TRIB3 R84 variant affects glucose homeostasis by alterino the interplay between insulin sensitività and insulin secretion.

Results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate previous association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis. Methods Three samples of Europeans with fasting glucose <7.0 mmol/l, were studied. In sample 1 (n=791), the association between TRIB3 Q84R and impaired glucose regulation (IGR: either impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT), insulin sensitivity (ISI) and its interplay with early phase insulin secretion (i.e. disposition index, DI), were analyzed. Sample 2 (n=374) and sample 3 (n=394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination. Results R84 carriers were at higher risk of IGR: odds ratio (OR) for additive model=1.54, p=0.004 and 1.63, p=0.027, in sample 1 and 2. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively reduced from QQ to QR and RR individuals. A “triangulation approach” indicated that the association with IGR was mostly mediated by DI, rather than ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 7.0±3.2, 6.1±2.6, and 5.7±2.4 mg/min x Kg, p=0.022, in QQ, QR and RR individuals). Conclusions Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to alteration of the interplay between insulin sensitivity and secretion.