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-cells: modeling of ATP/ADP-Ca2+ interactions
Department of Medicine, University of Chicago, Chicago, Illinois
Submitted 16 December 2004 ; accepted in final form 20 June 2005
Glucose metabolism stimulates insulin secretion in pancreatic 
-cells. A consequence of metabolism is an increase in the ratio of ATP to ADP ([ATP]/[ADP]) that contributes to depolarization of the plasma membrane via inhibition of ATP-sensitive K+ (KATP) channels. The subsequent activation of calcium channels and increased intracellular calcium leads to insulin exocytosis. Here we evaluate new data and review the literature on nucleotide pool regulation to determine the utility and predictive value of a new mathematical model of ion and metabolic flux regulation in -cells. The model relates glucose consumption, nucleotide pool concentration, respiration, Ca2+ flux, and KATP channel activity. The results support the hypothesis that -cells maintain a relatively high [ATP]/[ADP] value even in low glucose and that dramatically decreased free ADP with only modestly increased ATP follows from glucose metabolism. We suggest that the mechanism in -cells that leads to this result can simply involve keeping the total adenine nucleotide concentration unchanged during a glucose elevation if a high [ATP]/[ADP] ratio exits even at low glucose levels. Furthermore, modeling shows that independent glucose-induced oscillations of intracellular calcium can lead to slow oscillations in nucleotide concentrations, further predicting an influence of calcium flux on other metabolic oscillations. The results demonstrate the utility of comprehensive mathematical modeling in understanding the ramifications of potential defects in -cell function in diabetes.
insulin; islets; adenosine triphosphate-sensitive potassium channels; mathematical model; oscillations
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