The purpose of this study was to examine the association between cardiorespiratory fitness, ectopic triglyceride accumulation, and insulin sensitivity among youth with and without type 2 diabetes. Subjects included 137 youth ages 13–18 years including 27 with type 2 diabetes, 97 overweight normoglycemic controls, and 13 healthy weight normoglycemic controls. The primary outcome measure was cardiorespiratory fitness defined as peak oxygen uptake indexed to fat free mass. Secondary outcomes included liver and muscle triglyceride content determined by 1H‐magnetic resonance spectroscopy and insulin sensitivity determined by frequently sampled intravenous glucose tolerance test. Despite similar measures of adiposity, peak oxygen uptake was 11% lower (38.9 ± 7.9 vs. 43.9 ± 6.1 ml/kgFFM/min, P = 0.002) and hepatic triglyceride content was nearly threefold higher (14.4 vs. 5.7%, P = 0.001) in youth with type 2 diabetes relative to overweight controls. In all 137 youth, cardiorespiratory fitness was negatively associated with hepatic triglyceride content (r = −0.22, P = 0.02) and positively associated with insulin sensitivity (r = 0.29, P = 0.002) independent of total body and visceral fat mass. Hepatic triglyceride content was also negatively associated with insulin sensitivity (r = −0.35, P < 0.001), independent of adiposity, sex, age, and peak oxygen uptake. This study demonstrated that low cardiorespiratory fitness and elevated hepatic triglyceride content are features of type 2 diabetes in youth. Furthermore, cardiorespiratory fitness and hepatic triglyceride are associated with insulin sensitivity in youth. Taken together, these data suggest that cardiorespiratory fitness and hepatic steatosis are potential clinical biomarkers for type 2 diabetes among youth.

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WHAT'S KNOWN ON THIS SUBJECT: Obesity is associated with cardiometabolic risk factors and chronic conditions, such as type 2 diabetes. However, a proportion of overweight and obese youth remain free from cardiometabolic risk factors and are considered metabolically healthy. WHAT THIS STUDY ADDS:This study provides insight into the determinants of cardiometabolic risk factors and the concept in health promotion of "fitness versus fatness." Hepatic lipid accumulation and not fitness level appears to drive cardiometabolic risk factor clustering among overweight and obese youth. abstract OBJECTIVE: Controversy exists surrounding the contribution of fitness and adiposity as determinants of the Metabolically Healthy Overweight (MHO) phenotype in youth. This study investigated the independent contribution of cardiorespiratory fitness and adiposity to the MHO phenotype among overweight and obese youth. METHODS:This cross-sectional study included 108 overweight and obese youth classified as MHO (no cardiometabolic risk factors) or non-MHO ($1 cardiometabolic risk factor), based on age-and genderspecific cut-points for fasting glucose, triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and hepatic steatosis.RESULTS: Twenty-five percent of overweight and obese youth were classified as MHO. This phenotype was associated with lower BMI z-score (BMI z-score: 1.8 6 0.3 vs 2.1 6 0.4, P = .02) and waist circumference (99.7 6 13.2 vs 106.1 6 13.7 cm, P = .04) compared with non-MHO youth. When matched for fitness level and stratified by BMI z-score (1.6 6 0.3 vs 2.4 6 0.2), the prevalence of MHO was fourfold higher in the low BMI z-score group (27% vs 7%; P = .03). Multiple logistic regression analyses revealed that the best predictor of MHO was the absence of hepatic steatosis even after adjusting for waist circumference (odds ratio 0.57, 95% confidence interval 0.40-0.80) or BMI z-score (odds ratio 0.59, 95% confidence interval 0.43-0.80). CONCLUSIONS:The MHO phenotype was present in 25% of overweight and obese youth and is strongly associated with lower levels of adiposity, and the absence of hepatic steatosis, but not with cardiorespiratory fitness. Pediatrics 2013;132:e85-e92 Obesity is associated with a clustering of cardiometabolic risk factors, including hypertension, insulin resistance, inflammation, and dyslipidemia. 1 However, cardiometabolic risk factor clustering is not an obligatory consequence of obesity. In fact, 18% to 44% of obese individuals are free from cardiometabolic risk factors. 2,3 The absence of cardiometabolic risk factor clustering in obese individuals is associated with lower measures of adiposity, including lower total fat mass, 4 abdominal obesity, 5,6 visceral fat mass, 3,7,8 and the absence of ectopic lipid accumulation. 9 Surprisingly, little attention has been paid to the modifiable factors as determinants of this "Metabolically Healthy Overweight" (MHO) phenotype. 10,11 This is particularly important, as the identification of modifiable behaviors associa...