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The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load.

ABSTRACT: BACKGROUND:A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid ?-oxidation. Chronic exposure to fatty acids due to an impaired ?-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D. METHODS:The variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (nACADS = 4,324; nACADM = 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (nACADS = 8,313; nACADM = 8,344). RESULTS:In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (?) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (? = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (? = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (? = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D. CONCLUSIONS:In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired ?-oxidation of fatty acids.

SUBMITTER: Hornbak M

PROVIDER: S-EPMC3022800 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load.

Hornbak Malene M Banasik Karina K Justesen Johanne M JM Krarup Nikolaj T NT Krarup Nikolaj T NT Sandholt Camilla H CH Andersson Åsa Å Sandbæk Annelli A Lauritzen Torsten T Pisinger Charlotta C Witte Daniel R DR Sørensen Thorkild A A TA Pedersen Oluf O Hansen Torben T

BMC medical genetics 20110106

<h4>Background</h4>A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased ...[more]

PMID: 21211036

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Project description:To identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.Fasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.There were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-?, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15-120 min), in South East/East Asians (60-120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P?0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B.Elevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.

Dataset Information

The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load.

Publications

The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load.

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