Cellular mechanisms of insulin resistance in humans.
Cellular mechanisms of insulin resistance in humans.
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DOI：
10.1016/s0002-9149(99)00350-1
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发表时间：
1999-07
期刊：
影响因子：
--
通讯作者：
G I Shulman
中科院分区：
文献类型：
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作者：
G I Shulman
碳核磁共振（13C NMR）波谱和磷（31P）波谱已被用来帮助确定胰岛素刺激肌肉糖原合成对正常人全身胰岛素刺激葡萄糖代谢的贡献，以及2型（非胰岛素依赖型）糖尿病患者这一过程的缺陷程度。对高血糖-高胰岛素夹持反应的评估表明，肌糖原合成异常，显然是由GLUT-4运输和/或己糖激酶活性缺陷介导的，在2型糖尿病胰岛素抵抗中起主要作用。对游离脂肪酸（FFA）引起人类胰岛素抵抗的机制的研究表明，游离脂肪酸水平的升高抑制葡萄糖转运，这可能是胰岛素受体底物（ir -1）相关磷脂酰肌醇3-激酶活性降低的结果。13C核磁共振波谱研究表明，2型糖尿病患者肝糖原浓度降低，肝糖异生率增加；因此，2型糖尿病患者较高的葡萄糖生成速率可完全归因于肝脏糖异生速率的增加。这些胰岛素抵抗的细胞机制可以通过与逆转2型糖尿病主要病理生理缺陷的药物联合治疗来解决。双胍类药物二甲双胍似乎通过抑制肝脏葡萄糖生成来降低葡萄糖，而噻唑烷二酮曲格列酮似乎可以增加外周组织对葡萄糖的清除。这两种药物联合使用比单独使用任何一种药物都能更好地控制血糖，而且不会刺激胰岛素分泌。
Carbon nuclear magnetic resonance (13C NMR) spectroscopy and phosphorus (31P) NMR spectroscopy have been used to help define the contribution of insulin-stimulated muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism in normal individuals and the extent to which this process is defective in patients with type 2 (non–insulin-dependent) diabetes. Assessments of the response to hyperglycemic–hyperinsulinemic clamping have shown that abnormalities of muscle glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or hexokinase activity, play a major role in causing insulin resistance in type 2 diabetes. Studies of the mechanisms by which free fatty acids (FFA) cause insulin resistance in humans indicate that increased FFA levels inhibit glucose transport, which may be a consequence of decreased insulin receptor substrate (IRS-1)–associated phosphatidylinositol 3-kinase activity.13C NMR spectroscopy studies have documented that liver glycogen concentrations are reduced and the rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes; thus, the higher rate of glucose production in type 2 diabetes can be attributed entirely to increased rates of hepatic gluconeogenesis. These cellular mechanisms of insulin resistance can be addressed through combination therapy with agents that reverse the principal pathophysiologic defects of type 2 diabetes. The biguanide metformin appears to lower glucose by suppressing hepatic glucose production, whereas the thiazolidinedione troglitazone appears to increase glucose clearance by peripheral tissues. The two agents together have been shown to provide better glucose control than either drug alone, without stimulating insulin secretion.