Insulin Resistance in Youth Without Diabetes Is Not Related to Muscle Mitochondrial Dysfunction

Abstract Context: Obesity, insulin resistance (IR), and diabetes are increasing in youth, especially in girls. IR is associated with muscle mitochondrial dysfunction in youth and adults with diabetes. However, it is unknown whether this relationship is present in youth prior to development of diabetes. Objective: Assess IR and mitochondrial function, including sex differences, in nondiabetic youth. Design: Cross-sectional study of youth in the Exploring Perinatal Outcomes among Children, Resistance to InSulin in Type 1 And Type 2 diabetes, and Androgens and Insulin Resistance Study cohorts. Setting: Academic medical university. Participants: Two hundred seventy-five youth, 13 to 19 years old [43% males: 17.1 (16.52, 17.63) years, body mass index z-score (BMI-Z) 0.36, 64.7% Tanner 5; 57% females: 17.2 (16.43, 17.67) years, BMI-Z 0.72, 78.9% Tanner 5]. Interventions: Fasting laboratories, oral glucose tolerance test, and 31P magnetic resonance spectroscopy. Main Outcome Measures: IR [triglyceride:high-density lipoprotein (HDL) ratio, Matsuda index, and homeostasis model for insulin resistance (HOMA-IR)] and muscle mitochondrial function (adenosine 5′-diphosphate time constant and oxidative phosphorylation rate). Results: Compared with males, females were more insulin resistant, with higher triglyceride:HDL ratio [1.95 (1.30, 2.79) vs 1.69 (1.21, 2.23), P = 0.042], HOMA-IR [3.18 (2.42, 4.39) vs 2.76 (2.02, 4.08), P = 0.035], and fasting free fatty acids (FFAs) and lower Matsuda score [3.98 (2.71, 5.96) vs 5.39 (3.43, 7.57), P < 0.001]. After adjustment for the higher BMI and Tanner stage and lower physical activity levels seen in females, there were no sex differences in mitochondrial function nor in any IR measure except FFAs. We did not find an association between measures of IR and mitochondrial function. Conclusions: The greater IR seen in adolescent girls vs boys is mostly explained by differences in BMI and physical activity. Mitochondrial function does not appear to be related to IR in a large cohort of nondiabetic youth. In a large cohort of adolescents, early insulin resistance assessed by oral glucose tolerance test is found only in girls and is not accompanied by postexercise muscle mitochondrial dysfunction measured with spectroscopy.