Normalization of skeletal muscle glycogen synthesis and glycolysis in rosiglitazone-treated Zucker fatty rats: an in vivo nuclear magnetic resonance study.
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 (13)C nuclear magnetic resonance (NMR) spectroscopy to measure skeletal muscle glucose uptake and its distributed fluxes (glycogen synthesis and glycolysis), and (31)P 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-(13)C(2) glucose label incorporation into 1-(13)C glycogen, 3-(13)C lactate, and 3-(13)C alanine during a euglycemic ( approximately 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.
Jucker
Beat M
BM
Cardiovascular and Urogenital Investigational Biology and Product Support, GlaxoSmithKline, UW2940, 709 Swedeland Road, King of Prussia, PA 19406, USA. beat_m_tucker@gsk.com
Schaeffer
Thomas R
TR
Haimbach
Robin E
RE
McIntosh
Thomas S
TS
Chun
Daniel
D
Mayer
Matthew
M
Ohlstein
Derek H
DH
Davis
Hugh M
HM
Smith
Stephen A
SA
Cobitz
Alexander R
AR
Sarkar
Susanta K
SK
D000818:Animals; D004195:Disease Models, Animal; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone