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

Abstract

Aims/hypothesis The 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 the previously reported 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; defined as impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT) and insulin sensitivity (ISI), and its interplay with early-phase insulin secretion (i.e. disposition index [DI]) were analysed. 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: OR for the additive model 1.54, p=0.004, and 1.63, p=0.027, in samples 1 and 2, respectively. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively lower from QQ to QR and RR individuals. A 'triangulation approach' indicated that the association with IGR was mostly mediated by DI rather than by ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 38.8±17.7, 33.8±14.4, and 31.6±13.3 μmol min −1 kg −1, p=0.022, in QQ, QR and RR individuals, respectively. Conclusions/interpretation Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this V. Trischitta and L. Frittitta contributed equally to this study.

Assessment of Human Tribbles Homolog 3 Genetic Variation (rs2295490) Effects on Type 2 Diabetes Patients with Glucose Control and Blood Pressure Lowering Treatment

“…Interestingly, TRIB3 is a pseudo-kinase that plays a pivotal role in the insulin signaling transduction pathway (Du et al, 2003), and TRIB3 (rs2295490) G allele can lead to a gain-of-function amino acid substitution in the insulin target tissues (Liew et al, 2010). In addition, the genetic variation dose not directly affect fast blood glucose levels, but by altering the interplay between insulin sensitivity and secretion (Prudente et al, 2010), our results were in accordance with these findings.…”

Whole genome association scan for genetic polymorphisms influencing information processing speed

“…Numerous studies point to its involvement in metabolic processes, e.g., in a US Caucasian case-control sample, the functional TRIB3 Q84R polymorphism has been nominally associated with: type 2 diabetes (T2D) (OR = 1.17, p = .04), early-onset of T2D (OR = 1.32, p = .002), and among a non-diabetic subset, R84 carriers had higher glucose levels (p = .005) and lower insulinogenic (p = .03) and disposition index (p = .02) during an oral glucose tolerance test (Prudente et al, 2009). Further, in two independent Italian samples, R84 carriers were found to be at higher risk of impaired glucose regulation (OR = 1.54, p = .004 and OR= 1.63, p = .027) (Prudente et al, 2010). In a Chinese cohort, individuals with the same variant were found to be at risk for metabolic syndrome (OR = 2.349, p = .018), with a particular predisposition to carotid atherosclerosis, in part due to the effects of abdominal obesity (OR = 2.351, p = .012), hypertriglyceridemia (OR = 2.314, p = .00003), and insulin resistance (OR-1.697, p = .023) (Gong et al, 2009).…”

ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies

“…Besides the established role of abnormal insulin signaling in predisposing to insulin resistance [4], studies in animal models have proposed that insulin signaling is essential also for beta-cell insulin secretion [5], [6], [7], [8]. Along the same line of evidences, human non synonymous genetic variations which affect the insulin signaling pathway [9], [10], [11], [12] and which have been associated with in vivo insulin resistance [13], [14], are also able to affect insulin secretion in vivo [13], [15], in isolated human islets [8], [16], [17] and in cultured beta-cells [8], [18]. Thus, an intriguing scenario has emerged suggesting that abnormalities impairing insulin signaling play a role on glucose homeostasis not only by affecting glucose metabolism in liver and skeletal muscle, but also by inducing defective insulin secretion [19], [20].…”