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 C-13-nuclear magnetic resonance (NMR) spectroscopy. The rate-controlling steps of insulin-stimulated muscle glucose metabolism were assessed using P-31-NMR spectroscopic measurement of intramuscular glucose-6-phosphate (G-6-P) combined with a novel C-13-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 bg 58 +/- 11%, from 629 +/- 82 to 987 +/- 156 mu mol . m(-2) . min(-1) (P = 0.008), which was associated with an similar to 3-fold increase in rates of insulin-stimulated glucose oxidation (from 119 +/- 41 to 424 +/- 70 mu mol . m(-2) . min(-1); P = 0.018) and muscle glycogen synthesis (26 +/- 17 vs. 83 +/- 35 mu mol . l(-1) muscle . 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.