Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 691, Issue 1-3, Pages 297-306Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2012.07.030
Keywords
Type 2 diabetes; Dipeptidyl peptidase-4inhibitor; Glucagon-like peptide-1; beta cells; alpha cells; (GK rat)
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Funding
- Novartis
- Grants-in-Aid for Scientific Research [24659158] Funding Source: KAKEN
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Reduced beta 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 beta and a 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 (15mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, beta and a 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. beta cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced beta and a 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 beta cell mass in GK rats by facilitating the proliferation of islet endocrine cells. Copyright (C) 2012 Elsevier B.V. All rights reserved.
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