Contribution of calcium influx in mediating glucose-stimulated oxygen consumption in pancreatic islets.
In brain, muscle, and pancreatic islets, depolarization induces an increase in respiration, which is dependent on calcium influx. The goal of this study was to assess the quantitative significance of this effect in islets relative to glucose-stimulated ATP turnover, to examine the molecular mechanism mediating the changes, and to investigate the functional implications with respect to insulin secretion. Glucose (3-20 mmol/l) increased steady-state levels of cytochrome c reduction (32-66%) in isolated rat islets, reflecting an increased production of NADH, and oxygen consumption rate (OCR) by 0.32 nmol/min/100 islets. Glucose-stimulated OCR was inhibited 30% by inhibitors of calcium influx (diazoxide or nimodipine), whereas a protein synthesis inhibitor (emetine) decreased it by only 24%. None of the inhibitors affected cytochrome c reduction, suggesting that calcium's effect on steady-state OCR is mediated by changes in ATP usage rather than the rate of NADH generation. 3-isobutyl-1-methylxanthine increased insulin secretion but had little effect on OCR, indicating that the processes of movement and exocytosis of secretory granules do not significantly contribute to ATP turnover. At 20 mmol/l glucose, a blocker of sarcoendoplasmic reticulum calcium ATPase (SERCA) had little effect on OCR despite a large increase in cytosolic calcium, further supporting the notion that influx of calcium, not bulk cytosolic calcium, is associated with the increase in ATP turnover. The glucose dose response of calcium influx-dependent OCR showed a remarkable correlation with insulin secretion, suggesting that the process mediating the effect of calcium on ATP turnover has a role in the amplification pathway of insulin secretion.
Sweet
Ian R
IR
Robert H. Williams Laboratory, HSB K-165, Box 357710, University of Washington, 1959 NE Pacific St., Seattle, WA 98195-7710, USA. isweet@u.washington.edu
Gilbert
Merle
M
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats
D007328:Insulin; D009243:NAD; D009553:Nimodipine; D045304:Cytochromes c; D005947:Glucose; D002118:Calcium