Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20–250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8–30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance.
