Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice
Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice
复制标题
DOI：
10.1007/s00125-006-0552-5
复制
发表时间：
2007-02-01
期刊：
影响因子：
8.2
通讯作者：
Breyer, M. D.
中科院分区：
文献类型：
--
作者：
Rao, R.;Hao, C. -M.;Breyer, M. D.
在目前的研究中，糖原合成酶激酶3（GSK 3）的高度特异性肽抑制剂的作用，在高脂肪（HF）喂养的糖尿病小鼠模型中检查L 803-mts对葡萄糖代谢和BP的影响。将C57/BL 6 J小鼠置于HF饮食3个月并用L 803-mts处理20天，之后通过正常血-高胰岛素钳夹研究检查葡萄糖代谢。通过无线电遥测测量血压和心率。HF小鼠肥胖，糖耐量受损，血浆胰岛素和瘦素水平高。与HF组相比，L 803-mts治疗显著降低了HF+ L 803-mts组中维持正常血状态所需的胰岛素水平并使葡萄糖输注速率加倍。胰岛素未能抑制HF组的内源性葡萄糖产生速率，而HF+ L 803-mts组的内源性葡萄糖产生速率降低了75%，伴随着肝糖原合成酶活性和净肝糖原合成的增加。GSK 3抑制也降低外周胰岛素抵抗。与HF组相比，HF+ L 803-mts组的血糖消失率增加了60%。此外，心脏和腓肠肌的葡萄糖摄取也明显改善。虽然HF饮食后平均动脉压增加，但在L 803-mts治疗的12天期间没有显著变化。这些研究表明，在HF诱导的糖尿病小鼠模型中，GSK 3抑制改善了肝脏和外周胰岛素抵抗，但对BP没有影响。GSK 3可能是胰岛素抵抗的重要治疗靶点。
In the current study, the effect of a highly specific peptide inhibitor of glycogen synthase kinase 3 (GSK3) (L803-mts) on glucose metabolism and BP was examined in a high-fat (HF) fed mouse model of diabetes.C57/BL6J mice were placed on an HF diet for 3 months and treated with L803-mts for 20 days, following which glucose metabolism was examined by euglycaemic-hyperinsulinaemic clamp studies. BP and heart rate were measured by radio-telemetry.The HF mice were obese, with impaired glucose tolerance and high plasma insulin and leptin levels. L803-mts treatment significantly reduced the insulin levels and doubled the glucose infusion rate required to maintain a euglycaemic condition in the HF+L803-mts group compared with the HF group. Insulin failed to suppress the endogenous glucose production rate in the HF group while decreasing it by 75% in the HF+L803-mts group, accompanied by increased liver glycogen synthase activity and net hepatic glycogen synthesis. GSK3 inhibition also reduced peripheral insulin resistance. Plasma glucose disappearance rate increased by 60% in the HF+L803-mts group compared with the HF group. In addition, glucose uptake in heart and gastrocnemius muscle was markedly improved. Although mean arterial pressure increased following the HF diet, it did not change significantly during the 12 days of L803-mts treatment.These studies demonstrate that GSK3 inhibition improved hepatic and peripheral insulin resistance in a mouse model of HF-induced diabetes, but it failed to have an effect on BP. GSK3 may represent an important therapeutic target for insulin resistance.