INTRODUCTION: Friedreich's ataxia (FRDA) is a multisystem 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 magnetic resonance imaging) were assessed. RESULTS: Participants included 11 individuals with FRDA (4 female), median age 27 years (interquartile range 23, 39), body mass index 26.9 kg/m2 (24.1, 29.4), and 24 controls (11 female), 29 years (26, 39), 24.4 kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA [91 vs 83 mg/dL (5.0 vs 4.6 mmol/L), P <
.05]. Individuals with FRDA had lower insulin sensitivity (whole-body insulin sensitivity index 2.8 vs 5.3, P <
.01), higher postprandial insulin secretion (insulin secretory rate incremental area under the curve 30-180 minutes, 24 652 vs 17,858, P <
.05), and more suppressed postprandial endogenous glucose production (-.9% vs 26.9% of fasting endogenous glucose production, P <
.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. CONCLUSION: 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.