Immunoneutralization of endogenous glucagon reduces hepatic glucose output and improves long-term glycemic control in diabetic ob/ob mice
Immunoneutralization of endogenous glucagon reduces hepatic glucose output and improves long-term glycemic control in diabetic ob/ob mice
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DOI：
10.2337/db06-0222
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发表时间：
2006-10-01
期刊：
影响因子：
7.7
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Sorensen, Heidi;Brand, Christian L.;Shulman, Gerald I.
在 2 型糖尿病中，胰高血糖素水平相对于普遍的胰岛素和葡萄糖水平升高。相对高胰高血糖素血症与肝葡萄糖输出（HGO）增加和高血糖有关。因此，拮抗胰高血糖素的作用被认为是治疗 2 型糖尿病的一个有吸引力的目标。在当前的研究中，在糖尿病 ob/ob 小鼠中研究了用胰高血糖素单克隆抗体 (mAb) 消除胰高血糖素信号传导的效果。通过口服葡萄糖耐量试验 (OGTT) 和 HGO 测量来研究抑制胰高血糖素作用的急性效应。此外，还研究了亚慢性（5 天和 14 天）胰高血糖素 mAb 治疗对血浆葡萄糖、胰岛素、甘油三酯和 RbA(1c) (A1C) 水平的影响。 Glucagon mAb 治疗可减少 OGTT 后葡萄糖曲线下面积，减少 HGO，并增加肝糖原合成率。胰高血糖素单克隆抗体治疗 5 天可降低血浆葡萄糖和甘油三酯水平，而胰高血糖素单克隆抗体治疗 14 天可降低 AM。 总之，内源性胰高血糖素的急性和亚慢性中和可改善血糖控制，从而支持胰高血糖素拮抗剂可能代表糖尿病的有益治疗的论点。
In type 2 diabetes, glucagon levels are elevated in relation to the prevailing insulin and glucose levels. The relative hyperglucagonemia is linked to increased hepatic glucose output (HGO) and hyperglycemia. Antagonizing the effects of glucagon is therefore considered an attractive target for treatment of type 2 diabetes. In the current study, effects of eliminating glucagon signaling with a glucagon monoclonal antibody (mAb) were investigated in the diabetic ob/ob mouse. Acute effects of inhibiting glucagon action were studied by an oral glucose tolerance test (OGTT) and by measurement of HGO. In addition, the effects of subchronic (5 and 14 days) glucagon mAb treatment on plasma glucose, insulin, triglycerides, and RbA(1c) (A1C) levels were investigated. Glucagon mAb treatment reduced the area under the curve for glucose after an OGTT, reduced HGO, and increased the rate of hepatic glycogen synthesis. Glucagon mAb treatment for 5 days lowered plasma glucose and triglyceride levels, whereas 14 days of glucagon mAb treatment reduced AM In conclusion, acute and subchronic neutralization of endogenous glucagon improves glycemic control, thus supporting the contention that glucagon antagonism may represent a beneficial treatment of diabetes.