Effects of Hyperglycemia on Skeletal Muscle Glucose Metabolism in Healthy Subjects

Abstract

Background: Physiological hyperglycemia can induce skeletal muscle insulin resistance and alterations in metabolic glucose partitioning. We investigated the mechanisms driving this muscle glucotoxicity in response to a three day elevation of plasma glucose concentrations. Methods: Twenty-five lean, glucose tolerant subjects (mean ± SD age 46 ± 4 years; BMI 25 ± 1 kg/m2) underwent a euglycemic insulin clamp (80 mU/m2·min) at baseline and following three days of saline (n=5) or glucose (n=20) infusion to raise plasma glucose by 45 mg/dL. Oxidative (GOX), non-oxidative (NOGD) and total (TGD) glucose disposal were calculated from indirect calorimetry and glucose infusion rate. Skeletal muscle biopsies were obtained prior to and after each clamp for the determination of metabolite concentrations, protein phosphorylation and pyruvate dehydrogenase (PDH) activation status (PDHa). Data are presented as mean ± SE and were analyzed using two-way ANOVA. Results: Three days of glucose infusion increased basal (1.2 ± 0.1 vs. 4.3 ± 0.3) and insulin-stimulated (2.3 ± 0.2 vs. 4.8 ± 0.3 mg/kg/min) GOX by 3.5 and 2.2-fold, respectively (P<0.001), whereas NOGD was 51% lower (9.2 ± 2.6 vs. 4.5 ± 2.1 mg/kg/min; P<0.001), resulting in a 16% reduction in TGD (10.3 ± 2.4 vs. 8.7 ± 2.1 mg/kg/min; P<0.01). Muscle glycogen content was doubled (343 ± 18 vs. 759 ± 47 mmol/kg dry weight; P<0.001) and glycogen synthase phosphorylation (Ser641) was increased by 46% (P=0.03), whilst GSK3β phosphorylation (Ser9) tended to be reduced (P=0.07). Glucose infusion also reduced insulin-stimulated PDHa by 20% (P=0.02) and Akt phosphorylation (Ser473) by 27% (P=0.03). No changes were observed in the saline group. Conclusion: Hyperglycemia caused a robust increase in basal GOX, such that further insulin-stimulated activation of GOX (distal insulin signaling and PDH) was impaired. Deficits in NOGD, and subsequently, TGD likely occur as a consequence of perturbed glycogen synthase activation in the face of augmented muscle glycogen concentrations. Disclosure C. Shannon: None. A. Merovci: None. D. Tripathy: None. M. Abdul-Ghani: None. L. Norton: None. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..