Effect of ciglitazone on glucose uptake and insulin sensitivity in skeletal muscle of the obese (ob/ob) mouse: distinct insulin and glucocorticoid effects.
The oral hypoglycemic agent, ciglitazone, (5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione), was fed for nine days to genetically obese (ob/ob) mice aged 5 to 6 weeks. This treatment resulted in a lowering of plasma glucose and circulating insulin levels, but did not cause a fall in plasma corticosterone levels. Basal 2-deoxy-D-glucose uptake by the perfused hindquarters of ob/ob mice was unchanged by ciglitazone feeding. In the presence of 0.1 mU/mL insulin in the perfusion medium, there was a significant increase in the uptake rate of 2-deoxy-D-glucose by the skeletal muscle of ciglitazone-treated ob/ob mice, while there was no insulin effect in untreated ob/ob mice. Insulin at a concentration of 1 mU/mL caused a further stimulation of 2-deoxy-D-glucose transport. However, this response was significantly lower than the maximal stimulation in lean mice. Ciglitazone feeding did not have any effect on [5-3H]-glucose metabolism by the perfused muscle which remained subnormal, suggesting that the posttransport metabolism of glucose was limited by substrate availability. In the perfused mouse liver, net [14C]-glucose production from [14C]-lactate was unchanged by ciglitazone treatment while gluconeogenesis from [14C]-alanine was reduced. These findings show that ciglitazone produces its hypoglycemic effect by improving the insulin sensitivity in skeletal muscle, as others have reported in the adipose tissue. The presence of elevated plasma levels of corticosterone and lower levels of insulin in ciglitazone-treated ob/ob mice suggests that the adrenal glucocorticoids are responsible for the basal defects in glucose transport and the hyperinsulinemia is responsible for the insulin insensitivity.
D000302:Adrenal Cortex / Q000502:physiology; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D005938:Glucocorticoids / Q000502:physiology*; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000378:metabolism; D008820:Mice, Obese / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D003847:Deoxyglucose; D005947:Glucose; C039671:ciglitazone