Glycolytic Oscillations and Insulin Secretion
Monday, February 15, 1999 - 11:00am - 12:00pm
Keith Tornheim (Boston University Medical Center)
Normal insulin secretion is oscillatory in vivo and in vitro, with a period of about 5-10 min. The mechanism of generating these oscillations is not yet established, but a metabolic basis seems most likely for glucose-stimulated secretion. A useful model is the spontaneous glycolytic oscillations studied previously in muscle extracts, which are generated by AMP-dependent, autocatalytic activation of phosphofructokinase by its product fructose 1,6-bisphosphate. The glycolytic oscillations involve oscillations in the ATP/ADP ratio. In the context of the pancreatic $beta$-cell, these would cause alternate opening and closing of ATP-sensitive K+ channels, leading to the observed oscillations in membrane potential and Ca2+ influx, as well as having downstream effects on exocytosis. Spontaneous Ca2+ oscillations are an unlikely basis in this case, since intracellular stores are not of primary importance in the stimulus-secretion coupling; furthermore, insulin oscillations occur under conditions when intracellular Ca2+ levels are not changing. A neural basis could not account for insulin oscillations from perifused islets and clonal $beta$- cells. Observed oscillations in metabolite levels and fluxes further support a metabolic basis, as does the presence in beta-cells of the oscillatory isoform of phosphofructokinase (PFK-M).