Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes

Cell Metab. 2006 Jan;3(1):67-73. doi: 10.1016/j.cmet.2005.11.013.


To investigate the role of brain insulin action in the pathogenesis and treatment of diabetes, we asked whether neuronal insulin signaling is required for glucose-lowering during insulin treatment of diabetes. Hypothalamic signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase (IRS-PI3K) pathway, a key intracellular mediator of insulin action, was reduced in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM). Further, infusion of a PI3K inhibitor into the third cerebral ventricle of STZ-DM rats prior to peripheral insulin injection attenuated insulin-induced glucose lowering by approximately 35%-40% in both acute and chronic insulin treatment paradigms. Conversely, increased PI3K signaling induced by hypothalamic overexpression of either IRS-2 or protein kinase B (PKB, a key downstream mediator of PI3K action) enhanced the glycemic response to insulin by approximately 2-fold in STZ-DM rats. We conclude that hypothalamic insulin signaling via the IRS-PI3K pathway is a key determinant of the response to insulin in the management of uncontrolled diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose* / metabolism
  • Brain / metabolism*
  • Brain / physiology
  • Chromones / pharmacology
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / metabolism*
  • Insulin / physiology*
  • Insulin / therapeutic use
  • Male
  • Morpholines / pharmacology
  • Nerve Tissue Proteins / physiology*
  • Nerve Tissue Proteins / therapeutic use
  • Phosphoinositide-3 Kinase Inhibitors
  • Rats
  • Rats, Sprague-Dawley


  • Blood Glucose
  • Chromones
  • Insulin
  • Morpholines
  • Nerve Tissue Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one