[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
RW Gelling, GJ Morton, CD Morrison, KD Niswender, MG Myers, CJ Rhodes, MW Schwartz
Cell metabolism, 2006cell.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 …
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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