2171-P: Excessive Drinking Impairs FGF-21/Beta-Klotho-Mediated Protective Effects against Islet Dysfunction and Apoptosis in Mouse Pancreatic Islets

Abstract

Excessive alcohol consumption has negative effects on β-cell insulin secretion and survival, thus increasing the risks of type 2 diabetes mellitus (T2DM). Meanwhile, fibroblast growth factor 21 (FGF-21) is a potent metabolic regulator for lipid and glucose homeostasis. Recently, FGF-21 and its obligate co-receptor β-klotho (KLB) have been shown to inhibit alcohol ingestion and metabolism in mice and human, probably via the mediation of gastric emptying rate and initial alcohol metabolism. Despite this evidence, whether heavy alcohol intake modulates the expression and function of FGF-21 in mouse islets is still ambiguous. Therefore, this study aimed to investigate this issue using in vitro/ex vivo and in vivo cell/animal models. In ex vivo studies, islets isolated from of C57BL/6J mice were cultured and treated with 80 mM alcohol for 24 h, mimicking the excessive alcohol condition. In vivo studies, the mice were gavaged with 3 g/kg ethanol/respective saline up to 3 weeks. Ex vivo results showed that the expression of FGF-21 and KLB was upregulated, whereas its receptor FGFR1, FGFR2, FGFR3 and FGFR4 were downregulated. In addition, islet apoptosis was increased as demonstrated by ELISA kit. Moreover, the expression of bax and SIRT1 were also downregulated. In corroboration, in vivo studies showed that glucose homeostasis and islet function were impaired by excessive alcohol drinking as demonstrated by OGTT and GSIS results. Consistently, the expression profile of FGF-21/its receptors was similar to those observed in ex vivo condition. Meanwhile, the expression of islet function-related genes (insulin1/2, IRS, PDX1, GLUT2, etc.) was also downregulated in in vivo experiments. Our preliminary data indicate that excessive drinking may induce β-cell dysfunction and apoptosis through the inhibition of FGF-21/KLB expression, and that islet FGF-21 signaling is associated with alcohol homeostasis and T2DM. Disclosure B. Yang: None. P. Leung: None. Funding Research Grants Council of Hong Kong (CUHK14107415)