MOLECULAR GENETICS OF INSULIN RESISTANCE AND NONINSULIN-DEPENDENT DIABETES

胰岛素抵抗在糖尿病发病机制中的作用 包括肥胖和2型糖尿病在内的几种疾病状态 。我们已经调查了遗传因素的性质， 易发生胰岛素抵抗。此前，我们 在患者中发现了胰岛素受体基因的突变 患有几种与胰岛素抵抗相关的遗传综合征。 最近，几个变异序列已经在 编码胰岛素受体底物1(IRS-1)的基因；这些变体 据报道，这种序列在患者中更为普遍。 患有非胰岛素依赖型糖尿病。为了调查 这些氨基酸取代的意义，我们已经表达了 几种突变蛋白通过在哺乳动物细胞中的转染而获得。 然而，在我们的实验条件下，没有一个氨基 酸替换(包括最常见的变体， Gly972Arg-IRS-1)导致重组人 IRS-1。这些负面的观察结果并不支持这一假设 IRS-1基因氨基酸序列的多态与IRS-1 2型糖尿病患者胰岛素抵抗的原因。 我们还在进行临床调查，患者患有 各种形式的脂肪萎缩，其中大多数也有胰岛素 抵抗型糖尿病。我们已经开始了曲格列酮的治疗 以确定该制剂是否会改善代谢 在这些脂肪组织稀少的患者中进行对照。在 后续我们还将确定曲格列酮是否 会导致身体脂肪的增加。最后，我们正在建立细胞 作为这些患者DNA的来源，以便识别 导致遗传性脂肪萎缩患者脂肪萎缩的基因 综合征(尤其是Dunnigan综合征，部分型 一种常染色体显性遗传性脂肪萎缩 继承)。

Insulin resistance contributes to the pathogenesis of several disease states including obesity and type 2 diabetes mellitus . We have investigated the nature of the genetic factors that predipose to the development of insulin resistance. Previously, we have identified mutations in the insulin receptor gene in patients with several genetic syndromes associated with insulin resistance. More recently, several variant sequences have been identified in the gene encoding insulin receptor substrate-1 (IRS-1); these variant sequences have been reported to be more prevalent among patients with noninsulin-dependent diabetes mellitus. To investigate the signficance of these amino acid substitutions, we have expressed several of the mutant proteins by transfection in mammalian cells. However, under our experimental conditions, none of the amino acid substitutions (including the most common variant, Gly972Arg-IRS-1) caused a functional defect in recombinant IRS-1. These negative observations do not support the hypothesis that polymorphisms in the amino acid sequence of IRS-1 contribute to the cause of insulin resistance in patients with type 2 diabetes. We are also carrying out clinical investigation of patients with various forms of lipoatrophy, most of whom also have insulin resistant diabetes. We have initiated therapy with troglitazone in order to determine whether this agent will improve metabolic control in these patients with a paucity of adipose tissue. In the course of follow-up, we will also determine whether troglitazone leads to an increase in body fat. Finally, we are establishing cell lines as a source of DNA from these patients in order to identify the genes that cause lipoatrophy in patients with genetic forms of the syndrom (especially Dunnigan's syndrome, a form of partial lipoatrophy transmitted with an autosomal dominant from of inheritance).