Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.
Diabetologia. 2014 Mar;57(3):572-81. doi: 10.1007/s00125-013-3127-2. Epub 2013 Dec 6.
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.
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 ~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.
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.).
目的/假设：在禁食期间，肌肉线粒体功能可能会发生变化，但在胰岛素抵抗的人类中，胰岛素抵抗会降低。衰老和高脂血症可能是罪魁祸首，但机制尚不清楚。我们假设（1）胰岛素将无法增加非糖尿病胰岛素抵抗的年轻肥胖人群和 2 型糖尿病老年患者的线粒体氧化能力，（2）通过提高氧化能力和降低氧化应激来降低游离脂肪酸水平将改善胰岛素敏感性。
在胰岛素（4、40、100nmol/l）刺激前后，使用高分辨率呼吸计测量透化纤维和分离线粒体中的线粒体氧化能力，并使用荧光法评估 H2O2 的产生。使用高胰岛素-正常血糖钳夹结合稳定同位素测量组织特异性胰岛素敏感性。为了检验第二个假设，在一项为期 1 天的随机交叉研究中，通过当地广告招募了 15 名 2 型糖尿病患者进行资格评估。9 名患者符合纳入标准（BMI<35kg/m2；年龄<65 岁），并接受了包括口服 750mg 安慰剂或阿昔莫司的干预，并完成了干预。通过药房进行盲法随机分组；所有参与者、进行测量的研究人员和评估研究结果的人员均处于盲态。主要观察指标为胰岛素敏感性、氧化能力和氧化应激。
与瘦组相比，肥胖组的胰岛素敏感性和线粒体氧化能力分别降低了约 31%和 21%。肥胖组在胰岛素刺激下的底物氧化也减弱了。在 2 型糖尿病患者中，阿昔莫司使胰岛素敏感性提高了约 27%，并使 H2O2 的产生减少了约 45%，但没有改善基础或胰岛素刺激的线粒体氧化能力。没有出现有害的治疗副作用。
结论/解释：在胰岛素抵抗的年轻肥胖人群中，线粒体氧化能力的降低也可能独立于年龄发生。胰岛素抵抗发生在肌肉线粒体水平，并且不受降低 2 型糖尿病循环游离脂肪酸的影响。因此，线粒体功能的可塑性受损是一种内在现象，可能独立于脂毒性和葡萄糖摄取减少而发生。
临床试验 NCT00943059 资助：本研究部分由德国联邦教育和研究部资助德国糖尿病研究中心（DZD e.V.）。
