title: DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice.
abstract: The development of type 2 diabetes is accompanied by a progressive decline in β-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 β cells was studied in diabetic mice. Diabetic pancreatic β cell-specific C/EBPB transgenic (TG) mice exhibit decreased β-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 β 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 β-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 β 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 β cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic β cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.
authors: Division of Medical Chemistry, Department of Biophysics Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Health Sciences, Kobe 654-0142, Japan.
authors: Shinobu
authors: S
authors: Shimizu
authors: Tetsuya
authors: T
authors: Hosooka
authors: Tomokazu
authors: T
authors: Matsuda
authors: Shun-ichiro
authors: S
authors: Asahara
authors: Maki
authors: M
authors: Koyanagi-Kimura
authors: Ayumi
authors: A
authors: Kanno
authors: Alberto
authors: A
authors: Bartolome
authors: Hiroaki
authors: H
authors: Etoh
authors: Megumi
authors: M
authors: Fuchita
authors: Kyoko
authors: K
authors: Teruyama
authors: Hiroaki
authors: H
authors: Takahashi
authors: Hiroyuki
authors: H
authors: Inoue
authors: Yusuke
authors: Y
authors: Mieda
authors: Naoko
authors: N
authors: Hashimoto
authors: Susumu
authors: S
authors: Seino
authors: Yoshiaki
authors: Y
authors: Kido
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology; D000077597:Vildagliptin
chemical_list: D001786:Blood Glucose; D022782:CCAAT-Enhancer-Binding Protein-beta; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D007976:Leupeptins; D009570:Nitriles; D010455:Peptides; D011759:Pyrrolidines; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000077597:Vildagliptin; D000218:Adamantane; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde