Mek/Erk Signaling In Beta-Cells Bifunctionally Regulates Beta-Cell Mass And Glucose-Stimulated Insulin Secretion Response To Maintain Glucose Homeostasis

In diabetic pathology, insufficiency in beta-cell mass, unable to meet peripheral insulin demand, and functional defects of individual beta-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic beta-cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet-feeding conditions due to insufficient insulin production with lower beta-cell proliferation and reduced beta-cell mass, while in individual beta-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in beta-cells for glucose homeostasis, i.e., in regulating beta-cell mass as well as in controlling insulin exocytosis in individual beta-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.