Celebrities in the heart, strangers in the pancreatic beta cell:Voltage-gated potassium channels K_v7.1 and K_v11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes

Voltage‐gated potassium (K(v)) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss‐of‐function (LoF) mutations in KCNQ1, encoding K(v)7.1, and KCNH2 (hERG), encoding K(v)11.1, were found to exhibit post‐prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K(+) channels in pancreatic beta cell function, with emphasis on K(v)7.1 and K(v)11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre‐clinical, clinical and genome‐wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes

Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in beta-Cells

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor