Blachère J C, Pérusse F, Bukowiecki L J
Department of Physiology, Faculty of Medicine, Laval University, Quebec, Canada.
Metabolism. 2001 Aug;50(8):945-51. doi: 10.1053/meta.2001.24868.
We previously reported that long-term treatment of Zucker diabetic fatty (ZDF) rats with the selective beta(3) agonist CL-316243 normalizes glycemia, decreases plasma free fatty acids (FFA) concentration, improves insulin responsiveness, and increases glucose uptake, not only in brown and white adipose tissues, but also in skeletal muscles. Because muscles do not express typical beta(3) adrenoceptors, we postulated that the muscle effect was indirect and that it was possibly mediated by an activation of the glucose-fatty acid cycle. To test this hypothesis, we investigated the effects of Acipimox, a potent inhibitor of lipolysis in adipose tissue. Similar to CL-316243, Acipimox (150 mg/kg orally) markedly decreased plasma FFA, glucose, and insulin concentrations and improved glucose tolerance while reducing the insulin response in obese (350 to 400 g) ZDF rats. Plasma FFA concentrations were significantly correlated with plasma glucose and insulin concentrations (r =.72 and.83, respectively; P <.01), indicating strong metabolic relationships between these parameters. Euglycemic-hyperinsulinemic clamps combined with the 2-[(3)H]deoxyglucose method revealed that Acipimox markedly improved insulin responsiveness and significantly increased glucose uptake (Rg') in the diaphragm, the heart, and various skeletal muscles. Unlike CL-316243, Acipimox did not increase glucose use in brown or white adipose tissues. This selectivity shows that it is possible to improve diabetes in obese ZDF rats without necessarily stimulating thermogenesis in adipose tissues. Thus, decreasing plasma FFA with 2 drugs (Acipimox or CL-316243) that act via different mechanisms (acute inhibition of lipolysis or chronic stimulation of FFA oxidation) is associated with increased glucose uptake in muscles and enhanced insulin responsiveness. These observations support the hypothesis that CL-316243 may indirectly stimulate glucose uptake in muscles of type II diabetic rats by first stimulating brown adipose tissue (increasing uncoupling protein content and fatty acid oxidation) and progressively decreasing the levels of circulating FFA, resulting in activation of the glucose-fatty acid cycle or other mechanisms regulating insulin responsiveness in skeletal muscles.
我们之前报道，用选择性β(3)激动剂CL-316243长期治疗Zucker糖尿病脂肪（ZDF）大鼠可使血糖正常化，降低血浆游离脂肪酸（FFA）浓度，改善胰岛素反应性，并增加葡萄糖摄取，不仅在棕色和白色脂肪组织中如此，在骨骼肌中亦是如此。由于肌肉不表达典型的β(3)肾上腺素能受体，我们推测肌肉效应是间接的，可能是由葡萄糖-脂肪酸循环的激活介导的。为了验证这一假设，我们研究了阿西莫司（Acipimox）的作用，它是一种强效的脂肪组织脂解抑制剂。与CL-316243相似，阿西莫司（150 mg/kg口服）显著降低了肥胖（350至400 g）ZDF大鼠的血浆FFA、葡萄糖和胰岛素浓度，改善了葡萄糖耐量，同时降低了胰岛素反应。血浆FFA浓度与血浆葡萄糖和胰岛素浓度显著相关（r分别为0.72和0.83；P < 0.01），表明这些参数之间存在密切的代谢关系。正常血糖-高胰岛素钳夹结合2-[(3)H]脱氧葡萄糖方法显示，阿西莫司显著改善了胰岛素反应性，并显著增加了膈肌、心脏和各种骨骼肌中的葡萄糖摄取（Rg'）。与CL-316243不同，阿西莫司没有增加棕色或白色脂肪组织中的葡萄糖利用。这种选择性表明，在不必然刺激脂肪组织产热的情况下，有可能改善肥胖ZDF大鼠的糖尿病状况。因此，用两种通过不同机制起作用的药物（阿西莫司或CL-316243，即急性抑制脂解或慢性刺激FFA氧化）降低血浆FFA，与肌肉中葡萄糖摄取增加和胰岛素反应性增强相关。这些观察结果支持以下假设：CL-316243可能通过首先刺激棕色脂肪组织（增加解偶联蛋白含量和脂肪酸氧化）并逐渐降低循环FFA水平，从而间接刺激II型糖尿病大鼠肌肉中的葡萄糖摄取，导致葡萄糖-脂肪酸循环或其他调节骨骼肌胰岛素反应性的机制被激活。
