A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic beta-cell
2007 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 292, no 2, E373-E393 p.Article in journal (Refereed) Published
The pancreatic beta-cells respond to an increased glycolytic flux by secreting insulin. The signal propagation goes via mitochondrial metabolism, which relays the signal to different routes. One route is an increased ATP production that, via ATP-sensitive K+ (K-ATP) channels, modulates the cell membrane potential to allow calcium influx, which triggers insulin secretion. There is also at least one other "amplifying" route whose nature is debated; possible candidates are cytosolic NADPH production or malonyl-CoA production. We have used mathematical modeling to analyze this relay system. The model comprises the mitochondrial NADH shuttles and the mitochondrial metabolism. We found robust signaling toward ATP, malonyl-CoA, and NADPH production. The signal toward NADPH production was particularly strong. Furthermore, the model reproduced the experimental findings that blocking the NADH shuttles attenuates the signaling to ATP production while retaining the rate of glucose oxidation (Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T. Science 283: 981 - 985, 1999) and provides an explanation for this apparent paradox. The model also predicts that the mitochondrial malate dehydrogenase reaction may proceed backward, toward malate production, if the activity of malic enzyme is sufficiently high. An increased fatty acid oxidation rate was found to attenuate the signaling strengths. This theoretical study has implications for our understanding of both the healthy and the diabetic beta-cell.
Place, publisher, year, edition, pages
2007. Vol. 292, no 2, E373-E393 p.
systems biology, potassium-dependent adenosine triphosphate channel-independent, pathway of insulin secretion, reduced nicotinamide adenine dinucleotide, diabetes, fatty acid oxidation
Computer and Information Science
IdentifiersURN: urn:nbn:se:kth:diva-6059DOI: 10.1152/ajpendo.00589.2005ISI: 000243997100002PubMedID: 16849626ScopusID: 2-s2.0-33846882164OAI: oai:DiVA.org:kth-6059DiVA: diva2:10653
QC 20100823 Uppdaterad från manuskript till artikel (20100823)2005-09-072005-09-072012-01-08Bibliographically approved