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A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic -cell

¹Parallel Scientific Computing Institute/Computational Biology and Neurocomputing, Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden; ²Institute for Theoretical Biology, Humboldt University Berlin, Berlin, Germany; ³Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Institute and Hospital, Stockholm, Sweden; and ⁴Institute of Cancer Research and Molecular Medicine, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway

Submitted 28 November 2005 ; accepted in final form 13 July 2006

The pancreatic -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 -cell.

systems biology; potassium-dependent adenosine triphosphate channel-independent pathway of insulin secretion; reduced nicotinamide adenine dinucleotide; diabetes; fatty acid oxidation

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