Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and beta cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the a-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-beta cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing beta cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, beta cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both beta cell physiology and the pathogenesis of beta cell dysfunction in type 2 diabetes. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).