The functional Q84R polymorphism of mammalian Tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from 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.
Prudente
Sabrina
S
CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy. s.prudente@css-mendel.it
Hribal
Marta Letizia
ML
Flex
Elisabetta
E
Turchi
Federica
F
Morini
Eleonora
E
De Cosmo
Salvatore
S
Bacci
Simonetta
S
Tassi
Vittorio
V
Cardellini
Marina
M
Lauro
Renato
R
Sesti
Giorgio
G
Dallapiccola
Bruno
B
Trischitta
Vincenzo
V
D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D044465:White People
D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases