Hägerkvist Robert, Jansson Leif, Welsh Nils
Department of Medical Cell Biology, Uppsala University, S-75123 Uppsala, Sweden.
Clin Sci (Lond). 2008 Jan;114(1):65-71. doi: 10.1042/CS20070122.
The aim of the present study was to investigate whether imatinib affects insulin sensitivity and glucose disposal in HF (high-fat)-fed rats. Sprague-Dawley rats were fed either a standard pelleted rat food (low-fat diet) or an HF diet (60% fat) for 8 weeks. During the last 10 days of the HF diet regime, rats received saline alone or imatinib (50 or 100 mg/kg of body weight) daily by gavage. The higher dose of imatinib resulted in a decreased psoas fat pad weight in the HF-treated rats. Under euglycaemic hyperinsulinaemic clamp conditions, HF-fed rats exhibited increased insulin concentrations and decreased glucose disposal. The lower (50 mg/kg of body weight), but not the higher (100 mg/kg of body weight), dose of imatinib normalized insulin sensitivity and glucose disposal without affecting glucose metabolism in low-fat-fed rats. Hepatic glucose production at both fasting and hyperinsulinaemic conditions was only weakly affected by imatinib. We conclude that a moderate dose of imatinib efficiently counteracts HF-induced peripheral insulin resistance, and that further studies on the mechanisms by which imatinib increases insulin action in muscle and fat tissues might generate novel strategies for the treatment of Type 2 diabetes.
本研究的目的是调查伊马替尼是否会影响高脂喂养大鼠的胰岛素敏感性和葡萄糖代谢。将斯普拉格-道利大鼠分为两组，一组喂食标准颗粒大鼠饲料（低脂饮食），另一组喂食高脂饮食（60%脂肪），持续8周。在高脂饮食期的最后10天，大鼠每日通过灌胃单独给予生理盐水或伊马替尼（50或100mg/kg体重）。较高剂量的伊马替尼使高脂处理大鼠的腰大肌脂肪垫重量减轻。在正常血糖高胰岛素钳夹条件下，高脂喂养的大鼠胰岛素浓度升高，葡萄糖代谢降低。较低剂量（50mg/kg体重）而非较高剂量（100mg/kg体重）的伊马替尼可使低脂喂养大鼠的胰岛素敏感性和葡萄糖代谢恢复正常，且不影响其葡萄糖代谢。伊马替尼对空腹和高胰岛素血症条件下的肝葡萄糖生成仅有微弱影响。我们得出结论，中等剂量的伊马替尼可有效对抗高脂诱导的外周胰岛素抵抗，对伊马替尼增加肌肉和脂肪组织胰岛素作用机制的进一步研究可能会产生治疗2型糖尿病的新策略。
