Protection of pancreatic -cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

The aim of this study was to investigate the in vivo and in vitro effectsofexendin-4,apotentglucagon-likepeptide1agonist,on theprotectionofthepancreaticb-cellsagainsttheircelldeath.In in vivo experiments, we used b-cell-specific calmodulinoverexpressing mice where massive apoptosis takes place in their b-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1 a ,X -box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in b-cellspecific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess ofERstressoccursinthetransgenicb-cells,andthesuppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.