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The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes.

ABSTRACT: 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.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, <45 yr, or >or= 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets.Four different case-control samples comprising a total of 5,469 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.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).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.

SUBMITTER: Prudente S

PROVIDER: S-EPMC2630876 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes.

Prudente Sabrina S Scarpelli Daniela D Chandalia Manisha M Zhang Yuan-Yuan YY Morini Eleonora E Del Guerra Silvia S Perticone Francesco F Li Rong R Powers Christine C Andreozzi Francesco F Marchetti Piero P Dallapiccola Bruno B Abate Nicola N Doria Alessandro A Sesti Giorgio G Trischitta Vincenzo V

The Journal of clinical endocrinology and metabolism 20081104 1

<h4>Context</h4>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.<h4>Objective</h4>The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped o ...[more]

PMID: 18984671

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Project description:BackgroundAlthough cumulating evidence has suggested that early-onset type 2 diabetes mellitus (T2DM) conferred on patients a broader tendency for complications beyond vascular ones, a comprehensive analysis of patterns of complications across all relevant systems is currently lacking.MethodWe prospectively studied 1 777 early-onset (age at diagnosis ≤ 45 years) and 35 889 late-onset (>45 years) T2DM patients with matched unexposed individuals from the UK Biobank. Diabetes-specific and -related complications were examined using phenome-wide association analysis, with patterns identified by comorbidity network analysis. We also evaluated the effect of lifestyle modifications and glycemic control on complication development.ResultsThe median follow-up times for early-onset and late-onset T2DM patients were 17.83 and 9.39 years, respectively. Compared to late-onset T2DM patients, patients with early-onset T2DM faced a significantly higher relative risk of developing subsequent complications that primarily affected sense organs [hazard ratio (HR) 3.46 vs. 1.72], the endocrine/metabolic system (HR 3.08 vs. 2.01), and the neurological system (HR 2.70 vs. 1.81). Despite large similarities in comorbidity patterns, a more complex and well-connected network was observed for early-onset T2DM. Furthermore, while patients with early-onset T2DM got fewer benefits (12.67% reduction in pooled HR for all studied complications) through fair glycemic control (median HbA1c ≤ 53 mmol/mol) compared to late-onset T2DM patients (18.01% reduction), they seemed to benefit more from favorable lifestyles, including weight control, healthy diet, and adequate physical activity.ConclusionsOur analyses reveal that early-onset T2DM is an aggressive disease resulting in more complex complication networks than late-onset T2DM. Aggressive glucose-lowering intervention, complemented by lifestyle modifications, are feasible strategies for controlling early-onset T2DM-related complications.

Project description:Aims/hypothesisIdentifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.MethodsWe studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS.ResultsOf the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies.Conclusions/interpretationWe have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.

Dataset Information

The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes.

Publications

The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes.

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