Pioglitazone improves insulin signaling defects in skeletal muscle from Wistar fatty (fa/fa) rats.
The effects of pioglitazone, a novel antidiabetic insulin-sensitizing agent, on insulin signaling in skeletal muscles from genetically obese Wistar fatty rats and their lean littermates were studied. Increased tyrosine phosphorylation levels of insulin receptors (IRs) and insulin receptor substrate 1 (IRS-1) in response to insulin were not observed in fatty rats. Insulin-stimulated phosphatidylinositol (PI) 3-kinase activity was reduced in fatty rats. Administration of pioglitazone (3 mg/kg/day) to fatty rats for 10 or 18 days reversed the decline in the insulin-stimulated tyrosine phosphorylated IR and IRS-1 levels and the reduced insulin-stimulated PI 3-kinase activities. In contrast, insulin-stimulated tyrosine phosphorylation of IR and IRS-1 and PI 3-kinase activity in lean rats was not changed by pioglitazone. IR expression in fatty rats was down-regulated, which was not affected by pioglitazone. There was no difference between the PI 3-kinase expression levels in fatty and lean rats and pioglitazone did not change these expression levels. These results indicate that pioglitazone can correct the insulin signaling defects of Wistar fatty rats, thereby ameliorating insulin resistance.
Hayakawa
T
T
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Shiraki
T
T
Morimoto
T
T
Shii
K
K
Ikeda
H
H
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006614:Hindlimb; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019000:Phosphotyrosine / Q000032:analysis; D000077205:Pioglitazone; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000378:metabolism*; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin; D000077205:Pioglitazone