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Diabetologia. 2014 Mar;57(3):572-81. doi: 10.1007/s00125-013-3127-2. Epub 2013 Dec 6.

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.

Author information

1
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.

Abstract

AIMS/HYPOTHESIS:

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.

METHODS:

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.

RESULTS:

Insulin sensitivity and mitochondrial oxidative capacity were ~31% and ~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 ~27% and reduced H2O2 production by ~45%, but did not improve basal or insulin-stimulated mitochondrial oxidative capacity. No harmful treatment side effects occurred.

CONCLUSIONS/INTERPRETATION:

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.).

PMID:
24310562
DOI:
10.1007/s00125-013-3127-2
[Indexed for MEDLINE]

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