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

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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 (<jats:italic>ACADS</jats:italic>) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (<jats:italic>ACADM</jats:italic>) 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 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>The variants were genotyped using KASPar<jats:sup>®</jats:sup> 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 (<jats:italic>n</jats:italic> <jats:sub> <jats:italic>ACADS</jats:italic> </jats:sub>= 4,324; <jats:italic>n</jats:italic> <jats:sub> <jats:italic>ACADM</jats:italic> </jats:sub>= 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (<jats:italic>n</jats:italic> <jats:sub> <jats:italic>ACADS</jats:italic> </jats:sub>= 8,313; <jats:italic>n</jats:italic> <jats:sub> <jats:italic>ACADM</jats:italic> </jats:sub>= 8,344).</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>In glucose-tolerant individuals the minor C-allele of rs2014355 of <jats:italic>ACADS</jats:italic> associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), <jats:italic>P</jats:italic> = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), <jats:italic>P</jats:italic> = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), <jats:italic>P</jats:italic> = 0.03), and with increased insulin sensitivity ISI<jats:sub>Matsuda</jats:sub> (β = 2.9% (0.5%;5.2%), <jats:italic>P</jats:italic> = 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, <jats:italic>P</jats:italic> = 0.21). rs11161510 of <jats:italic>ACADM</jats:italic> did not associate with any indices of glucose-stimulated insulin release or with T2D.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>In glucose-tolerant individuals the minor C-allele of rs2014355 of <jats:italic>ACADS</jats:italic> was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids.</jats:p> </jats:sec>