Megan M Kelsey1, Allison Hilkin1, Laura Pyle1,2, Cameron Severn1,2, Kristina Utzschneider3,4, Rachael E Van Pelt5, Philip S Zeitler1, Kristen J Nadeau1. 1. University of Colorado School of Medicine, Department of Pediatrics, Aurora, CO, USA. 2. University of Colorado School of Medicine, Department of Biostatistics, Aurora, CO, USA. 3. VA Puget Sound Health Care System, Seattle, WA, USA. 4. University of Washington, Department of Medicine, Seattle, WA, USA. 5. University of Colorado School of Medicine, Department of Medicine, Aurora, CO, USA.
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.
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.
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