Lebovitz H E, Banerji M A
State University of New York, Health Science Center at Brooklyn, 11203, USA.
Recent Prog Horm Res. 2001;56:265-94. doi: 10.1210/rp.56.1.265.
Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin resistance is an increase in insulin secretion that results in hyperinsulinemia. If the hyperinsulinemia is sufficient to overcome the insulin resistance, glucose regulation remains normal; if not, type 2 diabetes ensues. Associated with insulin resistance, however, is a cluster of other metabolic abnormalities involving body fat distribution, lipid metabolism, thrombosis and fibrinolysis, blood pressure regulation, and endothelial cell function. This cluster of abnormalities is referred to as the insulin resistance syndrome or the metabolic syndrome. It is causally related not only to the development of type 2 diabetes but also to cardiovascular disease. A major unresolved issue is whether there is a single underlying cause of this syndrome and, if so, what might it be? Several promising hypotheses have been proposed. There are some data to support the hypothesis that fetal malnutrition imprints on metabolic regulatory processes that, in later adult life, predispose to the development of the insulin resistance syndrome. Visceral obesity also has been a candidate for the cause of the syndrome. Whatever mechanism is ultimately found to be responsible, it will undoubtedly have both genetic and environmental components. Among the biochemical mediators that are likely to be responsible for the interference with insulin's effects on intermediary metabolism are free fatty acids and other products from adipose tissue. Recent data suggest that the substances stimulate serine phosphorylation of molecules involved in the initial steps of insulin action, thereby blocking the ability of these molecules to be tyrosine phosphorylated and initiate the subsequent steps of the insulin action cascade. The thiazolidinediones are a new class of agents that have been developed to treat type 2 diabetic patients. These drugs act as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Following their binding to the receptor, the heterodimer molecule that contains the binding site is activated. The activated complex binds to the response elements of specific genes that regulate molecules that effect insulin action and lipid metabolism. These genes are either activated or inhibited. Specifically, the thiazolidinediones improve insulin action and decrease insulin resistance. The exact mechanism by which these agents decrease insulin resistance is not clear but they do decrease the elevated free fatty acid levels present in insulin-resistant patients and they appear to change the body distribution of adipose tissue. Treatment of insulin-resistant type 2 diabetic patients with thiazolidinediones not only improves glycemic control and decreases insulin resistance, it also improves many of the abnormalities that are part of the insulin resistance syndrome.
胰岛素抵抗是一种生理调节的改变，即固定剂量的胰岛素对葡萄糖代谢产生的效应低于正常个体。对胰岛素抵抗的正常代偿反应是胰岛素分泌增加，导致高胰岛素血症。如果高胰岛素血症足以克服胰岛素抵抗，葡萄糖调节仍保持正常；如果不能，则会发生2型糖尿病。然而，与胰岛素抵抗相关的是一系列其他代谢异常，涉及体脂分布、脂质代谢、血栓形成与纤溶、血压调节以及内皮细胞功能。这一系列异常被称为胰岛素抵抗综合征或代谢综合征。它不仅与2型糖尿病的发生有因果关系，还与心血管疾病有关。一个主要未解决的问题是该综合征是否存在单一的潜在病因，如果存在，可能是什么？已经提出了几个有前景的假说。有一些数据支持这样的假说，即胎儿期营养不良会影响代谢调节过程，在成年后期易引发胰岛素抵抗综合征。内脏肥胖也一直被认为是该综合征的病因之一。无论最终发现何种机制对此负责，无疑都将包含遗传和环境因素。在可能导致胰岛素对中间代谢作用受干扰的生化介质中，游离脂肪酸和来自脂肪组织的其他产物是其中一部分。最近的数据表明，这些物质刺激胰岛素作用初始步骤中涉及分子的丝氨酸磷酸化，从而阻断这些分子进行酪氨酸磷酸化并启动胰岛素作用级联后续步骤的能力。噻唑烷二酮类是一类新开发用于治疗2型糖尿病患者的药物。这些药物作为过氧化物酶体增殖物激活受体γ（PPARγ）激动剂。它们与受体结合后，包含结合位点的异二聚体分子被激活。激活的复合物与特定基因的反应元件结合，这些基因调节影响胰岛素作用和脂质代谢的分子。这些基因要么被激活，要么被抑制。具体而言，噻唑烷二酮类可改善胰岛素作用并降低胰岛素抵抗。这些药物降低胰岛素抵抗的确切机制尚不清楚，但它们确实能降低胰岛素抵抗患者中升高的游离脂肪酸水平，并且似乎能改变脂肪组织的身体分布。用噻唑烷二酮类治疗胰岛素抵抗的2型糖尿病患者不仅能改善血糖控制并降低胰岛素抵抗，还能改善作为胰岛素抵抗综合征一部分的许多异常情况。
