TheTRIB3Q84R Polymorphism and Risk of Early-Onset Type 2 Diabetes

Abstract

The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.

TRIB3 R84 variant affects glucose homeostasis by altering the interplay between insulin sensitivity and secretion

“…In addition, we also report that individuals carrying the R84 variant are characterised by altered interplay between insulin sensitivity and secretion as indicated by reduced DI values for OGTT. These data too represent a formal replication of a previous finding [9]; also in this case, when present and previous [9] data are metaanalysed a quite robustly significant association is reached. Taken together, these and previous [9] data suggest that the TRIB3 R84 variant exerts a deleterious role on glucose homeostasis by affecting the interplay between insulin sensitivity and insulin secretion; the subtle equilibrium is instrumental for the maintenance of glucose homeostasis TRIB3 R84 DI p=0.009.…”

“…Glucose and insulin profiles during OGTT Repeatedmeasurements ANCOVA models to assess differences across genotypes over time showed that plasma glucose and insulin levels during OGTT were progressively higher from this study and recently published data reporting a similar association [9]; the results obtained in a total number of 1,436 individuals, confirmed the association (adjusted β (SE) of log DI for each R84 allele=−0.15 (0.04), adjusted p=0.0007). We then asked whether the R84 effect on the risk of IGR was mediated either by DI or by ISI changes and tested it by a 'triangulation approach' in sample 1, for whom all the data needed to test these hypotheses were available.…”

“…When the current data are meta-analysed with those previously published for the association with type 2 diabetes [9], the statistical association becomes quite robust, especially for abnormal glucose homeostasis before age 45 years. In addition, we also report that individuals carrying the R84 variant are characterised by altered interplay between insulin sensitivity and secretion as indicated by reduced DI values for OGTT.…”

“…Given the stronger association with earlyonset type 2 diabetes (i.e. before age 45 years) observed in our previous study [9], meta-analysis was also performed for early-onset forms of abnormal glucose homeostasis (Fig. 1b).…”

“…In vivo, the R84 variant has been associated with insulin resistance [6,8] and with type 2 diabetes (C. Wee Liew, J. Bochenski, J. Hu, A.S. Krowleski and R.N. Kulkarni, unpublished data); this latter association is likely to be secondary to an altered interplay between insulin secretion and insulin action observed in R84 carriers [9]. As for any genetic study of complex traits, these findings-despite coherence with the biological function of the Q84R polymorphism-need to be replicated as much as possible, with results reaching a high level of statistical significance before they can be considered established.…”