Youth with type 2 diabetes have hepatic, peripheral, and adipose insulin resistance

Abstract

Adolescents with type 2 diabetes (T2D) have severe insulin resistance (IR) secondary to obesity, genetics, and puberty, and IR predicts metabolic comorbidities. Adults with T2D have multitissue IR, which has guided therapeutic developments, but this is not established in youth. We sought to assess adipose, hepatic, and peripheral insulin sensitivity in adolescents with and without T2D. Twenty-seven youth with T2D [age: 15.6 ± 0.4 yr; female: 78%; body mass index (BMI) percentile: 96.1 (52.6, 95.9), late puberty; hemoglobin A1c (HbA1c) 7.3% (6.2, 10.1)] and 21 controls of similar BMI, pubertal stage, and habitual activity were enrolled. Insulin action was measured with a four-phase hyperinsulinemic-euglycemic clamp (basal, 10, 16, and 80 mU·m−2·min−1 for studying adipose, hepatic, and peripheral IR, respectively) with glucose and glycerol isotope tracers. Total fat mass, fat-free mass, liver fat fraction, and visceral fat were measured with dual-energy x-ray absorptiometry (DXA) and MRI, respectively. Free fatty acids (FFAs), lipid profile, and inflammatory markers were also measured. Adolescents with T2D had higher lipolysis ( P = 0.012), endogenous glucose production ( P < 0.0001), and lower glucose clearance ( P = 0.002) during hyperinsulinemia than controls. In T2D, peripheral IR positively correlated to FFA ( P < 0.001), inflammatory markers, visceral ( P = 0.004) and hepatic fat ( P = 0.007); hepatic IR correlated with central obesity ( P = 0.004) and adipose IR ( P = 0.003). Youth with T2D have profound multitissue IR compared with BMI-equivalent youth without T2D. The development of multitissue interactions appears crucial to the pathogenesis of T2D. Therapeutic targets on multitissue IR may be of benefit, deserving of further research.