Heritability of Insulin Secretion, Peripheral and Hepatic Insulin Action, and Intracellular Glucose Partitioning in Young and Old Danish Twins

Poulsen, Pernille; Levin, Klaus; Petersen, Inge; Christensen, Kaare; Beck‐Nielsen, Henning; Vaag, Allan

doi:10.2337/diabetes.54.1.275

Cited by 146 publications

(151 citation statements)

References 34 publications

(39 reference statements)

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“…These findings cannot simply be attributed to a restricted range of BMI or ISI values in this healthy sample, since our heritability estimates of BMI and insulin sensitivity are very comparable to previous estimates [11,12,33]. Furthermore, the partial independence of genetic factors influencing beta cell function from those influencing BMI is congruent with the outcome of previous genome-wide association (GWA) studies addressing the genetic risk of diabetes.…”

Section: Discussionsupporting

confidence: 86%

“…Twin [2][3][4][5] and family studies [6][7][8][9][10] support the notion that people who develop type 2 diabetes have a strong genetic predisposition, which may be partly conveyed through genetic effects on insulin resistance. Two twin studies, for instance, showed a significant genetic contribution to insulin sensitivity, assessed by euglycaemic-hyperinsulinaemic clamp with heritability estimates of 37% and 55% [11,12]. Notwithstanding the importance of insulin sensitivity, genetic effects on beta cell function are likely to play a major role in the development of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Genetic influences on the insulin response of the beta cell to different secretagogues

Simonis-Bik

Eekhoff

Moor³

et al. 2009

Diabetologia

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Aims/hypothesis The aim of the present study was to estimate the heritability of the beta cell insulin response to glucose and to glucose combined with glucagon-like peptide-1 (GLP-1) or with GLP-1 plus arginine. Methods This was a twin-family study that included 54 families from the Netherlands Twin Register. The participants were healthy twin pairs and their siblings of the same sex, aged 20 to 50 years. Insulin response of the beta cell was assessed by a modified hyperglycaemic clamp with additional GLP-1 and arginine. Insulin sensitivity index (ISI) was assessed by the euglycaemic-hyperinsulinaemic clamp. Multivariate structural equation modelling was used to obtain heritabilities and the genetic factors underlying individual differences in BMI, ISI and secretory responses of the beta cell. Results The heritability of insulin levels in response to glucose was 52% and 77% for the first and second phase, respectively, 53% in response to glucose+GLP-1 and 80% in response to an additional arginine bolus. Insulin responses to the administration of glucose, glucose+GLP-1 and glucose + GLP-1 + arginine were highly correlated (0.62

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Genetic influences on the insulin response of the beta cell to different secretagogues

Simonis-Bik

Eekhoff

Moor³

et al. 2009

Diabetologia

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“…Despite the high number of statistically highly associated variants discovered in the last few years, the explained proportion of the interindividual variation reported in Inter99 for the combination of all 33 validated type 2 diabetes and/or fasting plasma glucose gene variants is only 5.8% for fasting plasma glucose and 4.2% to 5.7% for different estimates of glucose-stimulated insulin release in non-diabetic Danish people (data not shown). These numbers should be interpreted in relation to heritability estimates of 30% to 40% and 60% to 80% for fasting glucose and first-phase insulin release, respectively [32], indicating that 15% to 20% and 5% to 10%, respectively, of the genetic contribution to these traits has been accounted for. These estimates imply that a major part of the genetic contribution to these quantitative traits is yet to be unravelled.…”

Section: Discussionmentioning

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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“…Rates of glucose disposal, its partitioning into oxidation and nonoxidative glucose metabolism as well as fat oxidation were calculated as previously reported and expressed as mg (kg lean body mass) −1 min −1 [23]. Muscle biopsies were obtained from the vastus lateralis muscle under local anaesthesia during both basal and insulin-stimulated states.…”

Section: Clinical Examination and Muscle Biopsies In Twinsmentioning

confidence: 99%

Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle

et al. 2008

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Aims/hypothesis Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-genetic factors influence a component of the respiratory chain, COX7A1, previously shown to be downregulated in skeletal muscle from patients with type 2 diabetes. The specific aims were to: (1) evaluate the impact of genetic (single nucleotide polymorphisms [SNPs]), epigenetic (DNA methylation) and non-genetic (age) factors on the expression of COX7A1 in human skeletal muscle; and (2) investigate whether common variants in the COX7A1 gene are associated with increased risk of type 2 diabetes. Methods COX7A1 mRNA expression was analysed in muscle biopsies from young (n=110) and elderly (n=86) non-diabetic twins and related to measures of in vivo metabolism. Genetic variants (three SNPs) from the COX7A1 locus were genotyped in the twins and in two independent type 2 diabetes case-control cohorts (n=1466 and 6380, respectively). DNA methylation of the COX7A1 promoter was analysed in a subset of twins (ten young, ten elderly) using bisulphite sequencing. Results While DNA methylation of the COX7A1 promoter was increased in muscle from elderly compared with young twins (19.9±8.3% vs 1.8±2.7%; p=0.035), the opposite was found for COX7A1 mRNA expression (elderly 1.00±0.05 vs young 1.68 ± 0.06; p = 0.0005). The heritability of COX7A1 expression was estimated to be 50% in young and 72% in elderly twins. One of the polymorphisms investigated, rs753420, influenced basal COX7A1 expression in muscle of young (p=0.0001) but not of elderly twins. The transcript level of COX7A1 was associated with increased in vivo glucose uptake and V : O 2max (p=0.009 and p=0.001, respectively). We did not observe any genetic association between COX7A1 polymorphisms and type 2 diabetes after correcting for multiple testing. Diabetologia (2008) Conclusions/interpretation Our results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.

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Heritability of Insulin Secretion, Peripheral and Hepatic Insulin Action, and Intracellular Glucose Partitioning in Young and Old Danish Twins

Cited by 146 publications

References 34 publications

Genetic influences on the insulin response of the beta cell to different secretagogues

Genetic influences on the insulin response of the beta cell to different secretagogues

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

Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle

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