2型糖尿病分子分型和个体化诊疗技术

韩学尧　张思敏　胡承　梁华　邢丹

摘 要：本年度课题组继续完善建设各种研究队列，包括自然人群、糖尿病前期、糖尿病合并冠心病、糖尿病前期干预、糖尿病药物治疗队列，开展横断面和前瞻性研究，收集各个随访阶段的临床信息和生物学样本，筛选各种具有预测价值的生物标志物。对通过外显子组测序发现可能导致糖尿病的发生的胰岛素基因突变，利用细胞分子生物学研究手段进行功能研究，初步证实此基因突变是致病的；确认了PAX4（rs10229583）与中国汉族2型糖尿病的相关性；在前期发现中国汉族人群特有的2型糖尿病易感基因（NOS1AP基因SNP位点，rs12742393）位点的基础上，找出与基因型密切相关的差异表达的血清蛋白；研究发现KCNQ1基因区的SNPs与心电图QT间期延长有关。在糖尿病前期队列中，筛选到几个可能影响生活方式干预后体重变化、吡格列酮治疗后体重变化和胰岛素敏感性变化的遗传标志物；在2型糖尿病患者中，筛选出与几个与二甲双胍降糖疗效和体重变化相关的标志物。在糖尿病合并冠心病研究中，证实非酒精性脂肪肝使动脉粥样硬化的风险增加，即使在糖尿病早期无心肌缺血症状，也存在心血管疾病可能；低度蛋白尿和桡骨定量也可预测心血管疾病；研究发现Mir-22与肥胖、非酒精性脂肪肝和胰岛素抵抗状态相关。所有这些发现需要在独立样本和扩大样本后进一步证实，将来用于预测糖尿病发生、药物反应、分子分型和个体化诊疗。

关键词：2型糖尿病 生物标志物 分子分型

Abstract： In this year， this group has been working hard on establishing and improving the study cohorts including random samples， samples with pre-diabetes， samples with diabetes and coronary heart disease （CHD）， pre-diabetes samples with different interventions， samples with treatments of different anti-diabetic drugs. Several cross sectional studies and prospective studies are conducting， a lot of clinical information and biological samples were collected， and some biomarkers were screened for predicting type 2 diabetes and its large vessel complication. By exome sequencing， we identified an insulin mutation， which is being confirmed to cause diabetes through molecular biological laboratory methods. By case control study， we confirmed the association of PAX4-rs10229583 with type 2 diabetes in Chinese Han. By proteomics study， we screened three special protein associated with NOS1AP-rs12742393， which was proven to relate to the risk for type 2 diabetes in Chinese Han. Some genetic markers of KCNQ1 were found to have an effect on QTc of EKG. In pre-diabetes cohort， we found a few of SNPs might associate with weight changes or insulin sensitivity following interventions of life style and pioglitazone. In type 2 diabetes cohort with treatment of metformin， we screened some DNA variations maybe contributing to the different responses to metfromin in lowering blood glucose and weight loss.In type 2 diabetes with CHD， nonalcoholic fat liver， higher blood glucose， radialis bone mass and mild increased urinary albumin excretion might increase the risk of CHD.In addition， Mir-22 also were identified to associate with obesity， fat liver and insulin resistance. All the finding need to be confirmed in independent studies，and some might become the real biaomarker for predicting the development of diabetes and CHD， responses to anti-diabetic drugs，molecular typing of type 2 diabetes， and regimens of individualized treatment of diabetes.

Key Words： Type 2 diabetes； Biomarker； Molecular typing

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