UCP2启动子-866G/A基因多态性在腹透患者胰岛素抵抗中的作用及机制研究

Insulin resistance (IR) is an independent predictor of cardiovascular morbidity and mortality in patients on peritoneal dialysis (PD). PD patients are more likely to develop IR due to the glucose overload from the dialysate. Therefore it is crucial to investigate the IR related risk factors in this patient group. However, the development of insulin resistance in PD patients has individual difference. Our preliminary data showed that the wild type G allele in the promoter region -866 of the uncoupling protein 2(UCP2) gene correlated with the increased IR risk in PD patients. Further molecular analysis identified a binding site for the transcription factor Myogenin near this allele. Moreover, previous study indicated that the IR was associated with the down-regulation of the Miogenin expression. Thereby, we hypothesize that UCP2 SNP -866 may influence PD patients’ susceptibility of IR under glucose overload by regulating Myogenin ‘s effect on UCP2. This study will examine the relationship between UCP2 -866G/A SNP /UCP2 gene expression and IR in PD patients. We will also explore whether UCP2 -866 G/A SNP affects UCP2 expression by regulating its binding with Myogenin, and the potential pathways involved in. This study will benefit the understanding of predisposing factors of IR and development of individulized therapy for PD patients.

胰岛素抵抗是透析患者心血管事件的危险因素，而腹膜透析含糖透析液造成的糖负荷进一步促进胰岛素抵抗，是腹透面临的重要挑战之一。然而，腹透患者胰岛素抵抗的发生存在个体差异。我们前期研究发现解偶联蛋白2（UCP2）启动子（-866G/A）基因多态性与胰岛素抵抗的发生相关。进一步研究发现该位点附近存在转录因子Myogenin结合位点。有研究提示Myogenin可增加UCP2的表达。据此我们推测，UCP2 SNP-866可影响Myogenin对UCP2的转录作用，影响患者对高糖负荷的耐受性。本课题拟研究腹透患者UCP2-866位点SNP与UCP2表达及胰岛素抵抗的关系，并对其机制进行探讨。该研究对认识腹透胰岛素抵抗的易感因素，进行个体化治疗有重要意义。

与非糖尿病腹膜透析患者相比，糖尿病腹膜透析患者发生心血管事件及死亡的风险更高。临床上，不同患者新发糖尿病的危险性存在个体差异。本研究的目的在于从个体基因多态性角度探究解偶联蛋白2（UCP2）启动子-866G/A区域以及解偶联蛋白3（UCP3）启动子区域-55C/T基因多态性对腹透患者胰岛素抵抗以及新发糖尿病的影响，并探究相应的机制。我们通过临床研究发现，UCP2-866 位点为GG 的野生型等位基因较突变型等位基因AA/AG 导致胰岛素抵抗的统计学差异并不明显；而UCP3-55C/T位点突变型CT/TT基因型则是腹膜透析患者发生高胰岛素抵抗以及新发糖尿病的独立危险因素。通过基础研究，我们发现UCP3-55C/T位点的突变型基因型使UCP3的表达水平明显下降，而UCP3的水平与糖代谢密切相关，从而影响胰岛素抵抗。此外， UCP3-55C/T位点附近存在转录因子雌激素受体－α，也可以通过调控UCP3的表达从而影响糖代谢。本研究从基因多态性角度探索腹膜透析患者发生胰岛素抵抗的易感因素，有助于为临床上患者的个体化治疗提供重要的参考价值。