Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes
Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes
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DOI：
10.1016/j.cmet.2005.11.013
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发表时间：
2006-01-01
期刊：
影响因子：
29
通讯作者：
Schwartz, MW
中科院分区：
文献类型：
--
作者：
Gelling, RW;Morton, GJ;Schwartz, MW
为了研究脑胰岛素作用在糖尿病的发病机理和治疗中的作用，我们询问在糖尿病胰岛素治疗过程中是否需要神经元胰岛素信号传导。通过胰岛素受体底物 - 磷脂酰肌醇3-激酶（IRS-PI3K）途径的下丘脑信号传导，这是胰岛素作用的关键细胞内介导剂，在大鼠中降低了由不受控制的糖尿病（由链肽蛋白链球菌素（STZ-DM）引起的不受控制的糖尿病）。此外，在急性和慢性胰岛素治疗范式中，将PI3K抑制剂输注在STZ-DM大鼠的第三个大鼠大鼠的第三个脑室心室中。相反，由IRS-2或蛋白激酶B下丘脑过表达引起的PI3K信号传导增加（PKB，PKB，PI3K动作的关键下游介体）增强了STZ-DM大鼠中与2倍的胰岛素对胰岛素的血糖反应。我们得出的结论是，通过IRS-PI3K途径通过IRS-PI3K途径的下丘脑胰岛素信号传导是对不受控制的糖尿病管理中对胰岛素反应的关键决定因素。
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 similar to 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 similar to 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.