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Department of Endocrinology and Diabetes, School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
¹ Central Research Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd, 363 Shiosaki, Hokusei, Inabe, Mie 511-0406, Japan
² Department of Pharmacology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan

(Requests for offprints should be addressed to I Niki; Email: niki{at}med.oita-u.ac.jp)

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic ß-cells against their cell death. In in vivo experiments, we used ß-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their ß-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, 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 ß-cell-specific 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 of ER stress occurs in the transgenic ß-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

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