title: Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes.
abstract: 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.
authors.affiliation: Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington 98102, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gelling
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Niswender
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
mesh_terms: 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
chemical_list: 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