[PDF][PDF] Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes
RW Gelling, GJ Morton, CD Morrison, KD Niswender… - Cell metabolism, 2006 - cell.com
Cell metabolism, 2006•cell.com
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 …
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 …
Summary
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.
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