Metformin Treatment in Pubertal Youth With Obesity

Megan M Kelsey, Allison Hilkin, Laura Pyle, Cameron Severn, Kristina Utzschneider, Rachael E Van Pelt, Philip S Zeitler, Kristen J Nadeau
The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 7, July 2021, Pages e2622–e2632
https://doi.org/10.1210/clinem/dgab170

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 (S_i) 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 (S_i), insulin response [acute insulin response to glucose (AIR_g)], 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 S_i or secretion: S_i (0.85 ± 0.87 × 10⁻⁴/min⁻¹/μIU/mL, P = 0.34), AIR_g (−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 S_i 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.

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