1347-P: Improvement in Peripheral Insulin Sensitivity (IS) with Metformin (MET) in Adolescents with Type 1 Diabetes (T1D) Is Not Mediated by Muscle Mitochondrial Change

Abstract

T1D youth are insulin resistant and we recently demonstrated that whole-body IS improved after 3 months of MET therapy. We also found that youth with T1D and type 2 diabetes both have skeletal muscle mitochondrial dysfunction that correlated with IS, but with a unique pattern in T1D. We aimed to determine if improvement in IS in T1D youth following MET was related to improvement in mitochondrial function. Forty-nine youth aged 12-21 years with T1D participated in Effects of MEtformin on CardiovasculaR Function in AdoLescents with T1D (EMERALD), a randomized, double-blind, placebo-controlled study. Youth were randomized to 3 months of MET titrated to 1000mg BID over 4 weeks or placebo (PLA). Assessments prior to and after MET or PLA included a hyperinsulinemic euglycemic clamp (80 mU/m2/minute insulin) to evaluate IS (glucose infusion rate [GIR]) and, in a subset of youth, calf 31Phosphorus magnetic resonance spectroscopy (MRS) before, during, and after 90 sec of near-maximal isometric exercise to evaluate post-exercise muscle mitochondrial function. Change with treatment for each group was compared via t-test or Mann Whitney U, as appropriate. Twenty-two youth with pre/post MRS (n=12 MET, n=10 PLA, 16.3±2.1 years, 45% female, 91% Caucasian, BMI 25.6±3.9 kg/m2, 7.4±3.7 years T1D duration, HbA1c 8.2±1.1%) were included. GIR increased more in the MET group (MET 1.5 [1.1-2.1] vs. PLA 0.4 [-0.1-0.9] mg/kg/minute, p=0.024). There were no differences between groups in any mitochondrial measure (initial phosphocreatine [PCr] synthesis, ADP and PCr time constants, oxidative phosphorylation, maximal mitochondrial function) or the related measures of creatine kinase reaction or anaerobic glycolysis. In summary, metformin improves peripheral IS in T1D youth, but likely not via muscle mitochondrial-mediated mechanisms. Further research is needed to understand mitochondrial dysfunction and metformin-induced improvements in IS in T1D. Disclosure K.L. Tommerdahl: None. M. Cree-Green: None. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. A. Carreau: Advisory Panel; Self; Pfizer Inc. Y. Garcia Reyes: None. A.D. Baumgartner: None. M.S. Brown: None. B. Newcomer: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc. K.J. Nadeau: None. Funding American Diabetes Association (7-11-CD-08 to K.J.N.)