Normalization of Skeletal Muscle Glycogen Synthesis and Glycolysis in Rosiglitazone-Treated Zucker Fatty Rats

Abstract

The aim of this study was to characterize insulin-stimulated skeletal muscle glucose metabolism in Zucker fatty rats and to provide insight into the therapeutic mechanism by which rosiglitazone increases insulin-stimulated glucose disposal in these rats. Metabolic parameters were measured using combined in vivo ¹³C nuclear magnetic resonance (NMR) spectroscopy to measure skeletal muscle glucose uptake and its distributed fluxes (glycogen synthesis and glycolysis), and ³¹P NMR was used to measure simultaneous changes in glucose-6-phosphate (G-6-P) during a euglycemic-hyperinsulinemic clamp in awake Zucker fatty rats. Three groups of Zucker fatty rats (fatty rosiglitazone [FRSG], fatty control [FC], lean control [LC]) were treated for 7 days before the experiment (3 mg/kg rosiglitazone or vehicle via oral gavage). Rates of glycolysis and glycogen synthesis were assessed after treatment by monitoring 1,6-¹³C₂ glucose label incorporation into 1-¹³C glycogen, 3-¹³C lactate, and 3-¹³C alanine during a euglycemic (∼7–8 mmol/l)-hyperinsulinemic (10 mU · kg⁻¹ · min⁻¹) clamp. The FRSG group exhibited a significant increase in insulin sensitivity, reflected by an increased whole-body glucose disposal rate during the clamp (24.4 ± 1.9 vs. 17.6 ± 1.4 and 33.2 ± 2.0 mg · kg⁻¹ · min⁻¹ in FRSG vs. FC [P < 0.05] and LC [P < 0.01] groups, respectively). The increased insulin-stimulated glucose disposal in the FRSG group was associated with a normalization of the glycolytic flux (52.9 ± 9.1) to LC (56.2 ± 16.6) versus FC (18.8 ± 8.6 nmol · g⁻¹ · min⁻¹, P < 0.02) and glycogen synthesis flux (56.3 ± 11.5) to LC (75.2 ± 15.3) versus FC (16.6 ± 12.8 nmol · g⁻¹ · min⁻¹, P < 0.05). [G-6-P] increased in the FRSG and LC groups versus baseline during the clamp (13.0 ± 11.1 and 16.9 ± 5.8%, respectively), whereas [G-6-P] in the FC group decreased (−23.3 ± 13.4%, P < 0.05). There were no differences between groups in intramyocellular glucose, as measured by biochemical assay. These data suggest that the increased insulin-stimulated glucose disposal in muscle after rosiglitazone treatment can be attributed to a normalization of glucose transport and metabolism.