Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males.

A heterozygous missense mutation of the islet β cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset β cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the unstable MAFA protein. Here, we develop a S64F MafA mouse model to determine how β cell function is affected and find sex-dependent phenotypes. Heterozygous mutant males (MafAS64F/+) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca2+ signaling, DNA damage, aging, and senescence. MAFAS64F production in male human β cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFAWT. These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFAS64F carriers in a sex-biased manner

Obesity and diabetes mellitus association in rural community of Katana, South Kivu, in Eastern Democratic Republic of Congo : Bukavu Observ Cohort study results

Background: Factual data exploring the relationship between obesity and diabetes mellitus prevalence from rural areas of sub-Saharan Africa remain scattered and are unreliable. To address this scarceness, this work reports population study data describing the relationship between the obesity and the diabetes mellitus in the general population of the rural area of Katana (South Kivu in the Democratic Republic of the Congo). Methods: A cohort of three thousand, nine hundred, and sixty-two (3962) adults (>15 years old) were followed between 2012 and 2015 (or 4105 person-years during the observation period), and data were collected using the locally adjusted World Health Organization's (WHO) STEPwise approach to Surveillance (STEPS) methodology. The hazard ratio for progression of obesity was calculated. The association between diabetes mellitus and obesity was analyzed with logistic regression. Results: The diabetes mellitus prevalence was 2.8 % versus 3.5 % for obese participants and 7.2 % for those with metabolic syndrome, respectively. Within the diabetes group, 26.9 % had above-normal waist circumference and only 9.8 % were obese. During the median follow-up period of 2 years, the incidence of obesity was 535/100,000 person-years. During the follow-up, the prevalence of abdominal obesity significantly increased by 23 % (p < 0.0001), whereas the increased prevalence of general obesity (7.8 %) was not significant (p = 0.53). Finally, diabetes mellitus was independently associated with age, waist circumference, and blood pressure but not body mass index. Conclusion: This study confirms an association between diabetes mellitus and abdominal obesity but not with general obesity. On the other hand, the rapid increase in abdominal obesity prevalence in this rural area population within the follow-up period calls for the urgent promoting of preventive lifestyle measures

Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male β cells

Androgen Excess Produces Systemic Oxidative Stress and Predisposes to β-Cell Failure in Female Mice

In women, excess production of the male hormone, testosterone (T), is accompanied by insulin resistance. However, hyperandrogenemia is also associated with β-cell dysfunction and type 2 diabetes raising the possibility that androgen receptor (AR) activation predisposes to β-cell failure. Here, we tested the hypothesis that excess AR activation produces systemic oxidative stress thereby contributing to β-cell failure. We used normal female mice (CF) and mice with androgen resistance by testicular feminization (Tfm). These mice were exposed to androgen excess and a β-cell stress induced by streptozotocin (STZ). We find that following exposure to T, or the selective AR-agonist dehydrotestosterone (DHT), CF mice challenged with STZ, which are normally protected, are prone to β-cell failure and insulin-deficient diabetes. Conversely, T-induced predisposition to β-cell failure is abolished in Tfm mice. We do not observe any proapoptotic effect of DHT alone or in the presence of H2O2 in cultured mouse and human islets. However, we observe that exposure of CF mice to T or DHT provokes systemic oxidative stress, which is eliminated in Tfm mice. This work has significance for hyperandrogenic women; excess activation of AR by testosterone may provoke systemic oxidative stress. In the presence of a prior β-cell stress, this may predispose to β-cell failure

Lack of Wdr13 Gene in Mice Leads to Enhanced Pancreatic Beta Cell Proliferation, Hyperinsulinemia and Mild Obesity

WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was downregulated in the mutant islets, over expression of WDR13 in the pancreatic beta cell line (MIN6) resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Given the higher insulin levels and better glucose clearance in Wdr13 gene deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes