DPP4 inhibitor vildagliptin preserves beta-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

作者：Shimizu Shinobu; Hosooka Tetsuya; Matsuda Tomokazu; Asahara Shun ichiro; Koyanagi Kimura Maki; Kanno Ayumi; Bartolome Alberto; Etoh Hiroaki; Fuchita Megumi; Teruyama Kyoko; Takahashi Hiroaki; Inoue Hiroyuki; Mieda Yusuke; Hashimoto Naoko; Seino Susumu; Kido Yoshiaki^*

来源：Journal of Molecular Endocrinology, 2012, 49(2): 125-135.

DOI：10.1530/JME-12-0039

The development of type 2 diabetes is accompanied by a progressive decline in beta-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on beta cells was studied in diabetic mice. Diabetic pancreatic beta cell-specific C/EBPB transgenic (TG) mice exhibit decreased beta-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on beta cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased beta-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in beta cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in beta cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic beta cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes. Journal of Molecular Endocrinology (2012) 49, 125-135

• 出版日期2012-10