Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents 1,2,3

Background— Nonalcoholic fatty liver disease (NAFLD) and insulin resistance are common in overweight adolescents. Objective— The purpose of this study was to determine the relation between NAFLD and insulin sensitivity in liver and skeletal muscle by studying overweight adolescents with a normal or high intrahepatic triglyceride (IHTG) content, who were matched for age, sex, body mass index (BMI; in kg/m 2 ), and Tanner stage. Design— Stable-isotope-labeled tracer infusion and the hyperinsulinemic-euglycemic clamp procedure were used to assess skeletal muscle and hepatic insulin sensitivity, and magnetic resonance spectroscopy was used to assess the IHTG content in 10 overweight (BMI = 35.9 ± 1.3) adolescents with NAFLD (IHTG = 28.4 ± 3.4%) and 10 overweight (BMI = 36.6 ± 31.5) adolescents with a normal IHTG content (3.3 ± 0.5%). Results— The baseline plasma glucose concentration and the rate of appearance of glucose in plasma were the same in subjects with a normal (87.1 ± 1.2 mg/dL, 16.2 ± 1.1 μ mol · kg fat-free mass − 1 · min − 1 ) or high (89.2 ± 2.5 mg/dL, 16.3 ± 1.2 μ mol · kg fat-free mass − 1 · min − 1 ) IHTG content. However, compared with subjects who had a normal IHTG content, subjects with NAFLD had with insulin-resistant glucose metabolism, it is not clear which tissues are responsible for insulin resistance in adolescents. In the present study, the hyperinsulinemic-euglycemic clamp procedure and stable-isotope-labeled tracer infusion were used to evaluate liver and skeletal muscle insulin sensitivity in overweight adolescents with an elevated ( ≥ 10%) and normal ( ≤ 5%) IHTG content, who were carefully matched for sex, age, Tanner stage, and BMI. Our data show that subjects with NAFLD have a greater resistance to insulin-mediated glucose metabolism in both liver (decreased HISI) and skeletal muscle (impaired insulin-mediated glucose Rd) than do subjects with a normal IHTG content, despite normal fasting blood glucose and oral glucose tolerance in both groups. These results indicate that NAFLD is an important marker of impaired insulin action in multiple organs, which might not be detected by a standard medical examination. Our findings suggest that fat accumulation in the liver identifies a category of overweight adolescents who are at high risk of developing diabetes, hypertension, and coronary heart disease (CHD) in the future. Although measures of adiposity (ie, BMI, body fat mass, and percentage body fat) were similar in our 2 groups of subjects, those with NAFLD had evidence of abnormalities in multiple metabolic risk factors for CHD. Compared with the normal IHTG group, the NAFLD group had higher plasma triglyceride, total cholesterol, and LDL-cholesterol concentrations; a lower plasma HDL-cholesterol concentration; and a trend toward higher systolic and diastolic blood pressures. These results are consistent with findings in adults, which found that NAFLD is frequently associated with metabolic risk factors for CHD and the metabolic syndrome (23,24). Our data show that NAFLD in adolescents should be considered part of a constellation of co-occurring metabolic abnormalities that are associated with increased CHD risk in adults. Therefore, an elevated IHTG content identifies overweight