Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes
Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes
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DOI：
10.2337/diabetes.51.7.2074
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发表时间：
2002-07-01
期刊：
影响因子：
7.7
通讯作者：
Goodyear, LJ
中科院分区：
文献类型：
--
作者：
Musi, N;Hirshman, MF;Goodyear, LJ
二甲双胍是一种有效的降糖药物，通过减少肝脏葡萄糖生成和增加骨骼肌葡萄糖处理来降低血糖浓度；然而，二甲双胍作用的分子位点尚不清楚。amp激活的蛋白激酶（AMPK）活性随着细胞能量储存的消耗而增加，这种酶与刺激骨骼肌对葡萄糖的摄取和抑制肝脏糖异生有关。我们最近报道了AMPK在培养的大鼠肝细胞中被二甲双胍激活，介导二甲双胍对肝糖产生的抑制作用。在本研究中，我们评估了治疗剂量的二甲双胍是否会增加2型糖尿病患者体内AMPK的活性。二甲双胍治疗10周显著增加骨骼肌AMPK α 2活性，这与Thr172上AMPK磷酸化增加和乙酰辅酶a羧化酶-2活性降低有关。AMPK α 2活性的增加可能是由于肌肉能量状态的改变，因为二甲双胍治疗后ATP和磷酸肌酸浓度较低。二甲双胍诱导的AMPK活性增加与葡萄糖处理率和肌糖原浓度升高有关。这些发现表明二甲双胍在2型糖尿病患者中的代谢作用可能是由AMPK α 2的激活介导的。
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.