A Common Polymorphism in the Promoter of UCP2 Contributes to the Variation in Insulin Secretion in Glucose-Tolerant Subjects

Sesti, Giorgio; Cardellini, Marina; Marini, Maria Adelaide; Frontoni, Simona; D’Adamo, Monica; Guerra, S Del; Lauro, Davide; Nicolais, Pierluigi de; Sbraccia, Paolo; Prato, Stefano Del; Gambardella, S.; Federici, Massimo; Marchetti, Piero; Lauro, Renato

doi:10.2337/diabetes.52.5.1280

Cited by 121 publications

(112 citation statements)

References 30 publications

(26 reference statements)

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“…On the contrary, the AA genotype conferred an increased risk of type 2 diabetes (OR=1.84) in Italian women [22]. In line with that study, Sesti et al found that the A allele was associated with decreased glucose-stimulated insulin secretion in subjects with NGT as well as in human islets [43]. Here, we could not find any association between the −866G→A polymorphism and GDM in Scandinavian women despite the fact that our study had 99% power to detect the OR reported for the AA genotype in Italian women with type 2 diabetes [22], or for the G allele reported by Wang et al [20], as well as for the AA genotype reported in Caucasians [21].…”

Section: Irs1 G972rsupporting

confidence: 68%

Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

et al. 2005

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Aims/hypothesis: Gestational diabetes mellitus (GDM) and type 2 diabetes share a common pathophysiological background, including beta cell dysfunction and insulin resistance. In addition, women with GDM are at increased risk of developing type 2 diabetes later in life. Our aim was to investigate whether, like type 2 diabetes, GDM has a genetic predisposition by studying five common polymorphisms in four candidate genes that have previously been associated with type 2 diabetes. Materials and methods: We studied 1,777 unrelated Scandinavian women (588 with GDM and 1,189 pregnant non-diabetic controls) for polymorphisms in the genes encoding potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), insulin receptor substrate 1 (IRS1 G972R), uncoupling protein 2 (UCP2 −866G→A) and calpain 10 (CAPN10 SNP43 and SNP44). Results: The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050). In addition, the frequency of the K allele was increased in women with GDM (odds ratio [OR]=1.17, 95% CI 1.02−1.35; p=0.027), and this effect was greater under a dominant model (KK/EK vs EE) (OR=1.3, 95% CI 1.05−1.60; p=0.016). Analysis of the IRS1 G972R polymorphism showed that RR homozygosity was found exclusively in women with GDM (91.0, 8.3 and 0.7% vs 90.7,9.3 and 0.0% for GG, GR and RR genotypes, respectively; p=0.014). The genotype and allele frequencies of the other polymorphisms studied were not statistically different between the GDM and control women. Conclusions/interpretation: The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women.

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Section: Irs1 G972rsupporting

confidence: 68%

Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

et al. 2005

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“…For example the −866A allele is associated with decreased insulin secretion in Caucasians from Italy [4], while the same allele was associated with increased secretion in Northern European Caucasians, as ascertained in Utah [5]. Another study reported a reduced risk of type 2 diabetes in obese middle-aged humans with a −866G allele [6].…”

Section: Discussionmentioning

confidence: 96%

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

Kovacs

Hanson

et al. 2005

Diabetologia

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Aims/hypothesis: Uncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians. Methods: The coding and untranslated regions of UCP2, and approximately 1 kb of the 5′ upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives. Results: Five variants were identified: (1) a −866G/A in the 5′ upstream region; (2) a G/ A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3′ untranslated region. Among the 83 subjects whose DNA was sequenced, the −866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the −866G/A variant (as a representative of Ala55Val and the 3-bp ins/ del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the −866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass). Conclusions/interpretation: Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians.

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“…In particular, VV genotype, in comparison to those who have the AA or A/V genotype, have a lower degree of uncoupling, lower energy expenditure (Astrup et al 1999), higher exercise energy efficiency (Buemann et al 2001), and lower fat oxidation. However, it has been reported that persons with the I/D genotype have an increased basal metabolic rate, increased 24-h energy expenditure and decreased BMI (Esterbauer et al 2001), as well as a low deposition index (Walder et al 1998).Recently, the −866 G-allele has been described to influence UCP2 transcription, to be associated with reduced adipose tissue mRNA expression, reduced transcriptional activity in vitro and in vivo, high BMI, fat mass changes (Yoon et al 2007), increased risk of obesity (Esterbauer et al 2001;Argyropoulos and Harper 2002;Vogler et al 2005), increased insulin response to glucose and reduced risk of T2D (Krempler et al 2002;Esterbauer et al 2001;Sesti et al 2003).…”

Section: Introductionmentioning

confidence: 99%

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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A large array of gene involved in human longevity seems to be in relationship with insulin/ IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83±25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/ Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63-0.91; p=0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63-6.19; p=0.0006). The analysis also revealed lower HOMA-IR (Diff, −0.532, 95% CI, 0.886-0.17; p= 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014-0.05; p=0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, p=0.038) for AAV allele combination. In conclusion, A-IGF1R/ Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.

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A Common Polymorphism in the Promoter of UCP2 Contributes to the Variation in Insulin Secretion in Glucose-Tolerant Subjects

Cited by 121 publications

References 30 publications

Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

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