1935-P: Decoupling between ATP Utilization and Replenishment in Insulin Resistant Skeletal Muscle

Abstract

For optimal energy utilization, depletion and recovery of phosphocreatine (PCr) during exercise must be tightly coupled. Aim: To measure metabolites in vastus lateralis (VL) muscle of normal glucose tolerant (NGT) and type 2 diabetes mellitus (T2DM) subjects by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) during and following exercise. Matsuda index (MI) of insulin sensitivity, fasting plasma glucose (FPG), intramyocellular lipid concentration [IMCL], and mitochondrial density (MitoD) were also measured. Methods: 12 NGT (age=50±11y; A1c=5.6±0.3%; BMI=28.5±4.1kg/m-2) and 10 T2DM (age=53±10y; A1c=7.5±0.8%; BMI=30.4±4.6kg/m-2) subjects received an OGTT to determine MI. [IMCL] in VL was quantified by 1H-MRS. In 15 subjects (7 T2DM, 8 NGT) MitD was determined by electron microscopy. Results: The PCr recovery time constant (k) was lower in T2DM (0.01±0.004 vs. 0.02±0.01 s-1; p=0.05). Baseline [PCr] (25.3±3.0 vs. 28.5±3.3 mM; p=0.03) and average [PCr] over the last minute of exercise (14.5±4.7 vs. 20.9±4.7 mM; p<0.05) were lower in T2DM. PCr percent decrease, (%Δ), was negatively correlated with PCr recovery halftime, t (ρ=0.77; p<0.05). The initial rate of PCr depletion and initial rate of PCr recovery were correlated in NGT (r=0.83; p<0.05) but not in T2DM subjects (r=0.30; p=0.39). FPG negatively correlated with baseline [PCr] (ρ=-0.63; p<0.05) and MI negatively correlated with %Δ (ρ=-0.50; p<0.05) in all subjects. [IMCL] was increased in T2DM (6.9±1.2 vs. 9.1±1.4; p<0.05) and correlated negatively with t (ρ=0.47; p=0.03). MitoD in T2DM subjects correlated with k (r=0.76; p<0.05). Conclusion: These data suggest a disruption in the regulation of energy utilization and production of ATP and PCr, which may be due to reduced mitochondrial density and/or altered substrate dynamics in T2DM skeletal muscle. Disclosure J.A. Vasquez: None. C. Solis-Herrera: Advisory Panel; Self; Sanofi. D. Tripathy: None. M. Abdul-Ghani: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. G.D. Clarke: None. Funding National Institutes of Health (DK-24092-34 to R.A.D), (K25-DK-089012 to G.D.C.)