Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia

  1. Simon J Fisher, MD, PhD (sfisher{at},3
  1. 1Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110
  2. 2Department of Pharmacology and Physiology, New Jersey Medical School (UMDNJ), Newark, New Jersey 07101
  3. 3Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri 63110


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 (20−1.min−1) clamps and non-hypoglycemic 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 (GI) neurons and hypothalamic glucosensing protein expression (GLUTs, glucokinase) were measured.

Results: NIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (70%) hypothalamic c-fos activation in response to hypoglycemia, but not other stressors. GI 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 glucose transporter 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.


    • Received March 22, 2010.
    • Accepted June 4, 2010.