Protection of pancreatic beta-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 effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic beta-cells against their cell death. In in vivo experiments, we used beta-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their beta-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-1alpha, 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 beta-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 beta-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.
Tsunekawa
Shin
S
Department of Endocrinology and Diabetes, School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
Yamamoto
Naoki
N
Tsukamoto
Katsura
K
Itoh
Yuji
Y
Kaneko
Yukiko
Y
Kimura
Toshihide
T
Ariyoshi
Yoh
Y
Miura
Yoshitaka
Y
Oiso
Yutaka
Y
Niki
Ichiro
I
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D000077270:Exenatide; D006360:Heat-Shock Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
D015415:Biomarkers; D002147:Calmodulin; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D018832:Molecular Chaperones; D010455:Peptides; D014688:Venoms; D051742:Transcription Factor CHOP; D000077270:Exenatide