Hypothalamic insulin signaling is required for inhibition of glucose production

Nat Med. 2002 Dec;8(12):1376-82. doi: 10.1038/nm1202-798. Epub 2002 Nov 11.


Circulating insulin inhibits endogenous glucose production. Here we report that bidirectional changes in hypothalamic insulin signaling affect glucose production. The infusion of either insulin or a small-molecule insulin mimetic in the third cerebral ventricle suppressed glucose production independent of circulating levels of insulin and of other glucoregulatory hormones. Conversely, central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. Finally, third-cerebral-ventricle administration of inhibitors of ATP-sensitive potassium channels, but not of antagonists of the central melanocortin receptors, also blunted the effect of hyperinsulinemia on glucose production. These results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / etiology
  • Glucose / biosynthesis*
  • Hypothalamus / drug effects*
  • Hypothalamus / physiology
  • Insulin / pharmacology*
  • Male
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin / antagonists & inhibitors
  • Receptors, Melanocortin


  • Insulin
  • Potassium Channel Blockers
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • Glucose