Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

Abstract

Aims/hypothesis There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits. Methods OxPhos gene variants (n=10) that had been nominally associated (p<0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n=10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucosetolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study.Results The minor alleles of COX10 rs9915302 (p=0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p<0.01 to p<0.05) negative influence on indices of glucose-stimulated insulin secretion. Conclusions/interpretation We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in Electronic supplementary material The online version of this article

The role of mitochondrial reactive oxygen species in insulin resistance

“…This is complicated by the likely sensitivity of mitochondria (and H2O2 release) to acute changes in nutritional, hormonal and exercise environments, all of which may be hard to control in human studies. One interesting addendum to this is that there is at most only a small effect of common genetic variants within nuclear-encoded mitochondrial genes [200] or oxidative phosphorylation genes [201] in insulin resistance risk in humans, although this may be due to most studies relying on surrogate measures of muscle/adipose insulin sensitivity.…”