Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial

Muscle mitochondrial function can vary during fasting, but is lower during hyperinsulinaemia in insulin-resistant humans. Ageing and hyperlipidaemia may be the culprits, but the mechanisms remain unclear. We hypothesised that (1) insulin would fail to increase mitochondrial oxidative capacity in non-diabetic insulin-resistant young obese humans and in elderly patients with type 2 diabetes and (2) reducing NEFA levels would improve insulin sensitivity by raising oxidative capacity and lowering oxidative stress. Before and after insulin (4, 40, 100 nmol/l) stimulation, mitochondrial oxidative capacity was measured in permeabilised fibres and isolated mitochondria using high-resolution respirometry, and H2O2 production was assessed fluorimetrically. Tissue-specific insulin sensitivity was measured with hyperinsulinaemic-euglycaemic clamps combined with stable isotopes. To test the second hypothesis, in a 1-day randomised, crossover study, 15 patients with type 2 diabetes recruited via local advertisement were assessed for eligibility. Nine patients fulfilled the inclusion criteria (BMI < 35 kg/m(2); age < 65 years) and were allocated to and completed the intervention, including oral administration of 750 mg placebo or acipimox. Blinded randomisation was performed by the pharmacy; all participants, researchers performing the measurements and those assessing study outcomes were blinded. The main outcome measures were insulin sensitivity, oxidative capacity and oxidative stress. Insulin sensitivity and mitochondrial oxidative capacity were similar to 31% and similar to 21% lower in the obese groups than in the lean group. The obese participants also exhibited blunted substrate oxidation upon insulin stimulation. In the patients with type 2 diabetes, acipimox improved insulin sensitivity by similar to 27% and reduced H2O2 production by similar to 45%, but did not improve basal or insulin-stimulated mitochondrial oxidative capacity. No harmful treatment side effects occurred. Decreased mitochondrial oxidative capacity can also occur independently of age in insulin-resistant young obese humans. Insulin resistance is present at the muscle mitochondrial level, and is not affected by reducing circulating NEFAs in type 2 diabetes. Thus, impaired plasticity of mitochondrial function is an intrinsic phenomenon that probably occurs independently of lipotoxicity and reduced glucose uptake. Trial registration Clinical Trials NCT00943059 Funding This study was funded in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.).