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Diabetes 54:2807-2811, 2005
© 2005 by the American Diabetes Association, Inc.

Brief Genetics Reports

The Functional Q84R Polymorphism of Mammalian Tribbles Homolog TRB3 Is Associated With Insulin Resistance and Related Cardiovascular Risk in Caucasians From Italy

Sabrina Prudente1,2, Marta Letizia Hribal3, Elisabetta Flex2, Federica Turchi2, Eleonora Morini2, Salvatore De Cosmo1, Simonetta Bacci1, Vittorio Tassi1, Marina Cardellini3, Renato Lauro3, Giorgio Sesti3,4, Bruno Dallapiccola2,5, and Vincenzo Trischitta1,2,6

1 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
2 CSS-Mendel Institute, Rome, Italy
3 Department of Internal Medicine, University of "Tor Vergata", Rome, Italy
4 Department of Experimental and Clinical Medicine, University "Magna Grecia", Catanzaro, Italy
5 Department of Experimental Medicine and Pathology, University "La Sapienza", Rome, Italy
6 Department of Clinical Sciences, University "La Sapienza", Rome, Italy

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.

Address correspondence and reprint requests to Sabrina Prudente, PhD,Vincenzo Trischitta, MD, CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy. E-mail: s.prudente{at}css-mendel.itvincenzo.trischitta{at}uniroma1.it

Abbreviations: CVD, cardiovascular disease; MAF, minor allele frequency; NCBI, National Center for Biotechnology Information


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