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Glucose Metabolites Inhibit Protein Phosphatases and Directly Promote Insulin Exocytosis in Pancreatic ß-Cells

Department of Internal Medicine (A.S., M.L.), Karolinska Institutet, Stockholm South Hospital, SE 118 83 Stockholm, Sweden; Department of Molecular Medicine (A.M.E., S.V.Z., P.-O.B.), Karolinska Hospital, SE-171 76 Stockholm, Sweden; Belozersky Institute of Physico-Chemical Biology (S.V.Z.), Moscow State University, 119899 Moscow, Russia; and Department of Biochemistry and Molecular Biology (R.E.H.), College of Medicine, University of South Alabama, Mobile, Alabama 36688

Address all correspondence and requests for reprints to: Ake Sjöholm, Karolinska Institutet, Stockholm Söder Hospital, SE 118 83 Stockholm, Sweden.

In human type 2 diabetes mellitus, loss of glucose-sensitive insulin secretion is an early pathogenetic event. Glucose is the cardinal physiological stimulator of insulin secretion from the pancreatic ß-cell, but the mechanisms involved in glucose sensing are not fully understood. Specific ser/thr protein phosphatase (PPase) inactivation by okadaic acid promotes Ca²⁺ entry and insulin exocytosis in the ß-cell. We now show that glycolytic and Krebs cycle intermediates, whose concentrations increase upon glucose stimulation, not only dose dependently inhibit ser/thr PPase enzymatic activities, but also directly promote insulin exocytosis from permeabilized ß-cells. Thus, fructose-1,6-bisphosphate, phosphoenolpyruvate, 3-phosphoglycerate, citrate, and oxaloacetate inhibit PPases and significantly enhance insulin exocytosis, nonadditive to that of okadaic acid, at micromolar Ca²⁺ concentrations. In contrast, the effect of GTP is potentiated by okadaic acid, suggesting that the action of GTP does not require PPase inactivation. We conclude that specific glucose metabolites and GTP inhibit ß-cell PPase activities and directly stimulate Ca²⁺-independent insulin exocytosis. The glucose metabolites, but not GTP, seem to require PPase inactivation for their stimulatory effect on exocytosis. Thus, an increase in phosphorylation state, through inhibition of protein dephosphorylation by metabolic intermediates, may be a novel regulatory mechanism linking glucose sensing to insulin exocytosis in the ß-cell.

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