Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

Rung, Johan; Cauchi, Stéphane; Albrechtsen, Anders; Shen, Lishuang; Rocheleau, Ghislain; Cavalcanti-Proença, Christine; Bertucci, François; Balkau, Beverley; Bélisle, Alexandre; Borch‐Johnsen, Knut; Charpentier, G.; Dina, Christian; Durand, Emmanuelle; Elliott, Paul; Hadjadj, Samy; Järvelin, Marjo Riitta; Laitinen, Jaana; Lauritzen, Torsten; Marre, Michel; Mazur, Alexander; Meyre, David; Montpetit, Alexandre; Pisinger, Charlotta; Posner, Barry I.; Poulsen, Pernille; Pouta, Anneli; Prentki, Marc; Ribel‐Madsen, Rasmus; Ruokonen, Aimo; Sandbaek, Anelli; Serre, David; Tichet, Jean; Vaxillaire, Martine; Wojtaszewski, Jørgen F. P.; Vaag, Allan; Hansen, Torben; Polychronakos, Constantin; Pedersen, Oluf; Froguel, Philippe; Sladek, Robert

doi:10.1038/ng.443

Cited by 404 publications

(357 citation statements)

References 42 publications

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“…So far, genome-wide association studies (GWAS) and subsequent meta-analysis have identified 23 validated risk loci influencing risk of type 2 diabetes [1][2][3]. While many common gene variants have shown an influence on estimates of beta cell function, only few variants have an impact on insulin resistance [2,[4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

et al. 2010

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Aims/hypothesis A meta-analysis of 21 genome-wide association studies identified 11 novel genetic loci implicated in fasting glucose homeostasis. We aimed to evaluate the impact of these variants on insulin release and insulin sensitivity estimated from OGTTs. Methods Eleven variants in or near DGKB/TMEM195, ADCY5, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B and IGF1 were genotyped in 6,784 middle-aged participants of the population-based Inter99 cohort. Association studies of quantitative estimates of insulin release and insulin sensitivity were performed in 5,722 non-diabetic Danish participants on whom an OGTT was performed.Results Assuming an additive genetic model, carriers of the alleles increasing fasting glucose in DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B showed decreased glucosestimulated insulin release as assessed by the BIGTT-acute insulin response index (2.7-3.5%; p<0.005 for all) and by corrected insulin response (2.8-5.9%; p<0.03 for all). In addition, the PROX1 glucose-raising allele showed a 2.9% decreased corrected insulin response (p=0.03), while the hyperglycaemic allele of variants in or near ADRA2A, FADS1, CRY2 and C2CD4B were associated with a 2.6% to T. W. Boesgaard and N. Grarup contributed equally to this work. Diabetologia (2010) 53:1647-1655 DOI 10.1007/s00125-010-1753 9.3% decrease in one or both of two different OGTT-based disposition indices (p<0.02 for all). After correction for multiple testing, variants in the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with estimates of beta cell function. Conclusions/interpretation We found that the lead variants at the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response. This association underlines the importance of pancreatic beta cell dysfunction in the genetic predisposition to hyperglycaemia and type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

et al. 2010

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“…For example, the major allele of the lead single-nucleotide polymorphisms (SNP) in the IRS1 locus is associated with increased risk of type 2 diabetes mellitus, insulin resistance, and hyperinsulinemia [4], along with decreased HDL-C, increased TG, and increased risk of CAD. It remains unclear which of the metabolic risk factors are responsible for the increased CAD risk.…”

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confidence: 99%

Dyslipidemia: another brick in the wall. A feasible link in the OSA–cardiovascular disease axis

Juhász¹

2013

Sleep Breath

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Obstructive sleep apnea (OSA) is a frequent and often severe clinical condition that has been linked to cardiovascular diseases and metabolic disorders among others. The underlying mechanisms initiating and aggravating cardiovascular disorders are not clearly understood yet, oxidative stress and endothelial dysfunction are considered as major factors. A frequent consequence of OSA is diminished endothelial function including decreased nitric oxide (NO)-dependent vasodilation. A very recent review summarizing current experimental information from animal models gives a deep insight in the complexity of alterations in NO production in patients with OSA

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“…In the present study, the association of T2DM with 38 SNPs, that were previously identified and confirmed by genome wide association studies of European (32 SNPs) (1,(3)(4)(5)(6)(7)(8)(9) and South Asian (6 SNPs) (2) populations, was investigated in the Saudi population (RIYADH cohort). Among the 37SNPs passing quality control measures, 8 SNPs showed significant association with T2DM at the nominal level (P<0.05) and two other SNPs showed borderline significant associations.…”

Section: Discussionmentioning

confidence: 99%

eplication of genome wide association-validated loci for type 2 diabetes mellitus in the Saudi Arabian population

Al‐Daghri¹,

Alkharfy²,

Alokail³

et al. 2013

EJEA

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Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

Cited by 404 publications

References 42 publications

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

Dyslipidemia: another brick in the wall. A feasible link in the OSA–cardiovascular disease axis

eplication of genome wide association-validated loci for type 2 diabetes mellitus in the Saudi Arabian population

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