Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (falfa) rats
Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (falfa) rats
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DOI：
10.2337/diabetes.51.10.2903
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发表时间：
2002-10-01
期刊：
影响因子：
7.7
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Cline, GW;Johnson, K;Shulman, GI
肝脏和肌肉糖原合成缺陷是导致2型糖尿病患者餐后高血糖的主要因素。因此，通过抑制糖原合成酶激酶(GSK)-3激活糖原合成酶是一个潜在的新的治疗靶点。为了检验这种可能性，我们对Zucker糖尿病脂肪（fa/fa）大鼠进行了口服葡萄糖耐量试验（ogtt）和正糖-胰岛素钳夹研究。抑制GSK-3可使葡萄糖和胰岛素下面积分别减少41 +/- 2% （P < 0.001）和26 +/- 4% （P < 0.05）。分别为OGTT期间的浓度曲线。葡萄糖处理的改善主要是由于肝糖原合成增加了大约两倍。相比之下，肌糖原合成没有显著增加，尽管肌糖原合成酶活性被激活了大约三倍。在钳形研究中，GSK-3抑制剂治疗使肝糖原合成增加了约三倍，与胰岛素浓度无关。相反，肌肉葡萄糖摄取和肌糖原合成与药物治疗无关。GSK-3抑制剂治疗可降低糖尿病大鼠的空腹高血糖6.0 +/- 1.3 mmol/l，但对钳夹期间的葡萄糖处理无显著影响。总之，GSK-3抑制显著改善了口服葡萄糖处理，主要是通过增加肝糖原合成。这些研究表明，抑制GSK-3可能是治疗2型糖尿病患者的一个重要的新治疗靶点。
Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen synthase kinase (GSK)-3 represents a potential new therapeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 +/- 2% (P < 0.001) and 26 +/- 4% (P < 0.05) reduction in the area under the glucose and insulin. concentration curves, respectively, during the OGTT. This improvement in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen synthesis. In contrast, there was no significant increase in muscle glycogen synthesis despite an approximate threefold activation of muscle glycogen synthase activity. GSK-3 inhibitor treatment increased liver glycogen synthesis about threefold independent of insulin concentration during the clamp studies. In contrast, muscle glucose uptake and muscle glycogen synthesis were independent of drug treatment. GSK-3 inhibitor treatment lowered fasting hyperglycemia, in diabetic rats by 6.0 +/- 1.3 mmol/l but had no significant effect on glucose disposal during the clamp. In conclusion, GSK-3 inhibition significantly improved oral glucose disposal, mostly by increasing liver glycogen synthesis. These studies suggest that GSK-3 inhibition may represent an important new therapeutic target for treatment of patients with type 2 diabetes.