TheTRIB3Q84R Polymorphism and Risk of Early-Onset Type 2 Diabetes
Open Access
- 1 January 2009
- journal article
- research article
- Published by The Endocrine Society in Journal of Clinical Endocrinology & Metabolism
- Vol. 94 (1), 190-196
- https://doi.org/10.1210/jc.2008-1365
Abstract
Context: The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling. Objective: The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, in vitro insulin secretion from isolated human islets. Design: Four different case-control samples comprising a total of 5469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors. Results: In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00–1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10–1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04). Conclusions: 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.Keywords
This publication has 32 references indexed in Scilit:
- Role of theENPP1K121Q Polymorphism in Glucose HomeostasisDiabetes, 2008
- TRIB3 R84 Variant Is Associated With Impaired Insulin-Mediated Nitric Oxide Production in Human Endothelial CellsArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetesNature Genetics, 2008
- Analysis and Application of European Genetic Substructure Using 300 K SNP InformationPLoS Genetics, 2008
- Discerning the Ancestry of European Americans in Genetic Association StudiesPLoS Genetics, 2008
- Glutamine to Arginine Substitution at Amino Acid 84 of Mammalian Tribbles Homolog TRIB3 and CKD in Whites With Type 2 DiabetesAmerican Journal of Kidney Diseases, 2007
- Genetic Deletion of Trb3, the Mammalian Drosophila tribbles Homolog, Displays Normal Hepatic Insulin Signaling and Glucose HomeostasisDiabetes, 2007
- TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in LiverScience, 2003
- NIDDM in Mexican-American Families: Heterogeneity by age of onsetDiabetes Care, 1994
- Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up studyThe Lancet, 1992