CPT1a-Dependent Long-Chain Fatty Acid Oxidation Contributes to Maintaining Glucagon Secretion from Pancreatic Islets
Linford J.B. Briant,
Michael S. Dodd,
Margarita V. Chibalina,
Nils J.G. Rorsman,
Paul R.V. Johnson,
Peter Carmeliet,
Patrik Rorsman,
Jakob G. Knudsen
Affiliations
Linford J.B. Briant
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK
Michael S. Dodd
Department of Physiology, Anatomy & Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK; Faculty of Health and Life Sciences, Coventry University, Coventry CV1 5FB, UK
Margarita V. Chibalina
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
Nils J.G. Rorsman
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
Paul R.V. Johnson
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK
Peter Carmeliet
Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
Patrik Rorsman
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Metabolic Research, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Göteborg, Box 433, 405 30 Göteborg, Sweden
Jakob G. Knudsen
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Corresponding author
Summary: Glucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet α cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from α cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing α cell membrane potential and decreasing action potential amplitude. We demonstrate, by using experimental and computational approaches, that this is not mediated by the KATP channel, but instead due to reduced operation of the Na+-K+ pump. These data suggest that counter-regulatory secretion of glucagon is driven by fatty acid metabolism, and that the Na+-K+ pump is an important ATP-dependent regulator of α cell function. : Glucagon is secreted from pancreatic α cells in hypoglycemic conditions. Briant et al. demonstrate that this response is fueled by fatty acid oxidation. The energy generated by oxidation is used to maintain membrane potential dynamics, action potential morphology, and Na+-K+ pump activity. Keywords: islet, metabolism, glucose, Ca2+, KATP, liver, fasting
