Glucagon-like peptide 1 receptor agonist ameliorates the insulin resistance function of islet β cells via the activation of PDX-1/JAK signaling transduction in C57/BL6 mice with high-fat diet-induced diabetes.

Abstract

Long-term exposure to a high-fat diet(HFD) causes glucotoxicity and lipotoxicity in islet βcells and leads to the development of metabolic dysfunctions. Reductions in pancreatic and duodenal homeobox-1(PDX-1) expression have been shown to induce type2 diabetes mellitus by causing impairments to islet βcells. Glucagon-like peptide1(GLP-1) treatment reduces endogenous insulin resistance in HFD-induced type2 diabetes mellitus. In the present study, the underlying mechanism by which GLP-1 exerts its function in type2 diabetes mellitus was investigated. The effect of liraglutide(GLP-1receptor agonist) administration on glucose tolerance, insulin release, and glucose-dependent insulinotropic polypeptide level was detected in a HFD-induced diabetes C57/BL6mouse model. Moreover, the role of liraglutide administration on the activity of PDX-1 was quantified to demonstrate the association between the two indicators. The results showed that administration of liraglutide could ameliorate the impairments to βcells due to HFD consumption. Liraglutide restored the insulin capacity and stimulated glucose disposal by improving the function and increasing the number of islet βcells. Furthermore, the hyperplasia and redundant function of islet αcells were inhibited by liraglutide treatment as well. At the molecular level, administration of liraglutide induced the expression of PDX-1, MafA, p-JAK2and p-Stat3 in HFD model to relatively normal levels. It was suggested that the effect of liraglutide-induced activation of GLP-1 was exerted via activation of PDX-1 rather than its function in decreasing body weight. The study demonstrated that GLP-1 played an essential role in type2 diabetes mellitus.