A new hierarchical treatment strategy for diabetes revealed by Prof. Wei Zhang’s team: Individualized blood glucose control and vascular complications prevention for patients with type 2 diabetes mellitus (T2DM) based on TRIB3 molecular classification.
It is becoming a hot spot how to achieve an optimized method for glycemic control and vascular complications prevention with T2DM since China is challenged with the rapidly increased T2DM. If we can take advantage of personal genomic information to identify people who are at low risk for developing hypoglycemia (HbA1c% <6.5 %) and vascular complications compared with the current standard treatment regimen (HbA1c% >7.0%), it would has a great significance to promote the personalized therapy for T2DM. Prof. Wei Zhang’s team from Xiangya Hospital, Institute of Clinical Pharmacology of Central South University have focused on the Pharmacogenomics of T2DM for yeas and got a great discovery.
Their recent findings revealed that TRIB3 molecular classification could distinguish the T2DM patients with HbA1c% lower than 6.5% who are at lower risk for vascular complications. The results have been published in series of 《Cell》 and 《The Lancet》,EBioMedicine,(http://www.sciencedirect.com/science/article/pii/S2352396416304868 ; http://dx.doi.org/10.1016/j.ebiom.2016.10.025 ). The first author is Dr. Fazhong He.
TRIB3 plays an important role in maintaining blood glucose homeostasis through insulin-mediated Akt signaling pathway in different organs and tissues. Excessive activation of TRIB3 can result in increased risk of T2DM and cardiovascular complications for other metabolic syndrome. It has been reported that TRIB3 rs2295490 was closely associated with the risk of cardiovascular disease. In sight of this, we conducted a 2×2 factorial clinical trial to explore the relationship of TRIB3 genetic polymorphism and the risk of vascular complications for T2DM in four groups: intensive hypoglycemic therapy, local standard hypoglycemic therapy, continuous antihypertensive therapy and placebo-controlled treatment.
Our previous studies have shown that hypertensive patients carrying the AA genotype of TRIB3 (rs2295490) show a better antihypertensive effect after treatment of imidapril and calcium channel blockers. Our results from the ADVANCE project , including 1884 patients from 61 Chinese Clinical Research Center followed-up for 5 years demonstrated that T2DM patients carrying the TRIB3 (rs2295490) G allele had a significantly lower incidence of macrovascular and microvascular events after intensive glycemic control (HbA1c% <6.5%) treatment.
Now, the team members are continually keeping on the in-depth mechanism exploration to ascertain TRIB3 signal pathway and molecular target in order to translate the research results to drug development and clinical individualized treatment, improving the effectiveness and pertinence for early interventional treatment for T2DM patients.
张伟教授团队研究揭示糖尿病分层治疗新策略：
基于TRIB3分子分型的2型糖尿病个体化血糖控制及血管并发症防治
中国面临糖尿病及其血管并发症快速增长态势，如何进行良好的血糖控制及积极的血管并发症防治成为当前关注的热点及挑战。若能根据患者的基因信息，辨别哪些患者治疗过程中糖化血红蛋白（HbA1c%） 低于6.5% 不易发生低血糖，且心血管并发症较目前临床标准治疗（HbA1c% 高于7.0%）显著降低，对于推进糖尿病个体化治疗将有重大意义。中南大学湘雅医院临床药理研究所张伟教授课题组近年来关注糖尿病的临床药物基因组学研究，并取得重要发现。
课题组最近研究表明，通过对TRIB3分子分型能够辨别哪些糖尿病患者目标HbA1c%控制在6.5% 以下能够显著降低心血管事件发生率。该研究论文发表于《Cell》和 《Lancet》联合创办子刊《EBioMedicine》，论文第一作者为何发忠博士。
TRIB3能够在不同的器官和组织参与胰岛素介导的Akt信号通路调控，对维持机体血糖稳态具有重要作用。TRIB3过度激活能使2型糖尿病或其他代谢性疾病心血管并发症增加。已有研究表明，TRIB3（rs2295490）基因突变与心血管疾病风险显著相关。因此，我们在2×2析因设计大型临床试验深入探究了2型糖尿病患者经强化降糖和地方标准降糖，持续降压和安慰剂对照疗后，TRIB3基因变异与血管并发症之间的联系。
课题组前期研究表明携带TRIB3（rs2295490）AA基因型的高血压患者在接受咪达普利和钙离子通道阻滞剂治疗后显示出了更好的降压效果。而此次对ADVANCE项目61个中国临床研究中心1884名患者的研究表明，携带TRIB3（rs2295490）G等位基因的2型糖尿病患者在接受强化降糖治疗（HbA1c%<6.5%）并随访5年后，其大血管及微血管事件发生率显著降低。
目前，课题组正在进行更为深入的机制研究，旨在探明TRIB3信号转导通路和重要靶点，以期早日将研究成果应用于相关药物研发和临床个体化治疗，提高2型糖尿病患者早期干预治疗的有效性和针对性。
文章链接：
http://www.sciencedirect.com/science/article/pii/S2352396416304868;
http://dx.doi.org/10.1016/j.ebiom.2016.10.025
