Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects
Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects
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DOI：
10.1210/jc.2004-0745
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发表时间：
2005-02-01
影响因子：
5.8
通讯作者：
DeFronzo, RA
中科院分区：
文献类型：
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作者：
Kashyap, SR;Roman, LJ;DeFronzo, RA
2型糖尿病是一种以高胰岛素血症和动脉粥样硬化加速为特征的胰岛素抵抗状态。啮齿类动物的体内和体外研究表明，一氧化氮的产生在葡萄糖转运和胰岛素作用中起着重要作用。我们测定了10名2型糖尿病患者（血红蛋白A(1c) = 6.8 +/- 0.1%）和11名对照者在基础条件下和80 mU/m时骨骼肌中一氧化氮合酶（NOS）的活性(2)。在胰岛素使用前后4小时分别行正糖胰岛素钳夹和股外侧肌活检。在糖尿病患者中，与对照组相比，胰岛素刺激的葡萄糖处置（Rd）减少了50%。+/- 0.3 vs. 10.4 +/- 0.5 mg/kg。min, P < 0.01)。糖尿病组NOS基础活性明显降低（101 +/- 33 vs. 457 +/- 164 pmol/min,P < 0.05）。胰岛素作用4小时后，对照组NOS活性增加2.5倍（934 +/- 282 pmol/min）。而胰岛素未能刺激糖尿病患者NOS活性（86 +/- 28 pmol/min中心点mg蛋白，P = NS）。对照组和糖尿病患者肌肉中基础NOS蛋白含量相似，注射胰岛素后无变化。在对照组中，胰岛素刺激的NOS活性与空腹血浆胰岛素浓度呈负相关（r = -0.58, P = 0.05），与Rd呈正相关（r = 0.71, P = 0.03）。在对照组和糖尿病组中，Rd与胰岛素刺激的NOS活性相关（r = 0.52, P = 0.02）。我们得出结论，在控制良好的2型糖尿病患者中，基础和胰岛素刺激的肌肉NOS活性受损，并且胰岛素刺激的NOS活性缺陷与胰岛素抵抗的严重程度密切相关。提示NOS活性受损可能在2型糖尿病患者胰岛素抵抗中起重要作用。
Type 2 diabetes is an insulin-resistant state characterized by hyperinsulinemia and accelerated atherosclerosis. In vitro and in vivo studies in rodents have suggested that nitric oxide generation plays an important role in glucose transport and insulin action. We determined nitric oxide synthase (NOS) activity in skeletal muscle of 10 type 2 diabetic (hemoglobin A(1c) = 6.8 +/- 0.1%) and 11 control subjects under basal conditions and during an 80 mU/m(2).min euglycemic insulin clamp performed with vastus lateralis muscle biopsies before and after 4 h of insulin. In diabetics, insulin-stimulated glucose disposal (Rd) was reduced by 50%, compared with controls (5.4. +/- 0.3 vs. 10.4 +/- 0.5 mg/kg.min, P < 0.01). Basal NOS activity was markedly reduced in the diabetic group (101 +/- 33 vs. 457 +/- 164 pmol/min center dot mg protein,P < 0.05). In response to insulin,NOS activity increased 2.5-fold in controls after 4 h (934 +/- 282 pmol/min.mg protein, P < 0.05 vs. basal), whereas insulin failed to stimulate NOS activity in diabetics (86 +/- 28 pmol/min center dot mg protein, P = NS from basal). Basal NOS protein content in muscle was similar in controls and diabetics and did not change following insulin. In controls, insulin-stimulated NOS activity correlated inversely with fasting plasma insulin concentration (r = -0.58, P = 0.05) and positively with Rd (r = 0.71, P = 0.03). In control and diabetic groups collectively, Rd correlated with insulin-stimulated NOS activity (r = 0.52, P = 0.02). We conclude that basal and insulin-stimulated muscle NOS activity is impaired in well-controlled type 2 diabetic subjects, and the defect in insulin-stimulated NOS activity correlates closely with the severity of insulin resistance. These results suggest that impaired NOS activity may play an important role in the insulin resistance in type 2 diabetic individuals.