Impaired Β-cell Research Articles

β-Cell function in postmenopausal women with isolated post-challenge hyperglycemia.

Isolated post-challenge hyperglycemia (IPH) is an early stage of type 2 diabetes mellitus (T2DM), with fasting glucose <126 mg/dL and 2-h glucose ≥200 mg/dL. Observations of insulin secretion profile in subjects with IPH may provide an insight into the pathogenesis of T2DM in older women. We recruited 555 naturally postmenopausal women without a history of T2DM to the present study. All participants received a 75-g oral glucose tolerance test to determine whether they had IPH. General linear models were used to compare differences in glucose metabolism among subjects. Early phase insulin responses to oral glucose were significantly decreased in women with IPH versus those with impaired glucose tolerance (IGT) and normal glucose tolerance (geometric mean [95% confidence interval] insulinogenic index 61 [54-79] vs 90 [83-97] and 105 [96-116], respectively; P < 0.0001). In addition, there were significant decreases in late-phase insulin release as metabolic status shifted from normal glucose tolerance to IGT to IPH. In the present cohort, the relative contribution of early insulin secretion to 2-h glucose was no longer significant ( P = 0.15) after multiple factors, including indicators of insulin resistance and late-phase insulin release, were entered into the regression model simultaneously. The results demonstrate that postmenopausal women with IPH are characterized by impaired β-cell function. There were significant decreases in early and late-phase insulin release as glucose intolerance escalated. Disturbance in β-cell function seems to be an important factor associated with early T2DM in postmenopausal women.

Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population.

BackgroundThe association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes.MethodsThe study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-β were used to measure insulin resistance and β-cell secretory function, respectively.ResultsThe analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β-cell function.ConclusionIn the Russian population, genes, which affect insulin synthesis and secretion in the β-cells of the pancreas, play a central role in the development of T2DM.

P 155 - The role of aging and senescence on pancreatic β-cell function and proliferation

Aging and age-related diseases are associated with the impairment of tissue function and their regenerative capacity. In terms of pancreatic β-cells, it is well known that insulin resistance in peripheral tissues increases with age due to metabolic changes caused by adiposity or physical inactivity. But in the presence of functional β-cells, insulin resistance alone is insufficient to lead to type-2-diabetes. However, in combination with an insulin secretory dysfunction and a decreased β-cell mass coincided with advanced age, this leads to worsening of glucose tolerance and finally to hyperglycemia and the onset of type-2-diabetes. Investigations regarding the molecular basis of the limited proliferation capacity of aged endocrine pancreas revealed that cellular senescence seems to be involved. Senescence is characterized by an upregulation of tumor suppressor proteins such as p16Ink4a and p53, severe morphological diversifications or widespread changes in protein expression and secretion. But the impact of senescence-related changes on β-cell impairment has not yet been described. Therefore, by comparing lean C57Bl/6 J mice and adipose, diabetes-prone New Zealand Obese mice with diabetes-resistant B6.V-Lepob/J mice in different stages of age, we aim to characterize senescent β-cells and investigate the role of cellular senescence on β-cell functionality and proliferation.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

Baicalein protects rat insulinoma INS-1 cells from palmitate-induced lipotoxicity by inducing HO-1.

Objectiveβ-Cell dysfunction plays a central role in the pathogenesis of type 2 diabetes (T2D), and the identification of novel approaches to improve β-cell function is essential to treat this disease. Baicalein, a flavonoid originally isolated from the root of Scutellaria Baicalensis, has been shown to have beneficial effects on β-cell function. Here, the authors investigated the molecular mechanism responsible for the protective effects of baicalein against palmitate (PA)-induced impaired β-cell function, and placed focus on the role of heme oxygenase (HO)-1.MethodsRat pancreatic β-cell line INS-1 cells or mouse pancreatic islets were cultured with PA (500 μM) to induce lipotoxicity in the presence or absence of baicalein (50 μM), and the expressions of the ER stress markers, ATF-3, CHOP and GRP78 were detected by Western blotting and/or qPCR. The involvement of HO-1 was evaluated by HO-1 siRNA transfection and using the HO-1 inhibitor ZnPP.ResultsBaicalein reduced PA-induced ER stress and inflammation and enhanced insulin secretion, and these effects were associated with the induction of HO-1. Furthermore, these protective effects were attenuated by ZnPP and by HO-1 siRNA. Pretreatment of PD98059 (an ERK inhibitor) significantly inhibited the protective effects of baicalein and blocked HO-1 induction. On the other hand, CO production by RuCO (a CO donor) ameliorated PA-induced ER stress, suggesting that CO production followed by HO-1 induction may contribute to the protective effects of baicalein against PA-induced β-cell dysfunction.ConclusionBaicalein protects pancreatic β-cells from PA-induced ER stress and inflammation via an ERK-HO-1 dependent pathway. The authors suggest HO-1 induction in pancreatic β-cells appears to be a promising therapeutic strategy for T2D.

Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Impairs β-Cell Function In Vivo

Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-I signaling. We therefore examined the effects of mutation of five "inhibitory" Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β-cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A). Islets size, number, and mRNA levels of catalase and superoxide dismutase were increased, whereas those of nitric oxide synthase were decreased, in 7- to 10-week-old IRS25A-β mice compared with IRS2WT-β mice. However, glucose homeostasis and insulin secretion in IRS25A-β mice were impaired when compared with IRS2WT-β mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet β-cell transcription factors such as Nkx6.1 and MafA Similarly, components mediating the unfolded protein response were decreased in islets of IRS25A-β mice in accordance with their decreased insulin secretion. The beneficial effects of IRS25A on β-cell proliferation and β-cell transcription factors were evident only in 5- to 8-day-old mice. These findings suggest that elimination of inhibitory Ser phosphorylation sites of IRS2 exerts short-term beneficial effects in vivo; however, their sustained elimination leads to impaired β-cell function.

Add on DPP-4 inhibitor alogliptin alone or in combination with pioglitazone improved β-cell function and insulin sensitivity in metformin treated PCOS

ABSTRACTPurpose: Impaired β-cell function remains unaddressed in PCOS. The aim of the study was to evaluate whether dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (ALO) alone or in combination with pioglitazone (PIO) improves β-cell function along with insulin resistance (IR) in metformin (MET) treated obese women with PCOS with persistent IR. Materials and methods: In 12-week randomized study, ALO 25 mg QD (n=15) or ALO 25 mg QD and PIO 30 mg QD (n=15) was added to MET 1000 mg BID in PCOS women (aged 34.4 ± 6.5 years, BMI 39.0 ± 4.9 kg/m2, HOMA-IR 4.82 ± 2.52, mean ± SD). Model derived parameters of glucose homeostasis from the meal tolerance test (MTT) were determined. The ability of the β-cell function was assessed by the adaptation index (AI). Results: MET-ALO and MET-ALO-PIO resulted in a significant decrease of HOMA-IR (by 1.6±2.3 (p=0.039) and 2.9±3.3 (p=0.001), respectively) and an increase in insulin sensitivity (IS) after meal ingestion (oral glucose IS) by 31.4±97.5 ml·min–1·m–2 (p=0.007) vs 39.0±58.1 ml·min–1·m–2 (p=0.039), respectively. AI across the entire group was significantly improved from 329.6±200.6 to 442.5±303.9 (p=0.048). Conclusions: ALO alone and in combination with PIO improved IR along with dynamic IS and meal related β-cell function when added to MET treated PCOS.

Combined oral contraceptive and nitric oxide synthesis inhibition synergistically causes cardiac hypertrophy and exacerbates insulin resistance in female rats

Combined oral contraceptive (COC) use or inhibition of nitric oxide (NO) synthesis has been shown to cause hypertension and insulin resistance. However, the concomitant effects of COC and NO deficiency on the heart and glucose regulation are not well known. We therefore hypothesized that COC treatment during NO deficiency would lead to the development of cardiac hypertrophy that is associated with aggravated glucose deregulation, pro-inflammatory and pro-fibrotic biomarkers. Eight-week-old female Wistar rats were randomly allotted into control, NO deficient (NG-nitro-l-arginine methyl ester: L-NAME; 20.0mg/kg b.w.), COC-treated (1.0μg ethinylestradiol+5.0μg levonorgestrel, p.o) and L-NAME+COC-treated groups. The animals were treated daily for 6 weeks. Systolic blood pressure was estimated by tail-cuff plethysmography, insulin resistance (IR) and β-cell function were estimated by homeostatic model of assessment (HOMA-IR and HOMA-β). Pro-inflammatory (C-reactive protein; CRP and uric acid) and pro-fibrotic (plasminogen activator inhibitor-1; PAI-1) biomarkers were estimated in the plasma. Cardiac histological examination was also done. Results show that COC or L-NAME treatments led to increased blood pressure, HOMA-IR, impaired β-cell function, PAI-1, CRP and uric acid, without significant effect on cardiac mass. L-NAME+COC-treated group had significantly higher blood pressure, HOMA-IR, impaired β-cell function, PAI-1, CRP and cardiac mass than COC- or L-NAME-treated groups. Histological examination validated that COC use during NO deficiency causes cardiac hypertrophy. The present study demonstrates that COC treatment and NO deficiency synergistically causes cardiac hypertrophy that is associated with aggravated glucose deregulation, atherogenic dyslipidemia, pro-inflammatory and pro-fibrotic markers.

Exploring inter-organ crosstalk to uncover mechanisms that regulate β-cell function and mass.

Impaired β-cell function and insufficient β-cell mass compensation are twin pathogenic features that underlie type 2 diabetes (T2D). Current therapeutic strategies continue to evolve to improve treatment outcomes in different ethnic populations and include approaches to counter insulin resistance and improve β-cell function. Although the effects of insulin secretion on metabolic organs such as liver, skeletal muscle and adipose is directly relevant for improving glucose uptake and reduce hyperglycemia, the ability of pancreatic β-cells to crosstalk with multiple non-metabolic tissues is providing novel insights into potential opportunities for improving β-cell function and/or mass that could have beneficial effects in patients with diabetes. For example, the role of the gastrointestinal system in the regulation of β-cell biology is well recognized and has been exploited clinically to develop incretin-related antidiabetic agents. The microbiome and the immune system are emerging as important players in regulating β-cell function and mass. The rich innervation of islet cells indicates it is a prime organ for regulation by the nervous system. In this review, we discuss the potential implications of signals from these organ systems as well as those from bone, placenta, kidney, thyroid, endothelial cells, reproductive organs and adrenal and pituitary glands that can directly impact β-cell biology. An added layer of complexity is the limited data regarding the relative relevance of one or more of these systems in different ethnic populations. It is evident that better understanding of this paradigm would provide clues to enhance β-cell function and/or mass in vivo in the long-term goal of treating or curing patients with diabetes.

Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) represents a rapidly increasing threat to global public health. T2DM arises largely from obesity, poor diet, and lack of exercise, but it also involves genetic predisposition. Here we report that the KCNE2 potassium channel transmembrane regulatory subunit is expressed in human and mouse pancreatic β cells. Kcne2 deletion in mice impaired glucose tolerance as early as 5 wk of age in pups fed a Western diet, ultimately causing diabetes. In adult mice fed normal chow, skeletal muscle expression of insulin receptor β and insulin receptor substrate 1 were down-regulated 2-fold by Kcne2 deletion, characteristic of T2DM. Kcne2 deletion also caused extensive pancreatic transcriptome changes consistent with facets of T2DM, including endoplasmic reticulum stress, inflammation, and hyperproliferation. Kcne2 deletion impaired β-cell insulin secretion in vitro up to 8-fold and diminished β-cell peak outward K+ current at positive membrane potentials, but also left-shifted its voltage dependence and slowed inactivation. Interestingly, we also observed an aging-dependent reduction in β-cell outward currents in both Kcne2+/+ and Kcne2-/- mice. Our results demonstrate that KCNE2 is required for normal β-cell electrical activity and insulin secretion, and that Kcne2 deletion causes T2DM. KCNE2 may regulate multiple K+ channels in β cells, including the T2DM-linked KCNQ1 potassium channel α subunit.-Lee, S. M., Baik, J., Nguyen, D., Nguyen, V., Liu, S., Hu, Z., Abbott, G. W. Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus.

Body mass index trajectory patterns and changes in visceral fat and glucose metabolism before the onset of type 2 diabetes

We investigated BMI trajectory patterns before diabetes diagnosis and examined associated changes in visceral adiposity and glucose metabolism. 23,978 non-diabetic Japanese participants (2,789 women) aged 30–64 years were assessed with a mean follow-up of 7.6 years. Diabetes was diagnosed via fasting glucose, HbA1c, and self-report. Latent-class trajectory analyses were performed to identify BMI trajectories. Longitudinal changes in BMI, visceral adiposity, and glucose metabolism were estimated using mixed models. 1,892 individuals developed diabetes. Three distinct BMI trajectories were identified in adults developing and not developing diabetes, respectively. Among adults developing diabetes, 47.3% were classified as “medium BMI” (n = 895), and had increased mean BMI within the obesity category before diagnosis. The “low BMI” group (38.4%, n = 726) had an initial mean BMI of 21.9 kg/m2, and demonstrated small weight gain. The “high BMI” group (n = 271) were severely obese and showed greater increase in BMI until diagnosis. All groups which developed diabetes showed absolute and/or relative increase in visceral fat and impaired β-cell compensation for insulin resistance. All groups not developing diabetes showed measured variables were relatively stable during observation. These data suggest that visceral fat gain may induce β-cell failure in compensation for insulin resistance, resulting in diabetes regardless of obesity level.

Pancreatic impairment and Igf2 hypermethylation induced by developmental exposure to bisphenol A can be counteracted by maternal folate supplementation.

Increasing evidence indicates that bisphenol A (BPA), a widely manufactured environmental pollutant, can induce changes in DNA methylation paatterns, which is a potential mechanism linking this environmental exposure to disease development. We investigated the influence of developmental exposure to BPA on pancreatic DNA methylation patterns and whether maternal folate supplementation can modify the epigenetic status and pancreatic impairment induced by BPA. Our results showed that maternal dietary folate supplementation in rats exposed to BPA counteracted the observed BPA-induced pancreatic impairments in the offspring, which included disrupted insulin secretion and glucose intolerance, and impaired morphology and ultrastructure of β cells. Moreover, these pancreatic dysfunctions were shown to be associated with low expression and DNA hypermethylation of insulin-like growth factor-2 (Igf2) in islets induced by exposure to BPA during the developmental period. Importantly, maternal dietary folate supplementation was demonstrated to negate this Igf2 DNA hypermethylation in the offspring, which was consistent with the upregulation of Igf2 expression. Overall, our results suggest that early developmental exposure to BPA alters the DNA methylation of Igf2, that these altered methylation patterns are associated with impaired β-cell function in the offspring and that these effects can be counteracted by maternal folate supplementation. Copyright © 2017 John Wiley & Sons, Ltd.

Insulin Secretion and Resistance in Normoglycemic Patients with Sickle Cell Disease

Diabetes mellitus has been described in chronic hemolytic anemias, but data are scarce regarding glucose metabolism in normoglycemic patients. To address this issue, we evaluated insulin sensitivity and secretion in patients with sickle cell disease (SCD) and normal oral glucose tolerance test (OGTT). Forty-five adult patients with homozygous sickle cell disease and Hb S/β-thalassemia (β-thal) (mean age 42.5 ± 9.5 years) and 45 healthy individuals matched for age and body mass index (BMI) were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast. All patients had normal OGTT. Fasting glucose values did not differ significantly between groups, however, fasting insulin levels were significantly lower in the patient group compared to the control group (5.1 ± 2.7 μUI/mL vs. 11.3 ± 6.6 μUI/mL, p <0.005, respectively). Pancreatic β-cell insulin secretion index in the fasting state was significantly lower in patients with sickle cell disease compared with controls as assessed by calculations of the homeostatic model assessment for β-cell function (HOMA β%) (77.0 vs. 106.0%, respectively, p <0.001), while HOMA insulin resistance (HOMA IR), was lower in the sickle cell disease patients, albeit not statistically significant (0.8 vs. 1.1, respectively, p = 0.054). The HOMA β% was significantly correlated with ferritin levels (r = –526, p <0.001) (negative correlation) and with 25-hydroxy (OH)-vitamin D levels (r = 0.479, p <0.001) (positive correlation), even when adjusted for serum ferritin levels. Normoglycemic patients with sickle cell disease demonstrated impaired β-cell function with reduced insulin secretion even before OGTT was impaired.

Bioenergetics and Type 2 Diabetes

Hyperglycemia of type 2 diabetes mellitus (T2DM) develops when pancreatic β-cells damaged by chronic exposure to elevated blood glucose and lipids (glucolipotoxicity) fail to synthesize and secrete sufficient quantities of insulin for maintaining plasma glucose level. Despite intensive studies in this field, the molecular mechanism by which fatty acids (FA) cause β-cell impairment is not well understood. It still remains unknown what are the lipid- or glucose-derived molecules directly responsible for the impairment of β-cell function? Our studies showed that in addition to impaired insulin secretion and loss of biphasicity, T2D islets exhibited altered cell bioenergetics as evidenced by decreased oxygen consumption rate as compared to those of the control islets. We also discovered that fuel overload (high level of FA and glucose leads to incomplete FA oxidation and results in accumulation of toxic long-chain 3-OH-fatty acids that could induce oxidative stress and disrupt mitochondrial function. Timedependent impairments of bioenergetics due to chronic exposure to elevated blood glucose and lipids would be the consequence leading to pancreatic β-cell failure.

Impaired pancreatic β-cell compensatory function in Chinese patients with type 2 diabetes and high genetic risk: a 9-year prospective cohort study

BackgroundSeveral prospective studies have shown that a genetic risk score combining multiple loci could predict incident type 2 diabetes in white people, but few studies elucidated the underlying mechanism. We aimed to assess the combined effects of type 2 diabetes risk variants on predicting deterioration of blood glucose tolerance, and progressive changes in β-cell function and insulin sensitivity in a prospective cohort in the Chinese population. MethodsWe constructed a weighted genetic risk score model based on 40 variants associated with type 2 diabetes validated in an established cross-sectional Chinese population (n=6822). The weighted genetic risk score was categorised into tertiles (low risk<43·0, intermediate risk ≤43·0 to <46·7, high risk ≥46·7) to assess the score's predictive effect on incidence of type 2 diabetes and impaired glucose regulation, as well as changes in Stumvoll first and second phase insulin secretion indices, and Gutt's insulin sensitivity index. We used a community-based prospective cohort by recruiting participants from the Shanghai region of China, including participants with normal glucose tolerance and patients with impaired glucose regulation at baseline. We analysed the data using logistic, Cox, and multiple linear regression tests. Ethical approval was granted by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Informed patient consent was given by all participants. FindingsThe study commenced in 1998–99 with the enrolment of 2495 individuals at baseline, including 2192 individuals with normal glucose tolerance and 303 with impaired glucose regulation. Individuals were also invited to participate in another two follow-up examinations in 2002–03 and 2010–12. Over an average follow-up of 9·0 (SD 2·8) years, 260 individuals developed type 2 diabetes and 326 individuals developed impaired glucose regulation. The weighted genetic risk score as a ranked variable predicted incidence of type 2 diabetes and impaired glucose regulation in the logistic regression (odds ratio 1·24, 95% CI 1·10–1·39, p=0·0004) as well as in the Cox model (hazard ratio 1·13, 95% CI 1·03–1·24, p=0·013) after adjusting for age, sex, BMI, and smoking and alcohol status at baseline. Moreover, multiple linear regression revealed that the weighted genetic risk score as a ranked variable had a predictive effect on deterioration of β-cell function (β −0·0480 for first phase insulin secretion, and β −0·0303 for second phase insulin secretion, p<0·0001) but not insulin sensitivity (p=0·38) during the 9 year follow-up period. Only individuals in the lowest group had elevated first and second phase insulin secretion, which compensated for impaired insulin sensitivity. However, individuals in the other two groups had decreased first-phase insulin secretion accompanied by increased second-phase secretion to partly offset the initial low levels. InterpretationThe weighted genetic risk score predicted deterioration of blood glucose control through effects on β-cell function in this Chinese population. Individuals in the intermediate weighted or high weighted genetic risk score group showed progressive deterioration of β-cell function. FundingNational Science Foundation of China, the National 863 programme, the National 973 programme, the National Program for Support of Top-notch Young Professionals, Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support, and the Shanghai Jiao Tong Medical and Engineering Foundation.

Maternal Low Protein Isocaloric Diet Suppresses Pancreatic β-Cell Proliferation in Mouse Offspring via miR-15b.

The mechanism underlying the increased susceptibility of type 2 diabetes in offspring of maternal malnutrition is poorly determined. Here we tested the hypothesis that functional microRNAs (miRNAs) mediated the maternal low-protein (LP) isocaloric diet induced pancreatic β-cell impairment. We performed miRNA profiling in the islets from offspring of LP and control diet mothers to explore the potential functional miRNAs responsible for β-cell dysfunction. We found that LP offspring exhibited impaired glucose tolerance due to decreased β-cell mass and insulin secretion. Reduction in the β-cell proliferation rate and cell size contributed to the decreased β-cell mass. MiR-15b was up-regulated in the islets of LP offspring. The up-regulated miR-15b inhibited pancreatic β-cell proliferation via targeting cyclin D1 and cyclin D2. Inhibition of miR-15b in LP islet cells restored β-cell proliferation and insulin secretion. Our findings demonstrate that miR-15b is critical for the regulation of pancreatic β-cells in offspring of maternal protein restriction, which may provide a further insight for β-cell exhaustion originated from intrauterine growth restriction.

Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes.

AimsChanges in the islet vasculature have been implicated in the regulation of β-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the β-cell to compensate for the increased insulin demand in obesity eventually leads to diabetes; as a result of the complex interplay of genetic and environmental factors (e.g. ongoing inflammation within the islets) and impaired vascular function. The Angiopoietin/Tie (Ang/Tie) angiogenic system maintains vasculature and is closely related to organ inflammation and angiogenesis. In this study we aimed to identify whether the vessel area within the islets changes in diabetes and whether such changes would be triggered by the Tie-antagonist Ang-2.MethodsImmunohistochemical and qPCR analyses to follow islet vascularization and Ang/Tie levels were performed in human pancreatic autopsies and isolated human and mouse islets. The effect of Ang-2 was assessed in β-cell-specific Ang-2 overexpressing mice during high fat diet (HFD) feeding.ResultsIslet vessel area was increased in autopsy pancreases from patients with T2D. The vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD and under glucolipotoxic conditions (22.2 mM glucose/ 0.5 mM palmitate) in vitro in human and mouse islets, in contrast to its downregulation by cytokines (IL-1β, IFN-ɣ and TNF-α). Ang-1 on the other hand was oppositely regulated, with a significant loss under glucolipotoxic condition, a trend to reduce in islets from patients with T2D and an upregulation by cytokines. Modulation of such changes in Ang-2 by its overexpression or the inhibition of its receptor Tie-2 impaired β-cell function at basal conditions but protected islets from cytokine induced apoptosis. In vivo, β-cell-specific Ang-2 overexpression in mice induced hypervascularization under normal diet but contrastingly led to hypovascularized islets in response to HFD together with increased apoptosis and reduced β-cell mass.ConclusionsIslet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents β-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis.

Unexpected effects of the MIP-CreER transgene and tamoxifen on β-cell growth in C57Bl6/J male mice.

Transgenic mouse models have been fundamental in the discovery of factors that regulate β‐cell development, mass, and function. Several groups have recently shown that some of these models display previously uncharacterized phenotypes due to the transgenic system itself. These include impaired islet function and increased β‐cell mass due to the presence of a human growth hormone (hGH) minigene as well as impaired β‐cell proliferation in response to tamoxifen (TM) administration. We aimed to determine how these systems impact β‐cell mass and proliferation during high fat diet (HFD). To this end, we utilized C57Bl6/J male MIP‐CreER mice, which are known to express hGH, or wild‐type (WT) mice treated with vehicle corn oil or TM. In the absence of TM, MIP‐CreER mice fed a chow diet have increased β‐cell mass due to hypertrophy, whereas replication is unchanged. Similarly, after 1 week on HFD, MIP‐CreER mice have increased β‐cell mass compared to WT, and this is due to hypertrophy rather than increased proliferation. To assess the impact of TM on β‐cell proliferation and mass, WT mice were treated with vehicle corn oil or TM and then fed a chow diet or HFD for 3 days. We observed that TM‐treated mice have improved glucose homeostasis on chow diet but impaired β‐cell proliferation in response to 3 days HFD feeding. These results unveil additional complications associated with commonly used pancreas‐specific mouse models.

β-Cell death is decreased in women with gestational diabetes mellitus.

BackgroundGestational diabetes mellitus (GDM) affects approximately 7–17 % of all pregnancies and has been recognized as a significant risk factor to neonatal and maternal health. Postpartum, GDM significantly increases the likelihood of developing type 2 diabetes (T2D). While it is well established that insulin resistance and impaired β-cell function contribute to GDM development, the role of active β-cell loss remains unknown. Differentially methylated circulating free DNA (cfDNA) is a minimally invasive biomarker of β-cell loss in type 1 diabetes mellitus. Here we use cfDNA to examine the levels of β-cell death in women with GDM.MethodsSecond to third-trimester pregnant women with GDM were compared with women with normal pregnancy (PRG), women at postpartum (PP), and non-pregnant (NP) women. Fasting glucose levels, insulin, and C-peptide levels were measured. Serum samples were collected and cfDNA purified and bisulfite treated. Methylation-sensitive probes capable of differentiating between β-cell-derived DNA (demethylated) and non-β-cell-derived DNA (methylated) were used to measure the presence of β-cell loss in the blood.ResultsGDM was associated with elevated fasting glucose levels (GDM = 185.9 ± 5.0 mg/dL) and reduced fasting insulin and c-peptide levels when compared with NP group. Interestingly, β-cell derived insulin DNA levels were significantly lower in women with GDM when compared with PRG, NP, and PP groups (demethylation index: PRG = 7.74 × 10−3 ± 3.09 × 10−3, GDM = 1.01 × 10−3 ± 5.86 × 10−4, p < 0.04; NP = 4.53 × 10−3 ± 1.62 × 10−3, PP = 3.24 × 10−3 ± 1.78 × 10−3).ConclusionsThese results demonstrate that β-cell death is reduced in women with GDM. This reduction is associated with impaired insulin production and hyperglycemia, suggesting that β-cell death does not contribute to GDM during the 2nd and 3rd trimester of pregnancy.

Longitudinal Associations of Exposure to Perfluoroalkylated Substances in Childhood and Adolescence and Indicators of Adiposity and Glucose Metabolism 6 and 12 Years Later: The European Youth Heart Study.

To investigate the long-term association of exposure to perfluoroalkylated substances, including perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), during childhood (9 years) and adolescence (15 years) on indicators of adiposity and glucose metabolism in adolescence (15 years) and young adulthood (21 years). Secondarily, we aim to clarify the degree of tracking of exposure from childhood into young adulthood. Data derived from a large multicenter prospective cohort study, in which the same participants have been observed from childhood (N = 590), during adolescence (N = 444), and into young adulthood (N = 369). Stored plasma samples were analyzed for PFOS and PFOA. Indicators of adiposity comprising body height, body weight, sum of four skinfolds, and waist circumference, as well as indicators of glucose metabolism, comprising fasting blood glucose, triglyceride, and insulin levels, β-cell function, and insulin resistance, have been collected at all study waves. Multiple linear regression was applied in order to model earlier exposure on later outcome while controlling for baseline outcome levels, sex, age, and socioeconomic factors. Childhood exposure to PFOS was associated with indicators of adiposity at 15 years of age that are displayed in elevated BMI, skinfold thickness, and waist circumference, as well as increased skinfold thickness and waist circumference at 21 years of age. PFOA exposure in childhood was associated with decreased β-cell function at 15 years of age. We did not observe associations between exposure during adolescence and indicators of adiposity and glucose metabolism in young adulthood. This study found evidence for childhood exposure to PFOS and PFOA predicting adiposity at 15 and 21 years of age and impaired β-cell function at 15 years of age, respectively.