title: 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 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.
  
  
  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 (β) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (β = 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 β-oxidation of fatty acids.
authors.affiliation: Marie Krogh Center for Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Hornbak
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Justesen
authors.forename: Nikolaj T
authors.initials: NT
authors.lastname: Krarup
authors.forename: Camilla H
authors.initials: CH
authors.lastname: Sandholt
authors.forename: Åsa
authors.initials: Å
authors.lastname: Andersson
authors.forename: Annelli
authors.initials: A
authors.lastname: Sandbæk
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Charlotta
authors.initials: C
authors.lastname: Pisinger
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Thorkild A A
authors.initials: TA
authors.lastname: Sørensen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000235:genetics*; D044926:Butyryl-CoA Dehydrogenase / Q000235:genetics*; D016022:Case-Control Studies; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D015995:Prevalence
chemical_list: D001786:Blood Glucose; D007328:Insulin; D044926:Butyryl-CoA Dehydrogenase