ARE METABOLIC OSCILLATIONS RESPONSIBLE FOR NORMAL OSCILLATORY INSULIN-SECRETION

Normal insulin secretion is oscillatory in vivo and in vitro, with a p eriod of similar to 5-10 min. The mechanism of generating these oscill ations is not yet established, but a metabolic basis seems most likely for glucose-stimulated secretion. The rationale is that I)spontaneous oscillatory operation of glycolysis is a well-established phenomenon; 2) oscillatory behavior of glycolysis involves oscillations in the AT P/ADP ratio, which can cause alternating opening and closing of ATP-se nsitive K+ channels, leading to the observed oscillations in membrane potential and Ca2+ influx in pancreatic beta-cells, and may also have downstream effects on exocytosis; 3) spontaneous Ca2+ oscillations are an unlikely basis in this case, since intracellular stores are not of primary importance in the stimulus-secretion coupling, and furthermor e, insulin oscillations occur under conditions when intracellular Ca2 levels are not changing; 4) a neural basis cannot account for insulin oscillations from perifused islets and clonal beta-cells or from tran splanted islets or pancreas in vivo; 5) observed oscillations in metab olite levels and fluxes further support a metabolic basis, as does the presence in beta-cells of the oscillatory isoform of phosphofructokin ase (PFK-M). The fact that normal oscillatory secretion is impaired in patients with NIDDM: and in their near relatives suggests that such d erangement may be involved in the development of the disease; furtherm ore, this probably reflects an early defect in the regulation and oper ation of the fuel metabolizing/sensing pathways of the pancreatic beta -cell.