AMINO-ACID POLYMORPHISMS OF INSULIN-RECEPTOR SUBSTRATE-1 IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS
AMINO-ACID POLYMORPHISMS OF INSULIN-RECEPTOR SUBSTRATE-1 IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS
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DOI：
10.1016/0140-6736(93)92694-o
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发表时间：
1993-10-02
期刊：
影响因子：
168.9
通讯作者：
PEDERSEN, O
中科院分区：
文献类型：
--
作者：
ALMIND, K;BJORBAEK, C;PEDERSEN, O
由于相对或绝对胰岛素缺乏和胰岛素不敏感性参与了非胰岛素依赖型糖尿病（NIDDM）的病因学，我们检查了NIDDM患者是否表现出胰岛素受体底物-1（IRS-1）编码区的遗传变异，IRS-1是一种在胰岛素敏感和胰岛素样生长因子1（IGF 1）敏感组织中普遍存在的候选基因，包括决定葡萄糖产生和清除的那些和对胰腺β-细胞功能具有调节作用的那些。IRS-1作为连接胰岛素受体和IGF 1受体激酶与调节细胞代谢和生长的酶的衔接分子具有核心作用。应用单链构象多态性分析和直接核苷酸测序技术对86例非亲缘关系的NIDDM患者和76例正常血糖对照者的基因组DNA进行分析。10例NIDDM患者和3例对照者在密码子972处为杂合的多态性，其中甘氨酸被精氨酸取代。此外，在密码子513，6例NIDDM患者和2名对照具有杂合多态性，从丙氨酸到脯氨酸的转换。没有多态性携带者有两个氨基酸变异和IRS-1多态性的总等位基因频率是约3倍，在NIDDM患者比对照组（p=0.02）。这两个氨基酸取代位于接近酪氨酸磷酸化基序，胰岛素和IGF 1信号传递蛋白的推定识别位点。表型分析显示，与没有已知IRS-1多态性的患者相比，IRS-1变异的NIDDM患者的胰岛素抵抗程度没有差异。然而，密码子972变异携带者的空腹胰岛素和C肽水平显著降低。我们的研究结果表明，IRS-1的氨基酸多态性可能参与了晚发型NIDDM的一个子集的病因。
Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate gene that is ubiquitous in insulin-sensitive and insulin-like growth factor 1 (IGF1) sensitive tissues, including those that determine glucose production and clearance and those with regulatory effects on pancreatic beta-cell function. IRS-1 has a central role as an adaptor molecule that links the insulin-receptor and IGF1-receptor kinases with enzymes that regulate cellular metabolism and growth. Single-stranded conformation polymorphism analysis and direct nucleotide sequencing were applied to genomic DNA from 86 unrelated patients with NIDDM and 76 normoglycaemic controls. 10 of the patients with NIDDM and 3 of the controls were heterozygous at codon 972 for a polymorphism in which glycine was substituted with arginine. Moreover, at codon 513, 6 patients with NIDDM and 2 controls had a heterozygous polymorphism with a transition from alanine to proline. None of the polymorphism carriers had both aminoacid variants and the total allelic frequency of IRS-1 polymorphisms was about three times higher in patients with NIDDM than in controls (p=0.02). Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. Analysis of the phenotypes showed that patients with NIDDM who had IRS-1 variants did not differ in their degree of insulin resistance compared with patients without known IRS-1 polymorphisms. However, carriers of the codon 972 variant had significantly lower plasma levels of fasting insulin and C-peptide.Our results suggest that aminoacid polymorphisms in IRS-1 may be involved in the aetiology of a subset of late-onset NIDDM.