Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling.
Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling.
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DOI：
10.2337/db10-0958
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发表时间：
2011-05
期刊：
影响因子：
7.7
通讯作者：
Kieffer TJ
中科院分区：
文献类型：
--
作者：
Denroche HC;Levi J;Wideman RD;Sequeira RM;Huynh FK;Covey SD;Kieffer TJ
瘦素治疗已被发现逆转高血糖症，并防止死亡率在几个啮齿动物模型的1型糖尿病。然而瘦素介导的高血糖逆转机制尚未完全确定。肝脏是调节葡萄糖代谢的关键器官，也是瘦素作用的靶点。因此，我们假设外源性瘦素通过直接作用于肝细胞逆转链脲佐菌素（STZ）诱导的糖尿病小鼠的高血糖。在用高剂量STZ诱导小鼠糖尿病后，通过渗透泵植入物以超生理剂量递送重组小鼠瘦素14天。我们在患有STZ诱导的糖尿病的C57 Bl/6 J小鼠中描述了瘦素给药的效果，然后检查瘦素治疗是否可以逆转STZ诱导的高血糖症，其中肝脏瘦素信号传导被特异性破坏。高瘦素血症逆转糖尿病C57 Bl/6 J小鼠的高血糖症和高酮血症，并显着改善葡萄糖耐量。这些效应与血浆胰高血糖素和生长激素水平降低以及胰岛素敏感性显著增强有关，而骨骼肌葡萄糖摄取无变化。瘦素治疗也改善了STZ诱导的高血糖症和高酮血症的小鼠与破坏肝脏瘦素信号传导到类似的程度观察野生型同窝与STZ诱导的糖尿病。这些观察结果表明，高瘦素血症逆转STZ诱导的小鼠糖尿病的症状，并且这种作用不需要肝脏中的直接瘦素信号传导。
Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes. After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted. Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes. These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.