On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance
On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance
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通讯作者：
G. Shulman;Howard
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作者：
G. Shulman;Howard
据估计，到2020年，全球将有约2.5亿人受2型糖尿病影响（1）。虽然导致这种疾病的主要因素是未知的，但很明显，胰岛素抵抗在其发展中起着重要作用。这方面的证据来自于（a）疾病发作前10-20年存在胰岛素抵抗（2，3）;（B）横断面研究表明胰岛素抵抗是2型糖尿病患者的一致发现（3-6）;和（c）前瞻性研究表明胰岛素抗性是个体以后是否会变成糖尿病的最佳预测因子（2，3）。在这里，我集中在我们的理解人类胰岛素抵抗的一些最新进展，已经使用核磁共振光谱（NMR）。该技术利用了某些同位素（如1H、13 C和31 P）的核的自旋特性，这些同位素具有磁性成分，可用于非侵入性地测量细胞内代谢物的浓度，并评估正常和糖尿病受试者之间的生化差异。利用我实验室和其他实验室的NMR研究，我首先考虑葡萄糖磷酸化和转运在调节肌肉对胰岛素的反应中的控制。然后，我转向脂肪酸对胰岛素反应的影响，表明普遍接受的模型，试图解释胰岛素抵抗和肥胖的关联是不符合最近的研究结果。最后，我提出了一个替代模型，似乎适合这些和其他可用的数据。肌糖原合成对全身胰岛素刺激的葡萄糖代谢的贡献我们的初步研究解决了两个问题。首先，在正常人中，胰岛素刺激的肌糖原合成对全身胰岛素刺激的葡萄糖代谢的贡献是什么？第二，在多大程度上这一过程在2型糖尿病患者中存在缺陷（7）？我们用13 C核磁共振波谱法测定了肌糖原合成的速率，以监测[1-13 C]葡萄糖掺入肌糖原的速率，在模拟餐后条件的稳态血浆胰岛素和葡萄糖浓度下，我们发现糖尿病受试者的肌糖原合成比正常志愿者低约50%。当肌糖原合成的平均速率外推到全身时，肌糖原的合成占全身葡萄糖摄取的大部分，并且几乎所有的非氧化性葡萄糖代谢在两个正常人中。
It is estimated that by the year 2020 there will be approximately 250 million people affected by type 2 diabetes mellitus worldwide (1). Although the primary factors causing this disease are unknown, it is clear that insulin resistance plays a major role in its development. Evidence for this comes from (a) the presence of insulin resistance 10–20 years before the onset of the disease (2, 3); (b) cross-sectional studies demonstrating that insulin resistance is a consistent finding in patients with type 2 diabetes (3–6); and (c) prospective studies demonstrating that insulin resistance is the best predictor of whether or not an individual will later become diabetic (2, 3). Here, I focus on some recent advances in our understanding of human insulin resistance that have been made using nuclear magnetic resonance spectroscopy (NMR). This technique takes advantage of the spin properties of the nuclei of certain isotopes, such as 1 H, 13 C, and 31 P, which endow the isotopes with a magnetic component that can be used to measure the concentration of intracellular metabolites noninvasively and to assess biochemical differences between normal and diabetic subjects. Drawing on NMR studies from my laboratory and others, I first consider the control of glucose phosphorylation and transport in regulating muscle responses to insulin. I then turn to the effects of fatty acids on insulin responses , showing that commonly accepted models that attempt to explain the association of insulin resistance and obesity are incompatible with recent findings. Finally , I propose an alternative model that appears to fit these and other available data. Contributions of muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism Our initial studies addressed two questions. First, what is the contribution of insulin-stimulated muscle glyco-gen synthesis to whole-body insulin-stimulated glucose metabolism in normal individuals? Second, to what extent is this process defective in patients with type 2 diabetes (7)? We have measured rates of muscle glycogen synthesis using 13 C NMR spectroscopy to monitor the rate of [1-13 C]glucose incorporation into muscle glyco-gen. Under steady-state plasma concentrations of insulin and glucose that mimic postprandial conditions, we found that muscle glycogen synthesis was approximately 50% lower in diabetic subjects than in normal volunteers. When the mean rate of muscle glycogen synthesis was extrapolated to the whole body, the synthesis of muscle glycogen accounted for most of the whole-body glucose uptake, and virtually all of the nonoxidative glucose metabolism in both normal …