Glucose transport deficiency in diabetic animals is corrected by treatment with the oral antihyperglycemic agent pioglitazone.
Insulin-stimulated glucose uptake into muscle and fat involves regulation of the subcellular distribution and the expression of a specific facilitative glucose transporter protein (GLUT4). Peripheral glucose uptake is lowered in diabetes, and the expression of GLUT4 is depressed in animals that have been made diabetic (i.e. insulin deficient) by destruction of the pancreatic beta-cells. In the present study we found that GLUT4 expression is also decreased in an animal model for type II diabetes mellitus (noninsulin-dependent diabetes mellitus), KKAY obese mice. These KKAY mice have elevated circulating insulin levels, but target cell resistance to the metabolic actions of insulin. Treatment of both types of diabetic animals with pioglitazone, a new antihyperglycemic compound, corrects deficits in glucose transport and GLUT4 mRNA and protein abundance. Such corrections are, however, more readily detected in fat than in muscle. Increases in GLUT4 mRNA and protein levels and glucose transport function by pioglitazone are dependent upon the presence of circulating insulin. Treatment with pioglitazone alone is sufficient for correction of glucose transport in hyperinsulinemic insulin-resistant animals, but hypoinsulinemic animals require insulin therapy along with pioglitazone treatment for similar corrections. In these insulin-deficient animals, neither treatment with the drug alone nor minimal insulin replacement therapy results in substantial correction. Since insulin and this antihyperglycemic agent seem to work synergistically, it is likely that pioglitazone acts to amplify cellular responses to insulin.
Department of Biochemistry, Loyola University Stritch School of Medicine, Maywood, Illinois 60153.
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Hofmann
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Lorenz
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Colca
D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D000077205:Pioglitazone; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D005947:Glucose; D000077205:Pioglitazone