Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-8012, USA.
Lancet. 2010 Jun 26;375(9733):2267-77. doi: 10.1016/S0140-6736(10)60408-4.
Insulin resistance has long been associated with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitising effects of thiazolidinediones.
胰岛素抵抗长期以来一直与肥胖有关。40 多年前，Randle 和同事推测，脂质通过抑制糖酵解的关键点，损害肌肉对胰岛素刺激的葡萄糖利用。然而，过去二十年的研究表明，骨骼肌中脂质引起的胰岛素抵抗源于胰岛素刺激的葡萄糖转运活性的缺陷。脂肪变性的肝脏在抑制肝葡萄糖生成和刺激糖原合成方面对胰岛素也有抵抗。在肌肉和肝脏中，脂质的细胞内积累 - 即二酰基甘油 - 触发新型蛋白激酶 C 的激活，随后损害胰岛素信号。这个统一的假说解释了肥胖、2 型糖尿病、脂肪营养不良和衰老中胰岛素抵抗的机制，以及噻唑烷二酮类药物的胰岛素增敏作用。
