Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes.
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.
Gelling
Richard W
RW
Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington 98102, USA.
Morton
Gregory J
GJ
Morrison
Christopher D
CD
Niswender
Kevin D
KD
Myers
Martin G
MG
Rhodes
Christopher J
CJ
Schwartz
Michael W
MW
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D007328:Insulin / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology* / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D002867:Chromones; D007328:Insulin; D009025:Morpholines; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one