Prenatal androgen excess impairs beta cell function by decreased Sirtuin3 expression

Prenatal androgen exposure induces metabolic disorders in female offspring. However, the long-term effect of maternal testosterone excess on glucose metabolism, especially on pancreatic beta cell function, is rarely investigated. Our current study mainly focused on the effects of prenatal testosterone exposure on glucose metabolism and pancreatic beta cell function in aged female offspring. By using maternal mice and their female offspring as animal models, we found that prenatal androgen treatment induced obesity and glucose intolerance in aged offspring. These influences were accompanied by decreased fasting serum insulin concentration, elevated serum triglyceride and testosterone concentrations. Glucose stimulated insulin secretion in pancreatic beta cells of aged female offspring was also affected by prenatal testosterone exposure. We further confirmed that increased serum testosterone contributed to down regulation of Sirtuin 3 expression, activated oxidative stress and impaired pancreatic beta cell function in aged female offspring. Moreover, over-expression of Sirtuin 3 in islets isolated from female offspring treated with prenatal testosterone normalized the oxidative stress level, restored cyclic adenosine monophosphate and adenosine triphosphate generation, which finally improved glucose stimulated insulin secretion in beta cells. Taken together, these results demonstrated that prenatal testosterone exposure caused metabolic disturbance in aged female offspring via suppression of Sirtuin 3 expression and activation of oxidative stress in pancreatic beta cells.

The Role of Vascular Cells in Pancreatic Beta-Cell Function

Insulin-producing β-cells constitute the majority of the cells in the pancreatic islets. Dysfunction of these cells is a key factor in the loss of glucose regulation that characterizes type 2 diabetes. The regulation of many of the functions of β-cells relies on their close interaction with the intra-islet microvasculature, comprised of endothelial cells and pericytes. In addition to providing islet blood supply, cells of the islet vasculature directly regulate β-cell activity through the secretion of growth factors and other molecules. These factors come from capillary mural pericytes and endothelial cells, and have been shown to promote insulin gene expression, insulin secretion, and β-cell proliferation. This review focuses on the intimate crosstalk of the vascular cells and β-cells and its role in glucose homeostasis and diabetes.

Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

Aims/hypothesis Variants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B. Methods CRISPR/Cas9-induced global C2cd4b-knockout mice and zebrafish larvae with c2cd4a deletion were used to study the role of this gene in glucose homeostasis. C2 calcium dependent domain containing protein (C2CD)4A and C2CD4B constructs tagged with FLAG or green fluorescent protein were generated to investigate subcellular dynamics using confocal or near-field microscopy and to identify interacting partners by mass spectrometry. Results Systemic inactivation of C2cd4b in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female C2cd4b mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC, p = 0.01) and defective in vivo, but not in vitro, insulin secretion (p = 0.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (p = 0.003). In sharp contrast, male C2cd4b null mice displayed essentially normal glucose tolerance but an increase in body weight (p < 0.001) and fasting blood glucose (p = 0.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic beta cell function at larval stages in C2cd4a null zebrafish. Fasting blood glucose levels were also unaltered in adult C2cd4a-null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca2+. Binding partners for both included secretory-granule-localised PTPRN2/phogrin. Conclusions/interpretation Our studies suggest that C2cd4b may act centrally in the pituitary to influence sex-dependent circuits that control pancreatic beta cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in humans. Data availability The datasets generated and/or analysed during the current study are available in the Biorxiv repository (www.biorxiv.org/content/10.1101/2020.05.18.099200v1). RNA-Seq (GSE152576) and proteomics (PXD021597) data have been deposited to GEO (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152576) and ProteomeXchange (www.ebi.ac.uk/pride/archive/projects/PXD021597) repositories, respectively. Graphical abstract

Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity

In obesity, overexpression of the IRE1-regulated transcription factor XBP1s protects against metabolic dysfunction by stimulating adaptive remodeling of multiple tissues, most notably the liver. This observation suggests that pharmacologically increasing IRE1/XBP1s signaling might be an attractive approach to mitigate pathologies in obesity and its associated complications. Here, we tested this notion by treating diet-induced obese (DIO) mice with the pharmacologic IRE1/XBP1s activator IXA4. We show that IXA4 treatment selectively activated protective IRE1/XBP1s signaling in livers of DIO mice without inducing obesity-linked pathologies associated with IRE1 hyperactivity, such as liver inflammation and fibrosis. Chronic IXA4 treatment improved systemic glucose metabolism and feeding-induced insulin action in the liver of DIO mice. These improvements were linked to IRE1/XBP1s-induced remodeling of the liver transcriptome, which dampened glucose production and reduced hepatic steatosis. Further, we show that IXA4 treatment enhanced pancreatic beta cell function and insulin homeostasis, indicating that systemic activation of IRE1/XBP1s signaling engendered multi-tissue benefits that integrated to mitigate systemic metabolic dysfunction in DIO mice. Our findings show that selective pharmacological activation of protective IRE1/XBP1s signaling reprograms multiple metabolic tissues, such as liver and pancreas, and represents a potential strategy to correct metabolic alterations in obesity.

Effect of Dapagliflozin on Glycemic Variability in Patients with Type 2 Diabetes under Insulin Glargine Combined with Other Oral Hypoglycemic Drugs

Aim. To evaluate the effect of an inhibitor of sodium-glucose cotransporter 2 (SGLT-2 inhibitor, dapagliflozin) on glycemic variability in type 2 diabetes mellitus (T2D) under insulin glargine combined with oral hypoglycemic drugs, using a continuous glucose monitoring system (CGMS). Methods. This prospective, self-controlled, single-center clinical trial recruited 36 patients with T2D under combined insulin glargine and oral hypoglycemic drugs. General clinical data were collected. Fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated hemoglobin (HbA1c), and C-peptide levels were assessed before and four weeks of dapagliflozin (10 mg per day) treatment. Blood glucose was monitored for 72 hours before and after treatment using CGMS. Results. After treatment with dapagliflozin, FBG decreased from 6.74 ± 1.78 to 5.95 ± 1.13 mmol/L ( p < 0.05 ); PBG decreased from 13.04 ± 2.99 to 10.92 ± 3.26 mmol/L ( p < 0.05 ); HbA1c decreased from 7.37 ± 0.96 % to 6.94 ± 0.80 % . The proportion of patients with HbA 1 c < 7 % increased from 27.8% to 58.3%, and the proportion of patients with HbA 1 c < 7 % and without level 2 hypoglycemia increased from 27.8% to 55.6% ( p < 0.05 ). CGMS data showed reduction of the 24 h MBG, MAGE, time-above-range (TAR, >10 mmol/L), high blood glucose index (HBGI), glucose management indicator (GMI), and incremental area under the curve of the glucose level more than 10 mmol/L ( AUC > 10 ) and an increase of time-in-range (TIR, 3.9-10 mmol/L) with treatment. Homeostasis model assessment for pancreatic beta-cell function (HOMA-beta) increased significantly with treatment ( p < 0.05 ), and fewer insulin doses were required after the treatment, without increasing in hypoglycemia and urinary tract infection. Further, a stratified analysis showed that patients with higher pretreatment HbA1c and waist-to-hip ratio (WHR) had greater improvement in glycemic control. Conclusion. Dapagliflozin may reduce blood glucose levels, ameliorate glycemic variability, and improve pancreatic beta-cell function in patients with T2D under insulin glargine combined with other oral hypoglycemic drugs, especially in those with poor glucose control and abdominal obesity.