Glutamate inhibits protein phosphatases and promotes insulin exocytosis in pancreatic β-cells

In human type 2 diabetes mellitus, loss of glucose-sensitive insulin secretion from the pancreatic β-cell is an early pathogenetic event, but the mechanisms involved in glucose sensing are poorly understood. A messenger role has been postulated for l-glutamate in linking glucose stimulation to sustained insulin exocytosis in the β-cell, but the precise nature by which l-glutamate controls insulin secretion remains elusive. Effects of l-glutamate on the activities of ser/thr protein phosphatases (PPase) and Ca2+-regulated insulin exocytosis in INS-1E cells were investigated. Glucose increases l-glutamate contents and promotes insulin secretion from INS-1E cells. l-Glutamate also dose-dependently inhibits PPase enzyme activities analogous to the specific PPase inhibitor, okadaic acid. l-glutamate and okadaic acid directly and non-additively promote insulin exocytosis from permeabilized INS-1E cells in a Ca2+-independent manner. Thus, an increase in phosphorylation state, through inhibition of protein dephosphorylation by glucose-derived l-glutamate, may be a novel regulatory mechanism linking glucose sensing to sustained insulin exocytosis.