1833-P: PERK Inhibitors Enhanced Glucose-Stimulated Insulin Secretion in a Mouse Model of Type 2 Diabetes

Abstract

Background: PERK (pancreatic endoplasmic reticulum (ER) kinase) has been reported to have important implications in the generation, function, and viability of β cells. We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets, through induction of ER chaperone BiP and regulation of ER calcium, but not through the EIF2A-ATF4 pathway. In the current study, we investigated if PI have the same effects under metabolic stress condition. Methods: GSK2606414, a specific PERK inhibitor, was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. Male C57BL/6J mice were fed with high-fat diet combined with streptozotocin injections to mimic type 2 diabetes (DM). Several doses (6 ∼ 16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. Results: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain, insulin insufficiency, and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. Conclusion: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress, and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM. Disclosure Y. Yang: None. M. Kim: None. M. Kim: None. J. Kim: None. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. K. Park: None. H. Jung: None. Funding Korean Ministry of Health and Welfare (A062260)