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Diabetes 51:2066-2073, 2002
© 2002 by the American Diabetes Association, Inc.
Normalization of Skeletal Muscle Glycogen Synthesis and Glycolysis in Rosiglitazone-Treated Zucker Fatty Rats
An In Vivo Nuclear Magnetic Resonance Study
1 Cardiovascular and Urogenital Investigational Biology and Product Support, GlaxoSmithKline, King of Prussia, Pennsylvania
2 Laboratory of Animal Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania
3 Clinical Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania
4 Musculoskeletal Diseases, GlaxoSmithKline, King of Prussia, Pennsylvania
5 Clinical Development, GlaxoSmithKline, King of Prussia, Pennsylvania
6 Technology Development, GlaxoSmithKline, King of Prussia, Pennsylvania
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.
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