title: Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats.
abstract: Reduced β cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence β and α cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, β and α cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. β cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced β and α cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet β cell mass in GK rats by facilitating the proliferation of islet endocrine cells.
authors: Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors: Wataru
authors: W
authors: Inaba
authors: Hiroki
authors: H
authors: Mizukami
authors: Kosuke
authors: K
authors: Kamata
authors: Kazunori
authors: K
authors: Takahashi
authors: Kentaro
authors: K
authors: Tsuboi
authors: Soroku
authors: S
authors: Yagihashi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004435:Eating / Q000187:drug effects; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000150:complications / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013997:Time Factors; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D003849:Deoxyguanosine; D000077597:Vildagliptin; D000218:Adamantane