MEK/ERK Signaling in Β-Cells Bifunctionally Regulates Β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis

In diabetic pathology, insufficiency in β-cell massunable to meet peripheral insulin demand and functional defects of individual βcells to produce insulin are often concurrently observed, collectively causing hyperglycemia.Here we show that the phosphorylation of ERK1/2 is significantly decreased inthe islets of db/db mice as well asin those of a cohort of subjects with type 2 diabetes. In mice with abrogationof ERK signaling in pancreatic β cells through deletion of Mek1 and Mek2, glucoseintolerance aggravates under high-fat diet-fed conditions due to insufficientinsulin production with lower β-cell proliferation and reduced β-cell mass,while in individual β cells dampening of the number of insulin exocytosisevents is observed, with the molecules involved in insulin exocytosis being lessphosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in βcells for glucose homeostasis, i.e., in regulating β-cell mass as well as incontrolling insulin exocytosis in individual β cells, thus providing not only anovel perspective for the understanding of diabetes pathophysiology but also a potentialclue for new drug development for diabetes treatment.