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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. [ABSTRACT FROM AUTHOR]

Objective: To investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes. Methods: We studied type 2 diabetes progression in 1,480 patients with screen-detected type 2 diabetes from the ADDITION-Denmark study using information of redeemed prescriptions from the Register of Medicinal Products Statistics from 2001–2009 in Denmark. Patients were cluster randomized by general practitioners, who were randomized to treat type 2 diabetes according to either a conventional or a multifactorial intensive treatment algorithm. We investigated the genetic influence on diabetes progression by constructing a genetic risk score (GRS) of all 48 validated type 2 diabetes susceptibility variants, a GRS of 11 variants linked to β-cell function and a GRS of 3 variants linked to insulin sensitivity and assessed the association between number of risk alleles and time from diagnosis until first redeemed prescription of either any glucose lowering drug or an insulin drug. Results: The GRS linked to insulin sensitivity only nominally increased the risk of an early prescription redemption with an insulin drug by 39% (HR [95% C.I.] = 1.39 [1.09–1.77], p = 0.009] in patients randomized to the intensive treatment group. Furthermore, the strongest univariate predictors of diabetes progression for the intensive treatment group (measured as time to first insulin) were younger age (HR [95% C.I.] = 0.96 [0.93–0.99]), increased BMI (1.05 [1.01–1.09]), increased HbA1c (1.50 [1.36–.66]), increased TG (1.24 [1.11–1.39]) and reduced fasting serum HDL (0.37 [0.17–0.80]) at baseline. Similar results were obtained for the conventional treatment group. Conclusion: Higher levels of HbA1c, fasting circulating levels of triglyceride, lower HDL, larger BMI and younger age are significant determinants of early pharmacological intervention in type 2 diabetes. However, known common type 2 diabetes-associated gene variants do not appear to significantly affect disease progression. [ABSTRACT FROM AUTHOR]