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 mass unable to meet peripheral insulin demand and functional defects of individual β cells to produce 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 β cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet-fed conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β 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 β cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β 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.