MiR-7, miR-9 and miR-375 contribute to effect of Exendin-4 on pancreatic β-cells in high-fat-diet-fed mice

Abstract

Purpose: The purpose of this study was to test whether glucagon-like peptide-1 (GLP-1) receptor activation preserved pancreatic β-cells via the regulation of microRNAs and target genes in high-fat-diet-fed mice. Methods: C57BL/6 male mice were simultaneously treated with high-fat-diet (HFD) and GLP-1 analogue, Exendin-4 (Ex-4) (3 μg/kg/day or 30 μg/kg/day), i.p. or vehicle, for consecutive 13 weeks. Fasting blood glucose, postprandial blood glucose, ΔI30/ΔG30, HOMA-IR and HOMA-% β were measured in each group. Pancreatic β-cell mass was assessed by immunohistochemistry. The expression of miRNAs and related downstream genes were investigated using quantitative real-time PCR. Results: Thirteen weeks of Ex-4 treatment significantly reduced body weight and food intake in HFD-fed mice (P < 0.05). Insulin sensitivity, HOMA-IR and HOMA-% β were markedly improved in Ex-4-treated groups (P < 0.05). Histological examination revealed that β-cell mass was significantly increased in high dose Ex-4-treated mice (P < 0.05). Interestingly, Ex-4-treated islets displayed significant down-regulation of the expression of miR-7, miR-9 and miR-375 and up-regulation of the levels of mammalian target of rapamycin (mTOR), one cut homeobox 2 (OC-2) and phosphoinositide-dependent protein kinase-1 (P < 0.05). Conclusion: MicroRNAs and genes targeted in response to GLP-1 receptor agonism were involved in preserving β-cell mass and function in HFD-induced mice; which suggest a mechanism involving the GLP-1 receptor as a therapeutic approach for the treatment of type 2 diabetes mellitus and obesity. This study also shows the potential for elucidating other important therapeutic targets for diabetes.