Two-year treatment with metformin during puberty does not preserve β-cell function in youth with obesity.

Context Youth-onset type 2 diabetes is a disease of pubertal onset, associated with additional burden of pubertal insulin resistance on the β-cell. Objective Evaluate the impact of metformin treatment during puberty, a critical window of cardiometabolic change, on insulin sensitivity (Si) and compensatory β-cell response in youth with obesity. Setting Pediatric academic hospital clinical translational research center. Participants Healthy youth in early puberty (Tanner stage 2-3, T2-3) with normoglycemia and obesity (n=44). Intervention Double-blinded placebo-control trial of metformin during puberty (until Tanner stage 5 (T5)). Main outcome measures Si, insulin response (acute insulin response to glucose, AIRg), and disposition index (DI), estimated from frequently-sampled intravenous glucose tolerance testing, body fat (dual x-ray absorptiometry), other laboratory parameters; collected at baseline, T4 and T5. Placebo-subtracted treatment effect was calculated using linear mixed models. Results At T5, metformin treatment, adjusting for sex, race and baseline value, was associated with improved BMIz (-0.44±0.16, p=0.02), %body fat (-3.4±1.2%, p=0.06) and waist circumference (-11.3±3.2 cm, p=0.003). There were no significant treatment effects at T5 on insulin sensitivity or secretion: Si (0.85±0.87x10 -4/min -1/μIU/mL, p=0.34), AIRg (-259±386 μIU/mL, p=0.51), or DI (508±802 x10 -4/min -1, p=0.53). High baseline DI predicted longitudinal decline in DI. Conclusions Two years of metformin treatment in obese youth during puberty improved BMI and body fat, but not Si or β-cell function. Of note, high DI in early puberty may be predictive of later decline in DI. Further studies are needed to develop strategies for preservation of β-cell function in youth at risk for T2D.