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Pioglitazone improves insulin signaling defects in skeletal muscle from Wistar fatty (fa/fa) rats
T Hayakawa1, T Shiraki, T Morimoto
1Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Abstract:
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.
Insights
Pioglitazone, an insulin-sensitizing drug, corrects impaired insulin signaling in obese rats. This treatment improved insulin receptor function and phosphatidylinositol 3-kinase activity, suggesting a potential therapy for insulin resistance.
Area of Science:
- Endocrinology
- Metabolic Disorders
- Pharmacology
Background:
- Insulin resistance is a hallmark of obesity and type 2 diabetes.
- Skeletal muscle insulin signaling defects contribute to impaired glucose uptake.
- Wistar fatty rats exhibit genetic obesity and insulin resistance.
Purpose of the Study:
- To investigate the effects of pioglitazone on insulin signaling pathways in skeletal muscle.
- To determine if pioglitazone can ameliorate insulin resistance in Wistar fatty rats.
Main Methods:
- Studied insulin signaling in skeletal muscle from obese Wistar fatty rats and lean controls.
- Assessed insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation.
- Measured insulin-stimulated phosphatidylinositol (PI) 3-kinase activity.
- Administered pioglitazone to fatty rats and evaluated changes in signaling pathways.
Main Results:
- Obese rats showed reduced insulin-stimulated tyrosine phosphorylation of IR and IRS-1, and diminished PI 3-kinase activity.
- Pioglitazone treatment (10-18 days) restored these signaling defects in fatty rats.
- Pioglitazone did not alter insulin signaling in lean rats.
- Down-regulation of IR expression in fatty rats was unaffected by pioglitazone.
Conclusions:
- Pioglitazone effectively corrects insulin signaling defects in the skeletal muscle of Wistar fatty rats.
- The drug ameliorates insulin resistance by improving key components of the insulin signaling cascade.
- These findings highlight pioglitazone's therapeutic potential for managing insulin resistance.