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.


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.


Korean Ministry of Health and Welfare (A062260)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at