2型糖尿病分子分型和個體化診療技術

韓學堯　張思敏　胡承　梁華　邢丹

摘 要：本年度課題組繼續(xù)完善建設各種研究隊列，包括自然人群、糖尿病前期、糖尿病合并冠心病、糖尿病前期干預、糖尿病藥物治療隊列，開展橫斷面和前瞻性研究，收集各個隨訪階段的臨床信息和生物學樣本，篩選各種具有預測價值的生物標志物。對通過外顯子組測序發(fā)現(xiàn)可能導致糖尿病的發(fā)生的胰島素基因突變，利用細胞分子生物學研究手段進行功能研究，初步證實此基因突變是致病的；確認了PAX4（rs10229583）與中國漢族2型糖尿病的相關性；在前期發(fā)現(xiàn)中國漢族人群特有的2型糖尿病易感基因（NOS1AP基因SNP位點，rs12742393）位點的基礎上，找出與基因型密切相關的差異表達的血清蛋白；研究發(fā)現(xiàn)KCNQ1基因區(qū)的SNPs與心電圖QT間期延長有關。在糖尿病前期隊列中，篩選到幾個可能影響生活方式干預后體重變化、吡格列酮治療后體重變化和胰島素敏感性變化的遺傳標志物；在2型糖尿病患者中，篩選出與幾個與二甲雙胍降糖療效和體重變化相關的標志物。在糖尿病合并冠心病研究中，證實非酒精性脂肪肝使動脈粥樣硬化的風險增加，即使在糖尿病早期無心肌缺血癥狀，也存在心血管疾病可能；低度蛋白尿和橈骨定量也可預測心血管疾病；研究發(fā)現(xiàn)Mir-22與肥胖、非酒精性脂肪肝和胰島素抵抗狀態(tài)相關。所有這些發(fā)現(xiàn)需要在獨立樣本和擴大樣本后進一步證實，將來用于預測糖尿病發(fā)生、藥物反應、分子分型和個體化診療。

關鍵詞：2型糖尿病 生物標志物 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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