Muscle Insulin Resistance in Youth with Obesity and Normoglycemia is Associated with Altered Fat Metabolism.

Abstract

This study aimed to phenotype and compare adipose, hepatic, and muscle insulin sensitivity (IS) in a diet- and physical activity-controlled cohort of normoglycemic youth with obesity with that of participants without obesity (controls) to distinguish early metabolic abnormalities in pediatric obesity. Thirty-eight participants (17 in the control group [BMI < 85th percentile] and 21 youth with obesity [BMI ≥ 95th percentile]; age: 12-21 years; 76% female; Tanner stage 4-5; sedentary) were enrolled. Tissue-specific IS was measured using a four-phase hyperinsulinemic-euglycemic clamp with glucose and glycerol isotope tracers to assess suppression of endogenous glucose release and lipolysis by insulin. Intramyocellular lipid content was assessed by 1 H-magnetic resonance spectroscopy, and hepatic fat fraction (HFF) and visceral fat were assessed by magnetic resonance imaging. Calf-muscle mitochondrial activity was measured with exercise-stimulated 31 P-magnetic resonance spectroscopy. Youth with obesity had higher HFF (P < 0.001), visceral fat (P = 0.024), and intramyocellular lipid content (P = 0.017) and lower muscle (glucose clearance rate [P < 0.001]), adipose (P < 0.0001), and hepatic IS (P < 0.003). Mitochondria postexercise response was not different. In participants with obesity, muscle IS inversely correlated with HFF (r = 0.700, P = 0.002) and suppressed free fatty acid concentrations (r = -0.65, P = 0.003). Inactive normoglycemic youth with obesity had decreased muscle, adipose, and hepatic IS. Free fatty acids and liver fat were inversely associated with muscle IS, which argues for lipid-targeted interventions.