Series introduction: the molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular diseases.
Series introduction: the molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular diseases.
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DOI：
10.1172/jci10533
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发表时间：
2000-01
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影响因子：
--
通讯作者：
A. Saltiel
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作者：
A. Saltiel
在1922年Banting和Best发现胰岛素之后，人们普遍认为人类糖尿病完全是由于激素分泌不足。然而，10年后，Himsworth（1）注意到糖尿病患者对胰岛素的反应存在差异，并提出胰岛素不敏感，而不是胰岛素缺乏，是许多糖尿病患者的定义性生化缺陷。直到贝尔森和Yalow（2）开发出放射免疫测定法，这一想法才得到认真考虑，他们发现成人发病（2型）糖尿病受试者的循环胰岛素水平往往高于平均水平。后来来自Roth（3）、Reaven（4，5）、Olefsky（6）和其他人的研究证实了这些发现，并为胰岛素抵抗在糖尿病中起主要作用的观点提供了机制基础。我们现在知道，2型糖尿病的病理生理学涉及三个器官系统的缺陷，这些器官系统共同产生异常的葡萄糖和脂质代谢（7）。虽然关于原发性病变和不同组织的相对重要性存在一些不确定性，但肝脏和外周靶组织（如脂肪和肌肉以及胰腺β细胞）中的代谢缺陷都有助于该综合征。胰岛素抵抗，其定义为对正常循环浓度的胰岛素的反应性降低的状态，现在被认为是2型糖尿病的特征性特征，并导致所有这些组织的异常。在多个人群中进行的各种前瞻性流行病学研究表明，2型糖尿病在胰岛素作用恶化的连续过程中进展，从外周胰岛素抵抗开始，以胰岛素分泌丧失结束（图1）.1）。在大多数患者中，胰岛素抵抗可以在葡萄糖耐受不良恶化之前很久就被检测到。胰岛素抵抗是一种相当常见的状态，与衰老和久坐不动的生活方式以及遗传倾向有关。国家似乎是由肥胖推动的，或者在某种程度上是肥胖的结果。由于胰岛素抵抗而发生的碳水化合物和脂质代谢的随后失调进一步加剧了其进展。胰腺的β细胞通常通过增加基础和餐后胰岛素分泌来补偿胰岛素抵抗状态。在某些时候，β细胞不再能够补偿，无法对葡萄糖做出适当的反应。这最终导致葡萄糖稳态的恶化和葡萄糖耐受不良的发展。在特定年份中，约有5 - 10%的葡萄糖不耐受患者进展为明显的糖尿病，随着胰岛素抵抗的增加，糖尿病继续恶化。脂肪细胞产生更多的脂肪酸，肝脏以不受调节的方式产生更多的葡萄糖，并且β细胞经历完全衰竭，导致疾病的晚期，其中可能需要高剂量的外源性胰岛素。图1 2型糖尿病的代谢分期即使没有糖尿病，胰岛素抵抗也是其他人类疾病状态的关键特征。胰岛素作用受损与高胰岛素血症结合导致多种异常，包括甘油三酯升高、HDL水平降低、VLDL分泌增强、凝血障碍、血管阻力增加、类固醇激素水平变化、外周血流量减弱和体重增加。因此，胰岛素抵抗通常与向心性肥胖、高血压、多囊卵巢综合征、血脂异常和动脉粥样硬化有关。这种症状通常被称为X综合征或胰岛素抵抗综合征（8）。胰岛素作用受损是否直接导致这些患者的所有症状仍不清楚。然而，胰岛素抵抗的广泛流行及其与严重代谢异常的相关性已被广泛接受。在这一系列的观点中，我们将试图提供一些关于胰岛素抵抗的病理生理学的见解。在考虑这种疾病的分子基础之前，有必要了解正常细胞中涉及的途径。杰弗里·佩森和我讨论了胰岛素作用的细胞生物学，推测了可能导致激素作用减弱的分子缺陷。Gerald Shulman专注于葡萄糖代谢的变化，这些变化是胰岛素抵抗患者和动物模型的特征，试图确定胰岛素作用受损引起的代谢途径的关键改变。由于充分了解胰岛素抵抗的病因至关重要，Michael Stern假设了这种状态的遗传易感性以及基因与环境之间的相互作用。Takashi Kadowaki介绍了胰岛素抵抗动物模型的最新进展，这导致了对这种疾病基础的惊人见解。Kenneth Polonsky及其同事讨论了胰岛素抵抗和胰岛素分泌之间的相互作用，探索了导致糖尿病的失代偿状态的机制。Jeffrey Flier和Barbara Kahn讨论了肥胖在胰岛素抵抗中的复杂作用，集中讨论了能量摄取和消耗的中枢控制如何直接影响外周组织中的胰岛素作用。胰岛素抵抗对心血管系统的影响是了解与这种状态相关的危险因素的关键领域。亨利金斯伯格调查这一领域摆脱了大多数糖尿病学家的葡萄糖为中心的观点，把重点放在脂质和脂蛋白代谢的调节。最后，Jerrold Olefsky讨论了旨在增强胰岛素作用从而逆转胰岛素抵抗的新药理学方法，以及某些药物可能发挥作用的机制。
Following the discovery of insulin by Banting and Best in 1922, it was widely assumed that human diabetes was due exclusively to a deficiency in the secretion of the hormone. However, 10 years later Himsworth (1) noted variations in the responses of diabetic patients to insulin and proposed the notion that insulin insensitivity, not insulin deficiency, was the defining biochemical defect in many diabetics. This idea was not considered seriously until the development of the radioimmunoassay by Berson and Yalow (2), who showed that subjects with adult onset (type 2) diabetes tended to exhibit higher than average levels of circulating insulin. Later studies from Roth (3), Reaven (4, 5), Olefsky (6), and others corroborated these findings and provided a mechanistic basis for the idea that insulin resistance plays a major role in diabetes. We now know that the pathophysiology of type 2 diabetes involves defects in three organ systems that conspire together to produce abnormal glucose and lipid metabolism (7). While there is some uncertainty regarding the primary lesion and the relative importance of the different tissues, metabolic defects in liver and in peripheral target tissues, such as fat and muscle and pancreatic β cells, all contribute to the syndrome. Insulin resistance, which is defined as a state of reduced responsiveness to normal circulating concentrations of insulin, is now recognized as a characteristic trait of type 2 diabetes and contributes to abnormalities in all of these tissues. Various prospective epidemiological studies across several population groups indicate that type 2 diabetes progresses over a continuum of worsening insulin action, beginning with peripheral insulin resistance and ending with a loss of insulin secretion (Figure (Figure1).1). In most patients, insulin resistance can be detected long before the deterioration of glucose intolerance occurs. Insulin resistance is a quite common state, associated with aging and a sedentary lifestyle, as well as a genetic predisposition. The state seems to be fueled by, or perhaps to a certain extent the result of, obesity. The ensuing dysregulation of carbohydrate and lipid metabolism that occurs as a consequence of insulin resistance further exacerbates its progression. β cells of the pancreas normally compensate for the insulin-resistant state by increasing basal and postprandial insulin secretion. At some point, the β cells can no longer compensate, failing to respond appropriately to glucose. This ultimately leads to the deterioration of glucose homeostasis and the development of glucose intolerance. Approximately 5 to 10% of glucose-intolerant patients in a given year progress to frank diabetes, which continues to worsen as insulin resistance increases. Adipose cells generate more fatty acids, the liver produces more glucose in an unregulated fashion, and the β cells undergo complete failure, resulting in the late stages of the disease, where high doses of exogenous insulin may be required. Figure 1 Metabolic staging of Type 2 diabetes Even in the absence of diabetes, insulin resistance is a key feature of other human disease states. Impaired insulin action coupled with hyperinsulinemia leads to a variety of abnormalities, including elevated triglycerides, low levels of HDL, enhanced secretion of VLDL, disorders of coagulation, increased vascular resistance, changes in steroid hormone levels, attenuation of peripheral blood flow, and weight gain. Thus, insulin resistance is often associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia, and atherosclerosis. This constellation of symptoms is often referred to as syndrome X, or insulin resistance syndrome (8). Whether impaired insulin action is directly responsible for all of the symptoms in these patients remains unclear. However, the broad prevalence of insulin resistance and its association with profound metabolic abnormalities are widely accepted. In this Perspective series, we will attempt to provide some insight into the pathophysiology of insulin resistance. Before considering the molecular basis for this disorder, it is essential to understand the pathways involved in normal cells. Jeffrey Pessin and I discuss the cell biology of insulin action, speculating about possible molecular defects responsible for the attenuation of the actions of the hormone. Gerald Shulman focuses on changes in glucose metabolism that are characteristic of patients and animal models with insulin resistance, in an attempt to identify key alterations in metabolic pathways caused by impaired insulin action. Because it is critical to fully understand the etiology of insulin resistance, Michael Stern hypothesizes about the genetics underlying susceptibility to this state, and the interaction between genes and the environment. Takashi Kadowaki presents an update on animal models of insulin resistance, which have led to startling insights into the basis of this disorder. Kenneth Polonsky and colleagues discuss the interaction between insulin resistance and insulin secretion, exploring the mechanisms leading to states of decompensation that result in diabetes. Jeffrey Flier and Barbara Kahn discuss the complex role of obesity in relation to insulin resistance, concentrating on how the central control of energy uptake and expenditure might also directly influence insulin action in peripheral tissues. The impact of insulin resistance on the cardiovascular system is a critical area for understanding the risk factors associated with this state. Henry Ginsberg surveys this field by escaping from the glucocentric view of most diabetologists, to focus on the regulation of lipid and lipoprotein metabolism. Finally, Jerrold Olefsky discusses new pharmacological approaches designed to enhance insulin action and thus to reverse insulin resistance and the mechanisms by which certain of these drugs may exert their effects.