroxidase and catalase activity and malondialdehyde levels in the suspensions were also examined. The expression of upstream regulators of oxidative stress, such as protein kinase C-α (PKC-α), phospho-PKC-α and P47phox, were determined by Western blot analysis and real-time PCR. In addition, apoptosis was evaluated in NIT-1 cells by flow cytometry assays and caspase-3 viability assays. Our results indicated that compared to the control group, PA induced an increase in lipid accumulation and apoptosis and a decrease in insulin secretion in NIT-1 cells. Oxidative stress in NIT-1 cells was activated after 48 h of exposure to PA. However, FL reversed the above changes. These effects were accompanied by the inhibition of PKC-α, phospho-PKC-α and P47phox expression and the activation of caspase-3. FL attenuates PA-induced apoptosis and insulin secretion dysfunction in NIT-1 pancreatic β-cells. The mechanism for this action may be associated with improvements in levels of oxidative stress.

Matrix metalloproteinase 2 contributes to pancreatic Beta cell injury induced by oxidative stress.

ObjectiveTo investigate the role of matrix metalloproteinase 2 (MMP2) in pancreatic beta cell injury induced by oxidative stress.MethodsRat pancreatic beta cell line INS-1 cells were treated with advanced glycation end-products (AGE) to induce intracellular oxidative stress. Intracellular MMP2 expression and activity were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and zymography, respectively. MMP2 expression and activity were manipulated by over-expression with recombinant MMP2 plasmids or knockdown with either MMP2 specific siRNA or inhibitors, and effects on apoptosis and insulin-secretion were measured by flow cytometry and ELISA.ResultsAGE treatment induced intracellular oxidative stress in INS-1 cells, as indicated by elevated ROS levels, apoptotic cell death, and suppressed insulin secretion. This was accompanied by increased MMP2 expression and activity. However, Antioxidant N-acetylcysteine (NAC) treatment inhibited MMP2 expression and activity, and partially reversed cell apoptosis and insulin secretion dysfunction induced by AGE. Forced expression of MMP2 mimicked the effects of AGE treatment while inhibition of MMP2 either by a specific MMP2 inhibitor or MMP2 siRNA protected oxidative stress induced by AGE.ConclusionMMP2 expression and intracellular activity are increased by oxidative stress, contributing to cellular dysfunction and apoptosis in INS-1 cells after AGE challenge.

Resveratrol supplementation restores high-fat diet-induced insulin secretion dysfunction by increasing mitochondrial function in islet.

Resveratrol (RSV), a natural compound, is known for its effects on energy homeostasis. Here we investigated the effects of RSV and possible mechanism in insulin secretion of high-fat diet rats. Rats were randomly divided into three groups as follows: NC group (animals were fed ad libitum with normal chow for 8 weeks), HF group (animals were fed ad libitum with high-fat diet for 8 weeks), and HFR group (animals were treated with high-fat diet and administered with RSV for 8 weeks). Insulin secretion ability of rats was assessed by hyperglycemic clamp. Mitochondrial biogenesis genes, mitochondrial respiratory chain activities, reactive oxidative species (ROS), and several mitochondrial antioxidant enzyme activities were evaluated in islet. We found that HF group rats clearly showed low insulin secretion and mitochondrial complex dysfunction. Expression of silent mating type information regulation 2 homolog- 1 (SIRT1) and related mitochondrial biogenesis were significantly decreased. However, RSV administration group (HFR) showed a marked potentiation of glucose-stimulated insulin secretion. This effect was associated with elevated SIRT1 protein expression and antioxidant enzyme activities, resulting in increased mitochondrial respiratory chain activities and decreased ROS level. This study suggests that RSV may increase islet mitochondrial complex activities and antioxidant function to restore insulin secretion dysfunction induced by high-fat diet.

SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells.

We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. Sorcs1 belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from the trans-Golgi network (TGN) to the vacuole. Whole-body Sorcs1 KO mice, when made obese with the leptin(ob) mutation (ob/ob), developed diabetes. β Cells from these mice had a severe deficiency of secretory granules (SGs) and insulin. Interestingly, a single secretagogue challenge failed to consistently elicit an insulin secretory dysfunction. However, multiple challenges of the Sorcs1 KO ob/ob islets consistently revealed an insulin secretion defect. The luminal domain of SORCS1 (Lum-Sorcs1), when expressed in a β cell line, acted as a dominant-negative, leading to SG and insulin deficiency. Using syncollin-dsRed5TIMER adenovirus, we found that the loss of Sorcs1 function greatly impairs the rapid replenishment of SGs following secretagogue challenge. Chronic exposure of islets from lean Sorcs1 KO mice to high glucose and palmitate depleted insulin content and evoked an insulin secretion defect. Thus, in metabolically stressed mice, Sorcs1 is important for SG replenishment, and under chronic challenge by insulin secretagogues, loss of Sorcs1 leads to diabetes. Overexpression of full-length SORCS1 led to a 2-fold increase in SG content, suggesting that SORCS1 is sufficient to promote SG biogenesis.

A novel hierarchal-based approach to measure insulin sensitivity and secretion in at-risk populations.

The pathogenesis of type 2 diabetes is characterized by insulin resistance and insulin secretory dysfunction. Few existing metabolic tests measure both characteristics, and no such tests are inexpensive enough to enable widespread use. A hierarchical approach uses 2 down-sampled tests in the dynamic insulin sensitivity and secretion test (DISST) family to first determine insulin sensitivity (SI) using 4 glucose measurements. Second the insulin secretion is determined for only participants with reduced SI using 3 C-peptide measurements from the original test. The hierarchical approach is assessed via its ability to classify 214 individual test responses of 71 females with an elevated risk of type 2 diabetes into 5 bins with equivalence to the fully sampled DISST. Using an arbitrary SI cut-off, 102 test responses were reassayed for C-peptide and unique insulin secretion characteristics estimated. The hierarchical approach correctly classified 84.5% of the test responses and 94.4% of the responses of individuals with increased fasting glucose. The hierarchical approach is a low-cost methodology for measuring key characteristics of type 2 diabetes. Thus the approach could provide an economical approach to studying the pathogenesis of type 2 diabetes, or in early risk screening. As the higher cost test uses the same clinical protocol as the low-cost test, the cost of the additional information is limited to the assay cost of C-peptide, and no additional procedures or callbacks are required.

Cinnamtannin D-1 protects pancreatic β-cells from palmitic acid-induced apoptosis by attenuating oxidative stress.

In previous studies, A-type procyanidin oligomers isolated from Cinnamomum tamala were proved to possess antidiabetic effect and protect pancreatic β-cells in vivo. The aim of this study was to unveil the mechanisms of protecting pancreatic β-cells from palmitic acid-induced apoptosis by cinnamtannin D-1 (CD1), one of the main A-type procyanidin oligomers in C. tamala. CD1 was discovered to dose-dependently reduce palmitic acid- or H2O2-induced apoptosis and oxidative stress in INS-1 cells, MIN6 cells, and primary cultured murine islets. Moreover, CD1 could reverse palmitic acid-induced dysfunction of glucose-stimulated insulin secretion in primary cultured islets. These results indicate that reduction of apoptosis and oxidative stress might account for the protection effect of CD1, which provided a better understanding of the mechanisms of the antidiabetic effects of procyanidin oligomers.

The anti-inflammatory protein NUPR1 protects pancreatic islets from diabetogenic lipotoxic injury ex vivo

Background and aim: According to the so-called “nutrition overflow hypothesis”, type 2 diabetes results from nutrition-induced local tissue inflammation leading to insulin resistance, insulin secretory dysfunction and finally pancreatic β-cell loss. Free fatty acids (FFA) acting through toll-like receptors are key mediators of this lipotoxic inflammatory response. We previously demonstrated that the intracellular protein NUPR1 (p8) exerts potent anti-inflammatory and anti-diabetogenic effects in β-cells in vivo. Here we investigated the anti-lipotoxic potential of NUPR1 ex vivo in pancreatic islets of transgenic mice with β-cell-specific Nupr1 overexpression under the control of the rat insulin 1 promoter (Nupr1-Tg).

Development of an HbA1c-based conversion equation for estimating glycated albumin in a Korean population with a wide range of glucose intolerance.

BackgroundCompared to the golden standard glycation index of HbA1c, glycated albumin (GA) has potentials for assessing insulin secretory dysfunction and glycemic fluctuation as well as predicting diabetic vascular complications. However, the reference ranges of GA and a conversion equation need to be clearly defined. We designed this study to determine the reference ranges in patients with normal glucose tolerance (NGT) based on conventional measures of glycemic status and to devise a conversion equation for calculating HbA1c and GA in a Korean population.Methodology/Principal FindingsIn this multicenter, retrospective, cross-sectional study, we recruited antidiabetic drug-naïve patients with available glycemic variables including HbA1c, GA, and fasting plasma glucose regardless of glucose status. For the reference interval of serum GA, 5th to 95th percentile value of GA in subjects with NGT was adopted. The conversion equation between HbA1c and GA was devised using an estimating regression model with unknown break-points method. The reference range for GA was 9.0–14.0% in 2043 subjects. The 95th percentile responding values for FPG, and HbA1c were approximately 5.49 mmol/l, and 5.6%, respectively. The significant glycemic turning points were 5.868% HbA1c and 12.2% GA. The proposed conversion equation for below and above the turning point were GA (%) = 6.960+0.8963 × HbA1c (%) and GA (%) = −9.609+3.720 × HbA1c (%), respectively.Conclusions/SignificanceThese results should be helpful in future studies on the clinical implications of high GA relative to HbA1c and the clinical implementation of diabetes management.

Macrophage migration inhibitory factor is overexpressed in pancreatic cancer tissues and impairs insulin secretion function of β-cell

BackgroundUnderstanding the pathogenic mechanism of pancreatic cancer associated diabetes (PCDM) might help yield biomarkers for the early diagnosis of pancreatic cancer (PC) from population with new-onset diabetes. In the current study, we sought to determine the role of macrophage migration inhibitory factor (MIF) in PCDM pathogenesis.MethodsThe protein and mRNA levels of MIF in paraffin-embedded human PC samples, chronic pancreatitis specimens, and normal pancreas were measured by immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction. We measured serum levels of MIF in PC patients and controls. The biologic impacts of MIF overexpression on insulin secretion function of mice islets and β cells (HIT-T15) were investigated in vitro.ResultsMIF expression was significantly increased in pancreatic cancer tissues compared with chronic pancreatitis or normal pancreas specimens. The insulin secretion function of both islets and HIT-T15 cells was impaired by indirect co-cultured with PC cells or treated with conditioned media from them. Stable MIF knock-down significantly decreased the diabetogenic effect of PC cells, while MIF knock-in HPDE6 cells demonstrated a strong inhibitory effect on insulin secretion function of islets and HIT-T15 cells. MIF impaired βcell function by depressing the Ca2+ currents, decreasing L-type Ca2+ channel α1 subunit protein expression level, and enhancing p-Src activity. Mean serum level of MIF was significant higher in new-onset diabetes associated PC patients in comparison with other groups.ConclusionsMIF is up-regulated in patients with pancreatic cancer and causes dysfunction of insulin secretion in β-cells.

The anti-inflammatory protein p8 protects pancreatic islets from diabetogenic lipotoxic injury ex vivo

Background and aim: According to the so-called “nutrition overflow hypothesis”, type 2 diabetes results from nutrition-induced local tissue inflammation leading to insulin resistance, insulin secretory dysfunction and finally pancreatic beta cell loss. Free fatty acids acting through toll-like receptors are key mediators of this lipotoxic inflammatory response. We previously demonstrated that the intracellular protein p8 exerts potent anti-inflammatory and anti-diabetogenic effects in pancreatic beta cells in vivo. Here we investigated the anti-lipotoxic potential of p8 ex vivo in pancreatic islets of transgenic mice with beta cell-specific p8 overexpression.

P8 is a novel intracellular mediator of pancreatic β-cell protection that preserves insulin secretory function during inflammatory cell stress in vivo

Introduction: A current hypothesis considers type 2 diabetes a result of over nutrition-induced local inflammation leading to insulin resistance, insulin secretory dysfunction and pancreatic β-cell loss. The intracellular protein p8 has been shown to reduce tissue damage during acute pancreatitis. To investigate its role in the endocrine pancreas we generated transgenic mice with β-cell-specific p8 overexpression (Tg).

Evolution of diabetes: plasticity of epigenetic is a novel key to cause t2dm

Epigenetic modification of gene expression is one mechanism by which genetic susceptibility and environmental insults can lead to Type 2 Diabetes Mellitus (T2DM) problem worldwide. The peripheral insulin resistance is common during obesity and aging in animals and people, progression to T2DM is largely due to insulin secretory dysfunction and significant apoptosis of functional β-cells, leading to an inability to compensate for insulin resistance. It is recognized that environmental factors and genetic play an important role in the pathogenesis of diabetes. However, our knowledge surrounding molecular mechanisms by which these factors trigger β-cell dysfunction and diabetes is still limited. Epigenetic changes could account for the accelerated rates of chronic and persistent phenotype and genotype complications associated with diabetes. Epigenetic mechanisms are likely involved, especially in obesity and diabetes mellitus. It is not the only factor; there is a wide variety of potential modulators of the human epigenome which can be modified through phenotype and genotype. Epigenetic changes are defined as mitotically inheritable alterations in gene expression that are not related to changes in DNA sequence. In this article, we comprehensively review the role of UV radiation, DNA methylation, histone modifications and MicroRNA (miRs) effects in glucose metabolism in health and disease. It also address to understand epigenetic phenomena, which is directly attributable to technologies that allow researchers to pinpoint the genomic location of proteins package, and molecular events which underlie transcriptional changes or regulate access to DNA for the management of T2DM.

Diet‐induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism

Excessive uptake of fatty acids and glucose by adipose tissue triggers adipocyte dysfunction and infiltration of immune cells. Altered metabolic homeostasis in adipose tissue promotes insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Inflammatory and metabolic processes are mediated by certain proteolytic enzymes that share a common cellular target, protease-activated receptor 2 (PAR2). This study showed that human and rat obesity correlated in vivo with increased expression of PAR2 in adipose tissue, primarily in stromal vascular cells (SVCs) including macrophages. PAR2 was expressed more than other PARs on human macrophages and was increased by dietary fatty acids (palmitic, stearic, and myristic). A novel PAR2 antagonist, GB88 (5-isoxazoyl-Cha-Ile-spiroindene-1,4-piperidine), given orally at 10 mg/kg/d (wk 8-16) reduced body weight by ∼10% in obese rats fed a high-carbohydrate high-fat (HCHF) diet for 16 wk, and strongly attenuated adiposity, adipose tissue inflammation, infiltrated macrophages and mast cells, insulin resistance, and cardiac fibrosis and remodeling; while reversing liver and pancreatic dysfunction and normalizing secretion of PAR2-directed glucose-stimulated insulin secretion in MIN6 β cells. In summary, PAR2 is a new biomarker for obesity, and its expression is stimulated by dietary fatty acids; PAR2 is a substantial contributor to inflammatory and metabolic dysfunction; and a PAR2 antagonist inhibits diet-induced obesity and inflammatory, metabolic, and cardiovascular dysfunction.

Sweet and Sour β-Cells: ROS and Hif1α Induce Warburg-Like Lactate Production During Type 2 Diabetes

β-Cell dysfunction is a hallmark of type 2 diabetes (T2DM) and comprises insulin secretory dysfunction and/or reduced β-cell mass (1). Normal β-cell function requires tight coupling of glucose metabolism with insulin secretion via a well-defined pathway utilizing oxidative metabolism and ATP production (2). Moreover, β-cell gene expression and metabolism are tuned to suppress pathways that would otherwise disrupt glucose-stimulated insulin secretion (GSIS), such as lactate production (3,4). Oversupply of glucose during T2DM can disrupt GSIS (glucotoxicity) via excessive generation of reactive oxygen species (ROS) causing oxidative stress: β-cells are particularly susceptible due to relatively low expression of antioxidant enzymes (5). Therefore, understanding the mechanisms by which ROS contribute to β-cell dysfunction during T2DM is an important research goal. The new study by Sasaki et al. (6) identifies a novel mechanism by which ROS impair β-cell function during T2DM: by activating hypoxia-inducible factor 1α (Hif1α), switching on lactate production and impairing glucose oxidation and insulin secretion (Fig. 1). The authors studied Goto-Kakizaki (GK) rats, an inbred, polygenic model of nonobese T2DM with β-cell dysfunction, originally derived from Wistar rats, and found that dual antioxidant treatment significantly improved GSIS in vivo and in vitro, consistent with previous studies using the GK rat and other diabetic models such as Zucker diabetic fatty rats and db / db mice (5). Taken together, these findings reinforce the role of glucotoxicity and oxidative stress in β-cell dysfunction during T2DM. Furthermore, …

Neprilysin Deficiency Protects Against Fat-Induced Insulin Secretory Dysfunction by Maintaining Calcium Influx

Neprilysin contributes to free fatty acid (FFA)-induced cellular dysfunction in nonislet tissues in type 2 diabetes. Here, we show for the first time that with prolonged FFA exposure, islet neprilysin is upregulated and this is associated with reduced insulin pre-mRNA and ATP levels, oxidative/nitrative stress, impaired potassium and calcium channel activities, and decreased glucose-stimulated insulin secretion (GSIS). Genetic ablation of neprilysin specifically protects against FFA-induced impairment of calcium influx and GSIS in vitro and in vivo but does not ameliorate other FFA-induced defects. Importantly, adenoviral overexpression of neprilysin in islets cultured without FFA reproduces the defects in both calcium influx and GSIS, suggesting that upregulation of neprilysin per se mediates insulin secretory dysfunction and that the mechanism for protection conferred by neprilysin deletion involves prevention of reduced calcium influx. Our findings highlight the critical nature of calcium signaling for normal insulin secretion and suggest that interventions to inhibit neprilysin may improve β-cell function in obese humans with type 2 diabetes.

Multiscale modelling of insulin secretion during an intravenous glucose tolerance test

Dysfunctional insulin secretion from pancreatic β-cells plays a major role in the development of diabetes. The intravenous glucose tolerance test (IVGTT) is a widely used clinical test to assess β-cell function. The analysis of IVGTT data is conveniently performed using mathematical models, which need to be fairly simple to enable parameter identifiability (minimal models), but should at the same time have sound biological foundation at the cellular level. Using mathematical analysis and model reduction, we show here that our recent mathematical model of insulin secretory granule dynamics in β-cells provides mechanistic underpinning for our minimal model of pancreatic insulin secretion during an IVGTT.

Islet β cell mass in diabetes and how it relates to function, birth, and death

In type 1 diabetes (T1D) β cell mass is markedly reduced by autoimmunity. Type 2 diabetes (T2D) results from inadequate β cell mass and function that can no longer compensate for insulin resistance. The reduction of β cell mass in T2D may result from increased cell death and/or inadequate birth through replication and neogenesis. Reduction in mass allows glucose levels to rise, which places β cells in an unfamiliar hyperglycemic environment, leading to marked changes in their phenotype and a dramatic loss of glucose-stimulated insulin secretion (GSIS), which worsens as glucose levels climb. Toxic effects of glucose on β cells (glucotoxicity) appear to be the culprit. This dysfunctional insulin secretion can be reversed when glucose levels are lowered by treatment, a finding with therapeutic significance. Restoration of β cell mass in both types of diabetes could be accomplished by either β cell regeneration or transplantation. Learning more about the relationships between β cell mass, turnover, and function and finding ways to restore β cell mass are among the most urgent priorities for diabetes research.