Cree-Green, MelanieBergman, Bryan C.Cengiz, EdaFox, Larry A.Hannon, Tamara S.Miller, KelleeNathan, BrandonPyle, LauraKahn, DarcyTansey, MichaelTichy, EileenTsalikian, EvaLibman, IngridNadeau, Kristen J.2020-06-232020-06-232019-08Cree-Green, M., Bergman, B. C., Cengiz, E., Fox, L. A., Hannon, T. S., Miller, K., Nathan, B., Pyle, L., Kahn, D., Tansey, M., Tichy, E., Tsalikian, E., Libman, I., & Nadeau, K. J. (2019). Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes. The Journal of clinical endocrinology and metabolism, 104(8), 3265–3278. https://doi.org/10.1210/jc.2019-00129https://hdl.handle.net/1805/23059Context: Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. Objective: Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. Design: Double-blind, placebo-controlled clinical trial. Setting: Multi-center at eight sites of the T1D Exchange Clinic Network. Participants: A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. Intervention: Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. Main outcome measures: Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. Results: Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. Conclusions: Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.en-USPublisher PolicyType 1 diabetesAdolescenceInsulin deficiencyInsulin resistanceMetformin efficacyArticle