Caffeic Acid Dimethyl Ether Ameliorates Excessive Glucose and Lipid-Induced Insulin Secretion Dysfunction in Pancreatic Beta-Cells through the miR-378b–PI3K–AKT Pathway

Abstract

An important factor in the progression of type 2 diabetes mellitus is the malfunctioning insulin production by β-cells in the pancreas. Caffeic acid dimethyl ether (CADE) reduces resistance to insulin in alcoholic fatty liver disease, but both the therapeutic effects of CADE on excessive glucose and lipid-induced insulin secretion disorders and the underlying mechanisms are unknown. The aim of this research was to (i) explore how CADE impacts insulin production issues caused by a surplus of glucose and lipids β-cells and (ii) elucidate the underlying mechanism. The results of our research demonstrated that insulin production was reduced in the pancreas of mice given a high-fat -diet and streptozotocin, as well as in human 1.1B4 pancreatic β-cells treated with high -glucose and high -fat, with increased activity of miR-378b and decreased expression levels of p110α, p-AKT1/2, insulin receptor, p-FoxO1, and PDX-1. However, treatment with CADE ameliorated the insulin secretion impairment by decreasing the miR-378b level and reversing the inhibitory effects on the aforementioned factors. Overexpression of miR-378b exacerbated the insulin secretion disorder and inhibited the PI3K-AKT signaling pathway, whereas miR-378b deficiency relieved the insulin secretion disorder, activating the PI3K-AKT pathway. In addition, CADE ameliorated the impairment of insulin secretion and reversed the miR-378b overexpression-induced PI3K-AKT pathway inhibition. In conclusion, our study demonstrates that CADE ameliorated insulin secretion dysfunction induced by excess lipid and glucose in β-cells by downregulating miR-378b expression, thus promoting PI3K-AKT activation.