胰岛素抵抗的分子生物学。

D Müller-Wieland, R Streicher, G Siemeister, W Krone
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引用次数: 15

摘要

胰岛素抵抗是多种临床疾病的基本特征,如糖尿病、肥胖、原发性高血压,主要是由于细胞水平上激素作用的缺陷。在过去的十年中,包括重组DNA技术在内的新研究技术的应用为理解胰岛素的作用机制及其在分子水平上的改变铺平了道路。胰岛素作用的第一步是胰岛素受体的激活。胰岛素受体是一种四聚体蛋白,由两个细胞外α亚基和两个跨膜β亚基组成。胰岛素与α -亚基的结合引起细胞内酪氨酸残基上的β -亚基区域的自磷酸化,从而激活受体。激素信号随后如何在细胞内转导仍不清楚。激活的胰岛素受体似乎与细胞质受体底物偶联,可以影响不同的信号级联,引发细胞代谢和生长的多效激素反应。大多数参与胰岛素信号转导途径的蛋白质尚不清楚,但它们中的每一种都可能在各种形式的胰岛素抵抗中发挥作用。本文以胰岛素受体作为参与胰岛素作用的典型蛋白,综述了胰岛素受体活性、基因表达调控的分子机制,以及胰岛素抵抗性糖尿病患者胰岛素受体基因突变的作用。本文概述了临床医学和分子生物学的结合如何不仅有助于理解胰岛素的作用和胰岛素抵抗的发病机制,而且还为鉴别诊断、治疗和可能预防这种异质性但最常见的代谢和内分泌疾病开辟了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular biology of insulin resistance.

Insulin resistance is an essential feature of a great variety of clinical disorders, like diabetes mellitus, obesity, essential hypertension, and is primarily due to a defect in hormone action at the cellular level. In the past decade application of novel research techniques including recombinant DNA technology have paved the way to understand the mechanisms of insulin action and its alterations at the molecular level. The first step in insulin action is the activation of the insulin receptor. The insulin receptor is a tetrameric protein consisting of two extracellular alpha- and two transmembrane beta-subunits. Binding of insulin to the alpha-subunit causes autophosphorylation of the intracellular beta-subunit region on tyrosine residues thereby activating the receptor. How the hormonal signal is subsequently transduced within the cell is still quiet unclear. The activated insulin receptor appears to couple to cytosolic receptor substrates which can affect different signaling cascades eliciting the pleiotropic hormone response on cell metabolism and growth. Most proteins involved in the signal transduction pathway of insulin are not known yet, but each of them might play a role in the various forms of insulin resistance. Taking the insulin receptor as an exemplary protein involved in insulin action we review molecular mechanisms regulating insulin receptor activity, gene expression, and the role of natural occurring insulin receptor gene mutations in patients with insulin resistant diabetes mellitus. It is outlined how the combination of both clinical medicine and molecular biology not only helps to understand insulin action and the pathogenesis of insulin resistance, but also leads to new avenues in the differential diagnosis, therapy, and possibly prevention of this heterogenous but most frequent metabolic and endocrine disorder.

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