Iwanishi M, Kobayashi M
First Department of Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Metabolism. 1993 Aug;42(8):1017-21. doi: 10.1016/0026-0495(93)90016-h.
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.
一种新型口服制剂，5-[4-[2-(5-乙基-1,2-吡啶基)乙氧基]-苄基]-2,4-噻唑烷二酮，即吡格列酮，已被开发用于治疗非胰岛素依赖型糖尿病（NIDDM）。我们研究了其在高脂喂养的胰岛素抵抗大鼠中的有效性。给予该制剂（10毫克·千克-1·天-1）2周可使高脂血症和高胰岛素血症减轻，这表明高脂喂养大鼠体内的胰岛素敏感性有所增加。为阐明该药物的作用机制，我们检测了未治疗和经吡格列酮治疗的高脂喂养大鼠肌肉中胰岛素受体的胰岛素结合及激酶活性。吡格列酮治疗并未改变高脂喂养大鼠的胰岛素结合，但使胰岛素刺激的胰岛素受体自身磷酸化增加至对照动物的水平。在经吡格列酮治疗的高脂喂养大鼠中，对外源底物多聚Glu4-Tyr1的激酶活性也增加至对照动物的水平。这些结果提示，吡格列酮通过激活高脂喂养大鼠受体的酪氨酸激酶活性来增加胰岛素敏感性，并且该药物似乎是一种具有新作用模式的、对治疗伴有胰岛素抵抗的NIDDM有用的药物。
