Weyer C, Tataranni P A, Snitker S, Danforth E, Ravussin E
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA.
Diabetes. 1998 Oct;47(10):1555-61. doi: 10.2337/diabetes.47.10.1555.
Stimulation of beta3-adrenoceptors by selective agonists improves insulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta3-adrenoceptor stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta3-adrenoceptor agonist on insulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment with either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Insulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal (NOGD), oxidative glucose disposal (OGD) (indirect calorimetry), and splanchnic glucose output (SGO; beta3-[H3]glucose) were determined during a 100-min hyperinsulinemic-euglycemic glucose clamp (40 mU x m(-2) x min(-1)) before and after 4 and 8 weeks of treatment. The 24-h energy expenditure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rates of fat and carbohydrate were determined in a respiratory chamber before and after 8 weeks. After 4 weeks, treatment with CL 316,243 increased IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner (r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 316,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and leptin were unaffected by treatment, while free fatty acid concentrations increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 316,243 had no effect on heart rate or blood pressure and caused no cases of tremors. We conclude that treatment of lean male subjects with CL 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrate unequivocal metabolic effects of a highly selective beta3-adrenoceptor agonist in humans.
在各种肥胖和2型糖尿病的啮齿动物模型中，选择性激动剂刺激β3 - 肾上腺素能受体可改善胰岛素作用并刺激能量代谢。选择性β3 - 肾上腺素能受体刺激在人类中是否发挥代谢作用仍有待证实。在14名健康年轻瘦男性志愿者（年龄22.5±3.3岁，体脂15±5%[平均值±标准差]）中评估了一种高选择性β3 - 肾上腺素能受体激动剂对胰岛素作用、能量代谢和身体成分的影响，这些志愿者被随机分配接受为期8周的治疗，其中10人每天服用1500 mg的CL 316,243，4人服用安慰剂。在治疗4周和8周前后，通过100分钟高胰岛素 - 正常血糖葡萄糖钳夹（40 mU·m⁻²·min⁻¹）测定胰岛素介导的葡萄糖处置（IMGD）、非氧化葡萄糖处置（NOGD）、氧化葡萄糖处置（OGD）（间接测热法）和内脏葡萄糖输出（SGO；β3 - [H³]葡萄糖）。在呼吸室内测定8周前后的24小时能量消耗（24 - EE）、24小时呼吸商（24 - RQ）以及脂肪和碳水化合物的氧化率。4周后，CL 316,243治疗以血浆浓度依赖性方式增加IMGD（+45%，P < 0.01）（r = 0.76，P < 0.02）。这种效应是由于NOGD增加了82%（P < 0.01），而OGD和SGO保持不变。8周后对胰岛素作用的影响明显减弱；这与CL 316,243血浆浓度意外下降（-36%，P = 0.08）显著相关。此时，24 - RQ降低（P < 0.001），对应脂肪氧化增加23%（P < 0.01），碳水化合物氧化减少17%（P = 0.05）。8周后的24 - EE与基线无差异，体重和身体成分也无变化。血浆葡萄糖、胰岛素和瘦素浓度不受治疗影响，而游离脂肪酸浓度增加了41%（P < 0.05），同样与达到的CL 316,243血浆浓度呈线性关系（r = 0.67，P < 0.05）。CL 316,243治疗对心率或血压无影响，也未引起震颤病例。我们得出结论，用CL 316,243治疗瘦男性受试者可增加胰岛素作用和脂肪氧化，两者均呈血浆浓度依赖性。这是第一项明确证明高选择性β3 - 肾上腺素能受体激动剂在人类中具有代谢作用的研究。
