Two-Year Treatment With Metformin During Puberty Does Not Preserve β-Cell Function in Youth With Obesity
Megan M. Kelsey, Allison Hilkin, Laura Pyle, Cameron Severn, Kristina M. Utzschneider, Rachael E. Van Pelt, Philip Zeitler, Kristen J. Nadeau
Abstract
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 (T) 2-3] with normoglycemia and obesity (n = 44). INTERVENTION: Double-blinded placebo-control trial of metformin during puberty (until T5). MAIN OUTCOME MEASURES: Insulin sensitivity (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); and 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 BMI z-score (-0.44 ± 0.16, P = 0.02), percentage body fat (%body fat; -3.4 ± 1.2%, P = 0.06), and waist circumference (-11.3 ± 3.2cm, P = 0.003). There were no significant treatment effects at T5 on Si or secretion: Si (0.85 ± 0.87 × 10-4/min-1/μIU/mL, P = 0.34), AIRg (-259 ± 386 μIU/mL, P = 0.51), or DI (508 ± 802 × 10-4/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 type 2 diabetes.