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

• Published in: Cell metabolism Vol. 3; no. 1; pp. 67 - 73
• Main Authors: Gelling, Richard W., Morton, Gregory J., Morrison, Christopher D., Niswender, Kevin D., Myers, Martin G., Rhodes, Christopher J., Schwartz, Michael W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2006
• Subjects: 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; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Rats; Rats, Sprague-Dawley
• ISSN: 1550-4131; 1932-7420
• 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 ∼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 ∼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.