Glutamine to Arginine Substitution at Amino Acid 84 of Mammalian Tribbles Homolog TRIB3 and CKD in Whites With Type 2 Diabetes

Cosmo, Salvatore De; Prudente, Sabrina; Andreozzi, Francesco; Morini, Eleonora; Rauseo, Anna; Scarpelli, Daniela; Zhang, Xu Dong; Xu, Rui; Perticone, Francesco; Dallapiccola, Bruno; Sesti, Giorgio; Doria, Alessandro; Trischitta, Vincenzo

doi:10.1053/j.ajkd.2007.06.023

Cited by 14 publications

(11 citation statements)

References 5 publications

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“…The functional variation between Q84 and 84R TRB3 could also be due to differences in their conformational structures secondary to substitution of uncharged glutamine with charged arginine (38).…”

Section: Discussionmentioning

confidence: 99%

The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells

Liew¹,

Bocheński²,

Kawamori³

et al. 2010

J. Clin. Invest.

119

116

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Insufficient insulin secretion and reduced pancreatic β cell mass are hallmarks of type 2 diabetes (T2DM).Here, we confirm that a previously identified polymorphism (rs2295490/Q84R) in exon 2 of the pseudokinaseencoding gene tribbles 3 (TRB3) is associated with an increased risk for T2DM in 2 populations of people of mixed European descent. Carriers of the 84R allele had substantially reduced plasma levels of C-peptide, the product of proinsulin processing to insulin, suggesting a role for TRB3 in β cell function. Overexpression of TRB3 84R in mouse β cells, human islet cells, and the murine β cell line MIN6 revealed reduced insulin exocytosis, associated with a marked reduction in docked insulin granules visualized by electron microscopy. Conversely, knockdown of TRB3 in MIN6 cells restored insulin secretion and expression of exocytosis genes.Further analysis in MIN6 cells demonstrated that TRB3 interacted with the transcription factor ATF4 and that this complex acted as a competitive inhibitor of cAMP response element-binding (CREB) transcription factor in the regulation of key exocytosis genes. In addition, the 84R TRB3 variant exhibited greater protein stability than wild-type TRB3 and increased binding affinity to Akt. Mice overexpressing TRB3 84R in β cells displayed decreased β cell mass, associated with reduced proliferation and enhanced apoptosis rates. These data link a missense polymorphism in human TRB3 to impaired insulin exocytosis and thus increased risk for T2DM.

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Section: Discussionmentioning

confidence: 99%

The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells

Liew¹,

Bocheński²,

Kawamori³

et al. 2010

J. Clin. Invest.

119

116

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show abstract

“…Similarly, the r84 variant of TRIB3 has been associated with younger age at myocardial infarction among patients with T2DM 51 and with reduced glomerular filtration rate, although data on the latter are somewhat controver sial. 118 As mentioned above, the deleterious effects of impaired insulin signaling, which directly affects the endo thelium, might be partly responsible for the pathogenic role of insulin resistance in CvD. Endothelial dysfunction is often associated with insulin resistance states and rep resents one of the earliest steps in the development of athero sclerosis.…”

Section: Insulin Signaling Genes and Cvdmentioning

confidence: 98%

Insulin signaling regulating genes: effect on T2DM and cardiovascular risk

2009

Self Cite

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Type 2 diabetes mellitus (T2DM) is a complex disorder that has a heterogeneous genetic and environmental background. In this Review, we discuss the role of relatively infrequent polymorphisms of genes that regulate insulin signaling (including the K121Q polymorphism of ENPP1, the G972R polymorphism of IRS1 and the Q84R polymorphism of TRIB3) in T2DM and other conditions related to insulin resistance. The biological relevance of these three polymorphisms has been very thoroughly characterized both in vitro and in vivo and the available data indicate that they all affect insulin signaling and action as well as insulin secretion. They also affect insulin-mediated regulation of endothelial cell function. In addition, several reports indicate that the effects of all three polymorphisms on the risk of T2DM and cardiovascular diseases related to insulin resistance depend on the clinical features of the individual, including their body weight and age at disease onset. Thus, these polymorphisms might be used to demonstrate how difficult it is to ascertain the contribution of relatively infrequent genetic variants with heterogeneous effects on disease susceptibility. Unraveling the role of such variants might be facilitated by improving disease definition and focusing on specific subsets of patients.

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“…Although some evidence showed that a common TRIB3 genetic variation (rs2295490) was a risk factor for diabetic nephropathy, atherosclerosis, and coronary artery disease (Prudente et al, 2005, De Cosmo et al, 2007, Formoso et al, 2011, Gong et al, 2009), some low-frequency genetic variants, which are detected by re-sequencing of TRIB3 , can partially account for cardiovascular clinical outcomes in diabetes (Prudente et al, 2015). However, systematical study on the relationship between TRIB3 genetic variant (rs2295490) and antidiabetic or antihypertensive drug response, vascular complications, especially in a large and long-term follow-up T2DM clinical trial cohort have not been reported.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Chen

et al. 2016

EBioMedicine

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Effects of human tribbles homolog 3 (TRIB3) genetic variation (c.251 A > G, Gln84Arg, rs2295490) on the clinical outcomes of vascular events has not been evaluated in patients with type 2 diabetes after blood pressure lowering and glucose controlling treatment. We did an analysis of a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled clinical trial at 61 centers in China, with a follow-up period of 5 years. The major vascular endpoints were the composites of death from cardio-cerebral vascular diseases, non-fatal stroke and myocardial infraction, new or worsening renal and diabetic eye disease. A total of 1884 participants were included in our research with a 4.8 years median follow-up. For glucose lowering axis, patients with TRIB3 (rs2295490) AA (n = 609) genotype exhibited significantly reduced risk of major vascular events compared with AG + GG (n = 335) genotype carriers (Hazard ratio 0.72, 95% CI 0.55–0.94, p = 0.016), Paradoxically, the risk of vascular events were significantly increased in patients with AA (n = 621) compared to AG + GG (n = 319) genotype for intensive glucose control (Hazard ratio 1.46, 95% CI, 1.06–2.17, 35 p = 0.018). For blood pressure lowering axis, marginally significant difference was found between TRIB3 variant and coronary events. Our findings suggest that good glucose and blood pressure control exhibited greater benefits on vascular outcomes in patients with TRIB3 (rs2295490) G allele.

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Glutamine to Arginine Substitution at Amino Acid 84 of Mammalian Tribbles Homolog TRIB3 and CKD in Whites With Type 2 Diabetes

Cited by 14 publications

References 5 publications

The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells

The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells

Insulin signaling regulating genes: effect on T2DM and cardiovascular risk

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

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