Affiliation:
1. Diabetes and Metabolism Unit, Evans Department of Medicine and Department of Biochemistry, Boston University School of Medicine Boston, Massachusetts
Abstract
Normal insulin secretion is oscillatory in vivo and in vitro, with a period of ∼5–10 min. The mechanism of generating these oscillations is not yet established, but a metabolic basis seems most likely for glucose-stimulated secretion. The rationale is that 1) spontaneous oscillatory operation of glycolysis is a well-established phenomenon; 2) oscillatory behavior of glycolysis involves oscillations in the ATP/ADP ratio, which can cause alternating opening and closing of ATP-sensitive K+ channels, leading to the observed oscillations in membrane potential and Ca2+ influx in pancreatic β-cells, and may also have downstream effects on exocy-tosis; 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 furthermore, 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 clonai β-cells or from transplanted islets or pancreas in vivo; 5) observed oscillations in metabolite levels and fluxes further support a metabolic basis, as does the presence in β-cells of the oscillatory isoform of phosphofructokinase (PFK-M). The fact that normal oscillatory secretion is impaired in patients with NIDDM and in their near relatives suggests that such derangement may be involved in the development of the disease; furthermore, this probably reflects an early defect in the regulation and operation of the fuel metabolizing/sensing pathways of the pancreatic β-cell.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
122 articles.
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