Permutt M A, Elbein S C
Metabolism Division, Washington University School of Medicine, St. Louis, Missouri.
Diabetes Care. 1990 Mar;13(3):364-74. doi: 10.2337/diacare.13.3.364.
Insulin deficiency is a prominent feature of non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetes mellitus that could result from defects in the insulin gene. Cloning of this gene has permitted molecular-genetic studies including the definition of multiple-DNA-sequence polymorphisms detected with restriction endonucleases, or restriction-fragment-length polymorphisms (RFLPs), and the mapping of the insulin gene to the short arm of chromosome 11 adjacent to the insulinlike growth factor II (IGF-II) and tyrosine hydroxylase genes. The combined RFLPs for the insulin, IGF-II, and tyrosine hydroxylase genes make this a highly informative locus for genetic studies of the insulin gene in diabetes. Early studies of an RFLP consisting of variable-number tandem repeats (VNTR) of DNA near the insulin gene suggested an association of certain alleles with approximately 170 copies of the repeat unit with NIDDM. Although subsequent studies in NIDDM did not confirm this association, an association of different alleles defined by approximately 40 copies of the repeat unit in this VNTR region with IDDM has been demonstrated in multiple studies. This VNTR region and the multiple other RFLPs for this region have been used in linkage analysis to study the segregation of insulin genes in families. These studies have failed to demonstrate a major significant role for insulin-gene defects in NIDDM, maturity-onset diabetes of the young, or IDDM in American Blacks and Whites and under various models of inheritance. Several pedigrees with diabetes and defects of the insulin gene have been described, however, and a minor role for this gene in NIDDM cannot be eliminated from available studies. Similarly, the association studies of the insulin gene and IDDM suggest a minor modifying role undetectable in pedigree studies. The role of defects in or near the insulin gene in a small subset of NIDDM or in IDDM must await direct investigation of the insulin gene in diabetic individuals with the most recent methods for gene amplification and sequence analysis.
胰岛素缺乏是非胰岛素依赖型（NIDDM）和胰岛素依赖型（IDDM）糖尿病的一个显著特征，这可能是由胰岛素基因缺陷导致的。该基因的克隆使得分子遗传学研究成为可能，包括对用限制性内切酶检测到的多DNA序列多态性（即限制性片段长度多态性，RFLPs）的定义，以及将胰岛素基因定位到11号染色体短臂上，该区域与胰岛素样生长因子II（IGF-II）基因和酪氨酸羟化酶基因相邻。胰岛素、IGF-II和酪氨酸羟化酶基因的联合RFLPs使得该位点对于糖尿病中胰岛素基因的遗传学研究具有很高的信息量。早期对胰岛素基因附近由可变数目串联重复序列（VNTR）组成的RFLP的研究表明，某些含有约170个重复单元拷贝的等位基因与NIDDM有关联。尽管随后对NIDDM的研究并未证实这种关联，但多项研究已证明，在该VNTR区域中由约40个重复单元拷贝定义的不同等位基因与IDDM有关联。这个VNTR区域以及该区域的多个其他RFLPs已被用于连锁分析，以研究胰岛素基因在家族中的分离情况。这些研究未能证明胰岛素基因缺陷在美国黑人和白人的NIDDM、青年发病型糖尿病或IDDM中，以及在各种遗传模型下具有主要的显著作用。然而，已经描述了几个患有糖尿病且存在胰岛素基因缺陷的家系，现有研究尚不能排除该基因在NIDDM中发挥的次要作用。同样，胰岛素基因与IDDM的关联研究表明，其具有一种在系谱研究中无法检测到的次要修饰作用。胰岛素基因内部或附近的缺陷在一小部分NIDDM或IDDM中的作用，必须等待采用最新的基因扩增和序列分析方法对糖尿病个体的胰岛素基因进行直接研究。
