Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia
Open Access
- 14 June 2010
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 59 (9), 2271-2280
- https://doi.org/10.2337/db10-0401
Abstract
OBJECTIVE An impaired ability to sense and appropriately respond to insulin-induced hypoglycemia is a common and serious complication faced by insulin-treated diabetic patients. This study tests the hypothesis that insulin acts directly in the brain to regulate critical glucose-sensing neurons in the hypothalamus to mediate the counterregulatory response to hypoglycemia. RESEARCH DESIGN AND METHODS To delineate insulin actions in the brain, neuron-specific insulin receptor knockout (NIRKO) mice and littermate controls were subjected to graded hypoglycemic (100, 70, 50, and 30 mg/dl) hyperinsulinemic (20 mU/kg/min) clamps and nonhypoglycemic stressors (e.g., restraint, heat). Subsequently, counterregulatory responses, hypothalamic neuronal activation (with transcriptional marker c-fos), and regional brain glucose uptake (via 14C-2deoxyglucose autoradiography) were measured. Additionally, electrophysiological activity of individual glucose-inhibited neurons and hypothalamic glucose sensing protein expression (GLUTs, glucokinase) were measured. RESULTS NIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (3-fold) hypothalamic c-fos activation in response to hypoglycemia but not other stressors. Glucose-inhibited neurons in the ventromedial hypothalamus of NIRKO mice displayed significantly blunted glucose responsiveness (membrane potential and input resistance responses were blunted 66 and 80%, respectively). Further, hypothalamic expression of the insulin-responsive GLUT 4, but not glucokinase, was reduced by 30% in NIRKO mice while regional brain glucose uptake remained unaltered. CONCLUSIONS Chronically, insulin acts in the brain to regulate the counterregulatory response to hypoglycemia by directly altering glucose sensing in hypothalamic neurons and shifting the glycemic levels necessary to elicit a normal sympathoadrenal response.Keywords
This publication has 62 references indexed in Scilit:
- Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In VivoDiabetes, 2010
- AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neuronsAmerican Journal of Physiology-Cell Physiology, 2009
- Brain insulin infusion does not augment the counterregulatory response to hypoglycemia or glucoprivationMetabolism, 2009
- Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucoseAmerican Journal of Physiology-Endocrinology and Metabolism, 2009
- Lentivirus-mediated downregulation of hypothalamic insulin receptor expressionPhysiology & Behavior, 2007
- Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamusAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2007
- I.c.v. administration of the nonsteroidal glucocorticoid receptor antagonist, CP-472555, prevents exacerbated hypoglycemia during repeated insulin administrationNeuroscience, 2006
- Invited review c-Fos as a transcription factor: a stressful (re)view from a functional mapNeurochemistry International, 1998
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)The Lancet, 1998
- Evidence that the brain of the conscious dog is insulin sensitive.JCI Insight, 1995