背景:Friedreich的共济失调(FRDA)是一种由共济失调蛋白缺乏引起的多系统疾病。FRDA相关的糖尿病(DM)很常见。Frataxin支持骨骼肌线粒体氧化磷酸化(OXPHOS)能力,胰岛素敏感性的介质。我们的目的是测试无DM的FRDA成人骨骼肌健康与胰岛素敏感性和分泌之间的关系。
方法:病例对照研究(NCT02920671)。葡萄糖和胰岛素代谢(稳定同位素口服葡萄糖耐量试验),身体成分(双能X射线吸收法),身体活动(自我报告),和骨骼肌OXPHOS容量(肌酸化学交换饱和转移MRI)进行评估。
结果:参与者包括11名FRDA患者(4名女性),平均年龄27岁(IQR23,39),BMI26.9kg/m2(24.1,29.4),和24名对照(11名女性),29y(26,39),24.4kg/m2(21.8,27.0)。FRDA的空腹血糖较高(91vs.83mg/dL(5.0与4.6mmol/L),p<0.05)。FRDA患者的胰岛素敏感性较低(WBISI2.8vs.5.3,p<0.01),餐后胰岛素分泌较高(胰岛素分泌率iAUC30-180分钟,24,652vs.17,858,p<0.05),和更多抑制餐后内源性葡萄糖产生(-0.9%vs.26.9%的空腹EGP,p<0.05)。在回归分析中,较低的OXPHOS和不活动解释了胰岛素敏感性的一些差异。内脏脂肪增加导致胰岛素敏感性降低,而与FRDA无关。胰岛素分泌占敏感性(处置指数)没有差异。
结论:线粒体OXPHOS能力降低,不活动,和内脏肥胖有助于降低FRDA的胰岛素敏感性。较高的胰岛素分泌出现代偿性,当不足时,可以预示DM。需要进一步的研究来确定以肌肉或脂肪为中心的干预措施是否可以延迟FRDA相关的DM。
BACKGROUND: Friedreich\'s Ataxia (FRDA) is a multi-system disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM.
METHODS: Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer MRI) were assessed.
RESULTS: Participants included 11 individuals with FRDA (4 female), median age 27y (IQR 23, 39), BMI 26.9kg/m2 (24.1, 29.4), and 24 controls (11 female), 29y (26, 39), 24.4kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA (91 vs. 83mg/dL (5.0 vs. 4.6mmol/L), p<0.05). Individuals with FRDA had lower insulin sensitivity (WBISI 2.8 vs. 5.3, p<0.01), higher post-prandial insulin secretion (insulin secretory rate iAUC 30-180 minutes, 24,652 vs. 17,858, p<0.05), and more suppressed post-prandial endogenous glucose production (-0.9% vs. 26.9% of fasting EGP, p<0.05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different.
CONCLUSIONS: Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.