Effects of pioglitazone on glucose and lipid metabolism in Wistar fatty rats.
Insulin resistance is one of pathogenic factors for non-insulin-dependent diabetes mellitus (NIDDM). Pioglitazone (5-[4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzyl]-2,4-thiazolidinedione, AD-4833, also known as U-72, 107E) is a promising candidate to lower hyperglycemia by reducing insulin resistance. The genetically obese-hyperglycemic rats. Wistar fatty, were used to test the action of pioglitazone, because they develop severe insulin resistance in the peripheral tissues (muscle and adipose tissue) and liver. Pioglitazone administered orally (0.3-3 mg/kg/d for 7 days) dose dependently reduced hyperglycemia, hyperlipidemia, and hyperinsulinemia in male fatty rats. Pioglitazone improved glucose tolerance and augmented the glycemic response to exogenous insulin and clearance of plasma triglyceride. These effects on glucose and lipid metabolism seem to be due to increased insulin sensitivity and responsiveness in the peripheral tissues, because pioglitazone increased insulin-stimulated glycogen synthesis and glycolysis in the isolated soleus muscles, and insulin-stimulated glucose oxidation and lipogenesis in adipocytes. The latter effects were not accompanied by any changes in insulin binding. The actions of insulin mimickers (vanadate and vitamin K5), which act on the post-insulin binding sites, on these metabolic events were also potentiated by pioglitazone. These findings suggest that pioglitazone can improve glucose and lipid metabolism by reducing insulin resistance on the post-binding system. Therefore, pioglitazone may be efficacious for treating human NIDDM.
Research and Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Y
Y
Sugiyama
S
S
Taketomi
Y
Y
Shimura
H
H
Ikeda
T
T
Fujita
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009765:Obesity; 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