Prudente Sabrina, Hribal Marta Letizia, Flex Elisabetta, Turchi Federica, Morini Eleonora, De Cosmo Salvatore, Bacci Simonetta, Tassi Vittorio, Cardellini Marina, Lauro Renato, Sesti Giorgio, Dallapiccola Bruno, Trischitta Vincenzo
CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy.
Diabetes. 2005 Sep;54(9):2807-11. doi: 10.2337/diabetes.54.9.2807.
Insulin resistance plays a major role in dyslipidemia, cardiovascular disease, and type 2 diabetes. TRB3, a mammalian tribbles homolog, whose chromosomal region 20p13-p12 has been linked to human type 2 diabetes, impairs insulin signaling through the inhibition of Akt phosphorylation and is overexpressed in murine models of insulin resistance. We here report that the prevalent TRB3 missense Q84R polymorphism is significantly (P < 0.05) associated with several insulin resistance-related abnormalities in two independent cohorts (n = 178 and n = 605) of nondiabetic individuals and with the presence of a cluster of insulin resistance-related cardiovascular risk factors in 716 type 2 diabetic patients (OR 3.1 [95% CI 1.2-8.2], P = 0.02). In 100 additional type 2 diabetic patients who suffered from myocardial ischemia, age at myocardial ischemia was progressively and significantly (P = 0.03) reduced from Q84Q to Q84R to R84R individuals. To test the functional role of TRB3 variants, either Q84 or R84 TRB3 full-length cDNAs were transfected in human HepG2 hepatoma cell lines. As compared with control HepG2 cells, insulin-induced Ser473-Akt phosphorylation was reduced by 22% in Q84- (P < 0.05 vs. control cells) and by 45% in R84-transfected cells (P < 0.05 vs. Q84 transfected and P < 0.01 vs. control cells). These data provide the first evidence that TRB3 gene plays a role in human insulin resistance and related clinical outcomes.
胰岛素抵抗在血脂异常、心血管疾病和2型糖尿病中起主要作用。TRB3是一种哺乳动物tribbles同源物，其染色体区域20p13 - p12与人类2型糖尿病相关，它通过抑制Akt磷酸化损害胰岛素信号传导，并且在胰岛素抵抗的小鼠模型中过表达。我们在此报告，在两个独立的非糖尿病个体队列（n = 178和n = 605）中，普遍存在的TRB3错义Q84R多态性与几种胰岛素抵抗相关异常显著相关（P < 0.05），并且在716例2型糖尿病患者中与一组胰岛素抵抗相关的心血管危险因素的存在相关（OR 3.1 [95% CI 1.2 - 8.2]，P = 0.02）。在另外100例患有心肌缺血的2型糖尿病患者中，从Q84Q个体到Q84R个体再到R84R个体，心肌缺血的年龄逐渐且显著降低（P = 0.03）。为了测试TRB3变体的功能作用，将Q84或R84的TRB3全长cDNA转染到人HepG2肝癌细胞系中。与对照HepG2细胞相比，胰岛素诱导的Ser473 - Akt磷酸化在Q84转染的细胞中降低了22%（与对照细胞相比P < 0.05），在R84转染的细胞中降低了45%（与Q84转染的细胞相比P < 0.05，与对照细胞相比P < 0.01）。这些数据提供了首个证据，表明TRB3基因在人类胰岛素抵抗及相关临床结局中起作用。
