The goal of this work was to compare the effects of different antidiabetic therapies on the phenotype of skeletal muscle in type 2 diabetic subjects failing sulfonylurea therapy. Subjects were treated with a thiazolidinedione (troglitazone, TGZ) or a biguanide (metformin, MET) in addition to glyburide for 3 to 4 months. Insulin action was determined with a hyperinsulinemic (300 mU. m(-2). min(-1)) euglycemic (5.0 to 5.5 mmol/L) clamp. Biopsies were obtained from the vastus lateralis muscle for morphological analysis. Despite similar glycemic control, relative increases in the insulin-stimulated glucose disposal rate (GDR) were greater after TGZ treatment (37 +/- 8% increase, P <.05) than after MET (21 +/- 11%, P <.05). Neither treatment had any effect on fiber type composition of the muscle. Capillary density was reduced in diabetic subjects compared to a nondiabetic group (P <.01) and was increased with TGZ treatment (P <.05), while MET was without significant effect. Diabetic muscle also displayed a lower mitochondrial volume density that was unaltered by either treatment. Both TGZ and MET therapy resulted in a reduction in the lipid content of muscle (percent fiber volume as lipid droplets); the relative decrease tended to be greater for TGZ (-33% v -23% for MET). The relative (%) improvement in GDR was correlated with the change in lipid content (r = -0.756, P <.05) after TGZ treatment; no such relationship was observed for MET. From these results we conclude that the higher potency of TGZ to increase capillary density and reduce the lipid content of muscle may contribute to its greater ability to improve glucose disposal in skeletal muscle of type 2 diabetic individuals.
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