Kahn C Ronald
Joslin Diabetes Center, Harvard University Medical School, Boston, Massachusetts 02215, USA.
Exp Diabesity Res. 2003 Jul-Sep;4(3):169-82. doi: 10.1155/EDR.2003.169.
A central component of type 2 diabetes and the metabolic syndrome is insulin resistance. Insulin exerts a multifaceted and highly integrated series of actions via its intracellular signaling systems. Generation of mice carrying null mutations of the genes encoding proteins in the insulin signaling pathway provides a unique approach to determining the role of individual proteins in the molecular mechanism of insulin action and the pathogenesis of insulin resistance and diabetes. The role of the four major insulin receptor substrates (IRS1-4) in insulin and IGF-1 signaling have been examined by creating mice with targeted gene knockouts. Each produces a unique phenotype, indicating the complementary role of these signaling components. Combined heterozygous defects often produce synergistic or epistatic effects, although the final severity of the phenotype depends on the genetic background of the mice. Conditional knockouts of the insulin receptor have also been created using the Cre-lox system. These tissue specific knockouts have provide unique insights into the control of glucose homeostasis and the pathogenesis of type 2 diabetes, and have led to development of new hypotheses about the nature of the insulin action and development of diabetes.
胰岛素抵抗是2型糖尿病和代谢综合征的核心组成部分。胰岛素通过其细胞内信号系统发挥多方面且高度整合的一系列作用。培育携带胰岛素信号通路中蛋白质编码基因无效突变的小鼠，为确定单个蛋白质在胰岛素作用分子机制以及胰岛素抵抗和糖尿病发病机制中的作用提供了独特方法。通过创建靶向基因敲除小鼠，已对四种主要胰岛素受体底物（IRS1 - 4）在胰岛素和IGF - 1信号传导中的作用进行了研究。每种底物都产生独特的表型，表明这些信号传导成分具有互补作用。尽管表型的最终严重程度取决于小鼠的遗传背景，但联合杂合缺陷通常会产生协同或上位效应。还使用Cre - lox系统创建了胰岛素受体的条件性敲除小鼠。这些组织特异性敲除小鼠为葡萄糖稳态的控制和2型糖尿病的发病机制提供了独特见解，并引发了关于胰岛素作用本质和糖尿病发展的新假说。
