胰岛素抵抗的宫内因素和胰岛素受体基因多态性的研究

Insulin resistance (IR) is the core pathological basis of hypertension, hyperglycemia and lipidemia which are currently epidemic in Chinese population. It was known that heredity and environmental risk factors share the contribution to IR development. The purpose of this project is, from two angles of intrauterine environment and genetic susceptibility, to explore the pathogenesis of IR in a natural population whose birth records were preserved and whom we followed up for nearly 10 years, with a comprehensive means including epidemiology cohort study, clinical study, laboratory assay and molecular biology research. Main points of outcome presented as follow:1. Intrauterine growth retardation (IUGR) represented by low birth weight (LBW) and thin at birth was the independent risk factor contributing to IR development. The relative risk of suffering from IR during adulthood (47 to 53 years old) for the group of people with LBW (Birth weight less than 2500 g) was 10.5 times (95%CI:2.1~52.5) compare to the group whose birth weight at 3500 g or above. 2. The single nucleotide polymorphism (SNP) of insulin receptor gene affect individual's susceptibility of suffering from IR. A SNP was found at the site of EXON2-2257 of insulin .receptor gene among the natural population of northern China. Three genotypes of single nucleotide were presented at this site, out of 345 participants, 237 cases (68.7%), 13 cases (3.8%) and 95 cases (27.5%) were tested as the genotypes of CC (wild homozygote), TT (mutant homozygote) and CT (mutant heterozygote), respectively. The degree of IR according to Homeostasis Model Assessment (HOMA-IR) was the highest for the people with CC genotype, moderate for CT genotype and the lowest for TT genotype, with significantly statistics difference among three groups of genotype. Logistic analysis, after taking account of possible confounding factors, showed that the OR value of suffering from IR for the group of people with CT genotype was 0.45(95%CI:0.21~0.94) compare to the group with CC genotype. Namely, mutant heterozygote CT genotype at the site of EXON2-2257 may be the protection genotype, while wild homozygote CC genotype may be a susceptible genotype in relation to IR.3. Referring to the environmental factors in later life, hypertension, hypertriglyceridemia and .obesity were also the independent risk factors in relation to IR. Obesity during adulthood played a synergistic action with LBW or thin at birth in the contribution to IR.4. Simultaneous logistic analysis, with both LBW and SNP at site of EXON2-2257 in the same model and after adjusting for possible confounding factors, was performed to determine whether there is interaction effect between LBW and CT or CC genotype on IR. The result showed that the impact of both LBW and CT or CC genotype on IR remained same as before.This study firstly presented that both IUGR and polymorphism of insulin receptor gene EXON2-2257 played independent effect on IR during adulthood, namely, IUGR is an independent risk factor to IR, and CT genotype at the site of EXON2-2257 may protect individual from IR, while CC genotype may increase individual's susceptibility to IR. This study suggested that prevention of adult obesity remains an important strategy for decreasing the incidence of IR, particularly in the immediate future. While in the longer term, the benefit of prevention of IR and IR syndrome may also be derived from promotion of maternal nutrition before pregnancy and decreasing incidence of IUGR. The result of this study is also of consulting significance in detecting individual with susceptibility to IR out of population and taking individualized medication treatment at the due case.

从宫内发育不良和胰岛素受体基因异常两个角度探讨胰岛素抵抗的发生机理，分析遗传和宫内环境因素对胰岛素抵抗的相互作用。从而有助于早期从无表型人群中筛检出胰岛素抵抗的易患个体，达到对高血压、II型糖尿病和冠心病早期预防的目的。.