Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

eLife

Patrick E MacDonald¹  Haopeng Lin¹  Aliya F Spigelman¹  Tore Magnussen²  Mikkel Christensen³  Tina Vilsbøll⁴  Filip K Knop⁵  Timothy James⁶  Joseph C Madara⁷  Angela Kim⁸  Bradford B Lowell⁸  Ingrid Wernstedt Asterholm⁹  Yanling Wu⁹  Caroline Miranda⁹  Lisa Mellander⁹  Anna Benrick⁹  Lina Abdul Kadir^1,10  Thomas G Hill^1,10  Joely A Kellard^1,10  Linford JB Briant^1,11  Patrik Rorsman^1,12  Jakob G Knudsen^1,13  Kinga Suba^1,14  Victoria Salem^1,14 

[1] Alberta Diabetes Institute, Li Ka Shing Centre for Health Research Innovation, Edmonton, Canada;Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark;Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark;Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark;Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark;Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark;Steno Diabetes Center Copenhagen, Copenhagen, Denmark;Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark;Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark;Steno Diabetes Center Copenhagen, Copenhagen, Denmark;Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Department of Clinical Biochemistry, John Radcliffe, Oxford NHS Trust, Oxford, United Kingdom;Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States;Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States;Program in Neuroscience, Harvard Medical School, Boston, United States;Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden;Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;Department of Computer Science, University of Oxford, Oxford, United Kingdom;Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden;Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark;Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom;

关键词: islets;    glucagon;    brain glucose sensing;    counter-regulation;    vasopressin;    Human;    Mouse;   

DOI  :  10.7554/eLife.72919

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

【 授权许可】

CC BY