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Interaction of Glycolysis and Mitochondrial Respiration in Metabolic Oscillations of Pancreatic Islets

Richard Bertram ^*, Leslie S. Satin , Morten Gram Pedersen , Dan S. Luciani  and Arthur Sherman ^¶

^* Department of Mathematics and Programs in Neuroscience and Molecular Biophysics, Florida State University, Tallahassee, Florida; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia; Department of Physics, Technical University of Denmark, Kgs. Lyngby, Denmark; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada; and ^¶ Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence: Address reprint requests to Richard Bertram, Dept. of Mathematics, Florida State University, Tallahassee, FL 32306. Tel.: 850-644-7195; E-mail: bertram{at}math.fsu.edu.

Insulin secretion from pancreatic ß-cells is oscillatory, with a typical period of 2–7 min, reflecting oscillations in membrane potential and the cytosolic Ca²⁺ concentration. Our central hypothesis is that the slow 2–7 min oscillations are due to glycolytic oscillations, whereas faster oscillations that are superimposed are due to Ca²⁺ feedback onto metabolism or ion channels. We extend a previous mathematical model based on this hypothesis to include a more detailed description of mitochondrial metabolism. We demonstrate that this model can account for typical oscillatory patterns of membrane potential and Ca²⁺ concentration in islets. It also accounts for temporal data on oxygen consumption in islets. A recent challenge to the notion that glycolytic oscillations drive slow Ca²⁺ oscillations in islets are data showing that oscillations in Ca²⁺, mitochondrial oxygen consumption, and NAD(P)H levels are all terminated by membrane hyperpolarization. We demonstrate that these data are in fact compatible with a model in which glycolytic oscillations are the key player in rhythmic islet activity. Finally, we use the model to address the recent finding that the activity of islets from some mice is uniformly fast, whereas that from islets of other mice is slow. We propose a mechanism for this dichotomy.

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