Glucose metabolites inhibit protein phosphatases and directly promote insulin exocytosis in pancreatic β-cells

Åke Sjöholm, Mikael Lehtihet, Alexandre M. Efanov, Sergei V. Zaitsev, Per Olof Berggren, Richard E. Honkanen

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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 β-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 β-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 β-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 β-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 β-cell.

Original languageEnglish (US)
Pages (from-to)4592-4598
Number of pages7
Issue number12
StatePublished - Dec 1 2002

ASJC Scopus subject areas

  • Endocrinology


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