Mechanism of troglitazone action in type 2 diabetes.
To examine the metabolic pathways by which troglitazone improves insulin responsiveness in patients with type 2 diabetes, the rate of muscle glycogen synthesis was measured by 13C-nuclear magnetic resonance (NMR) spectroscopy. The rate-controlling steps of insulin-stimulated muscle glucose metabolism were assessed using 31P-NMR spectroscopic measurement of intramuscular glucose-6-phosphate (G-6-P) combined with a novel 13C-NMR method to assess intracellular glucose concentrations. Seven healthy nonsmoking subjects with type 2 diabetes were studied before and after completion of 3 months of troglitazone (400 mg/day) therapy. After troglitazone treatment, rates of insulin-stimulated whole-body glucose uptake increased by 58+/-11%, from 629+/-82 to 987+/-156 micromol x m(-2) x min(-1) (P = 0.008), which was associated with an approximately 3-fold increase in rates of insulin-stimulated glucose oxidation (from 119+/-41 to 424+/-70 micromol x m(-2) x min(-1); P = 0.018) and muscle glycogen synthesis (26+/-17 vs. 83+/-35 micromol x l(-1) muscle x min(-1); P = 0.025). After treatment, muscle G-6-P concentrations increased by 0.083+/-0.019 mmol/l (P = 0.008 vs. pretreatment) during the hyperglycemic-hyperinsulinemic clamp, compared with no significant changes in intramuscular G-6-P concentrations in the pretreatment study, reflecting an improvement in glucose transport and/or hexokinase activity. The concentrations of intracellular free glucose did not differ between the pre- and posttreatment studies and remained >50-fold lower in concentration (<0.1 mmol/l) than what would be expected if hexokinase activity was rate-controlling. These results indicate that troglitazone improves insulin responsiveness in skeletal muscle of patients with type 2 diabetes by facilitating glucose transport activity, which thereby leads to increased rates of muscle glycogen synthesis and glucose oxidation.
Petersen
K F
KF
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA. kitt.petersen@yale.edu
Krssak
M
M
Inzucchi
S
S
Cline
G W
GW
Dufour
S
S
Shulman
G I
GI
D001823:Body Composition; D002839:Chromans / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006728:Hormones / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D006728:Hormones; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D019298:Glucose-6-Phosphate; D006003:Glycogen; D000077288:Troglitazone; D005947:Glucose