Pedersen O
Steno Diabetes Centre, Gentofte, Copenhagen, Denmark.
Exp Clin Endocrinol Diabetes. 1999;107(2):113-8. doi: 10.1055/s-0029-1212085.
Even among young, healthy individuals, there is more than a 10-fold variation in insulin sensitivity; however, taken in combination, all the known modifiers of insulin sensitivity - including obesity and a variety of environmental factors - explain less than one third of this variation. It is possible that genetic factors could account for the bulk of the variance observed, and hence play a major role in the development of impaired insulin sensitivity, ie insulin resistance. From the genetic point of view, insulin resistance is thought to be due to the inheritance of a number of mutations in a variety of genes. Three complementary approaches have been applied in the search for mutations: mutational analysis of candidate genes; linkage analysis of candidate genes or chromosomal regions for insulin resistance in familial type 2 diabetes; and random genome mapping with quantitative trait loci (QTL) analysis. Mutational analysis of the insulin signalling cascade has identified a glycine-arginine (Gly-Arg) substitution at codon 972 of the insulin receptor substrate-1 (IRS-1) gene with a carrier prevalence of 9% among Caucasians. Expression of this variant in 32-D cells is associated with a significant (20-30%) impairment of insulin-stimulated PI3-kinase activity, as well as reduced binding of IRS-1 to the p85 regulatory subunit of PI3-kinase. Genotype/phenotype studies stratified according to body mass index (BMI) indicate that obese subjects who are heterozygous for the mutant allele have a 50% decrease in insulin sensitivity, compared with wild-type obese subjects. This suggests that there may be an interaction between the mutant allele and obesity, such that, in the presence of obesity, the mutant variant may aggravate the obesity-associated insulin resistance. Mutational analysis has also shown that homozygous carriers of a codon Met 326 Ile mutation in the p85 subunit of phosphatidylinositol-3 (PI3)-kinase (about 2% of the Caucasian population) have lower glucose tolerance, glucose effectiveness. A further Asp to Tyr polymorphism has been identified at codon 905 of the gene encoding the regulatory subunit of glycogen-associated protein phosphatase-1 (PP1G). Individuals who are heterozygous for this polymorphism constitute 18% of the Caucasian population and appear to exhibit both tissue-specific and pathway-specific insulin resistance. It is likely that inherited insulin resistance will eventually prove to be related to subtle mutations in many such genes of the insulin signalling network and the numerous genetic components controlling energy metabolism.
即使在年轻健康的个体中，胰岛素敏感性也存在超过10倍的差异；然而，综合考虑所有已知的胰岛素敏感性调节因素——包括肥胖和各种环境因素——也只能解释不到三分之一的这种差异。有可能遗传因素是观察到的大部分差异的原因，因此在胰岛素敏感性受损即胰岛素抵抗的发生中起主要作用。从遗传学角度来看，胰岛素抵抗被认为是由于多种基因中多个突变的遗传。在寻找突变方面应用了三种互补方法：候选基因的突变分析；家族性2型糖尿病中胰岛素抵抗候选基因或染色体区域的连锁分析；以及利用数量性状基因座（QTL）分析进行随机基因组图谱绘制。胰岛素信号级联的突变分析在胰岛素受体底物-1（IRS-1）基因的第972密码子处发现了甘氨酸-精氨酸（Gly-Arg）替换，在白种人中携带者患病率为9%。该变体在32-D细胞中的表达与胰岛素刺激的PI3激酶活性显著降低（20%-30%）相关，同时IRS-1与PI3激酶的p85调节亚基的结合也减少。根据体重指数（BMI）分层的基因型/表型研究表明，与野生型肥胖受试者相比，突变等位基因杂合的肥胖受试者胰岛素敏感性降低50%。这表明突变等位基因与肥胖之间可能存在相互作用，即，在存在肥胖的情况下，突变变体可能会加重与肥胖相关的胰岛素抵抗。突变分析还表明，磷脂酰肌醇-3（PI3）激酶p85亚基中第326密码子甲硫氨酸（Met）突变为异亮氨酸（Ile）的纯合携带者（约占白种人人口的2%）具有较低的糖耐量和葡萄糖效能。在糖原相关蛋白磷酸酶-1（PP1G）调节亚基编码基因的第905密码子处还发现了另一种天冬氨酸（Asp）到酪氨酸（Tyr）的多态性。这种多态性杂合的个体占白种人人口的18%，似乎表现出组织特异性和途径特异性的胰岛素抵抗。遗传性胰岛素抵抗最终很可能被证明与胰岛素信号网络的许多此类基因以及控制能量代谢的众多遗传成分中的微小突变有关。
