Effect of pioglitazone on insulin receptors of skeletal muscles from high-fat-fed rats.
A new oral agent, 5-[4-[2-(5-ethyl-12-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione, or pioglitazone, has been developed for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). We examined its effectiveness in high-fat-fed rats resistant to insulin. Administration of the agent (10 mg.kg-1 x d-1) for 2 weeks resulted in decreases in hyperlipidemia and hyperinsulinemia, indicating that insulin sensitivity had increased in vivo in high-fat-fed rats. To clarify the mechanism of the drug, we examined insulin binding and kinase activity of insulin receptors from muscles of both untreated and treated high-fat-fed rats. Pioglitazone treatment did not change insulin binding in high-fat-fed rats, but increased insulin-stimulated autophosphorylation of insulin receptors to the level of control animals. Kinase activity toward an exogenous substrate, poly Glu4-Tyr1, in pioglitazone-treated high-fat-fed rats was also increased to the level of control animals. These results suggest that pioglitazone increases insulin sensitivity by activating tyrosine kinase activity of receptors in high-fat-fed rats, and this drug appears to be a useful one with a new mode of action for the treatment of NIDDM with insulin resistance.
Iwanishi
M
M
First Department of Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Kobayashi
M
M
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004041:Dietary Fats / Q000008:administration & dosage*; D004591:Electrophoresis, Polyacrylamide Gel; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000201:enzymology; D008297:Male; D009132:Muscles / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D010766:Phosphorylation; D000077205:Pioglitazone; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones
D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D000077205:Pioglitazone