Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats
Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats
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DOI：
10.2337/diabetes.50.11.2530
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发表时间：
2001-11-01
期刊：
影响因子：
7.7
通讯作者：
Tang-Christensen, M
中科院分区：
文献类型：
--
作者：
Larsen, PJ;Fledelius, C;Tang-Christensen, M
已经表明肠促胰岛素胰高血糖素样肽-1（GLP-1）的餐后释放在人体中充当内源性饱腹感因子。然而，在大鼠中，这方面的证据不明确，可能是因为GLP-1降解酶二肽基肽酶-IV的内源性活性非常高。在本研究中，我们表明，静脉注射GLP-1（100和500 μ g/kg）减少饥饿大鼠的食物摄入量60分钟。这种作用是药物特异性的，因为它被先前给予100 μ g/kg毒蜥外泌肽（9-39）抑制，并且当单独给予（500 μ g/kg）时，生物学上无活性的GLP-1（1-37）对食物摄入没有影响。GLP-1的急性静脉内给药也引起对水摄入的剂量依赖性抑制，并且这种作用同样被之前的毒蜥外泌肽给药完全消除（9-39）。静脉给予100和500 μ g/kg GLP-1后，观察到利尿显著增加。使用新型长效注射型GLP-1衍生物NN 2211，在正常大鼠和新生儿谷氨酸盐处理（MSG）肥胖大鼠中研究了GLP-1及其衍生物的急性和亚慢性厌食潜力。我们先前表明，MSG处理的动物对集中给药GLP-1的厌食作用不敏感（7-37）。将正常和MSG损伤大鼠随机分配至接受NN 2211或溶剂的组中。在正常和MSG给药大鼠中，单次推注NN 2211可引起对过夜摄食量和饮水量的显著剂量依赖性抑制，并增加利尿。正常和MSG给药大鼠亚慢性多次给予NN 2211（200 μ g/kg），每日两次，持续10天，导致摄食量严重抑制。两组的摄食量显著减少均伴有体重减轻，最低稳定在初始体重的85%左右。最初的饮水量和利尿量波动是短暂的，因为它们在治疗的几天内恢复正常。在正常和MSG给药肥胖大鼠中，NN 2211给药期间均观察到甘油三酯和瘦素血浆水平降低。在后续研究中，正常大鼠的7天NN 2211给药期结束时，分别通过间接量热法和双能X射线吸收测定法测定能量消耗（EE）和身体组成。与溶媒给药大鼠相比，NN 2211和配对饲喂大鼠的总EE降低，与观察到的体重减轻相对应，因此每单位瘦体重的EE不受影响。尽管最初对体液平衡有影响，但通过身体组成、血浆电解质和红细胞压积分析证实，NN 2211对体内水分稳态无致弱作用。这与成对喂养的动物相反，成对喂养的动物显示出血液浓缩和脂肪质量百分比增加的趋势。本系列实验表明，GLP-1完全能够通过外周可及部位抑制大鼠的摄食。体重的减轻伴随着循环瘦素水平的降低，表明体脂的减少。NN 2211给药引起的显著体重减轻对体内水分稳态无不利影响。因此，长效GLP-1衍生物可能被证明是有效的减肥治疗剂，用于超重的2型糖尿病患者。
Postprandial release of the incretin glucagon-like peptide-1 (GLP-1) has been suggested to act as an endogenous satiety factor in humans. In rats, however, the evidence for this is equivocal probably because of very high endogenous activity of the GLP-1 degrading enzyme dipeptidyl peptidase-IV. In the present study, we show that intravenously administered GLP-1 (100 and 500 mug/kg) decreases food intake for 60 min in hungry rats. This effect is pharmacologically specific as it is inhibited by previous administration of 100 mug/kg exendin(9-39), and biologically inactive GLP-1(1-37) had no effect on food intake when administered alone (500 mug/kg). Acute intravenous administration of GLP-1 also caused dose-dependent inhibition of water intake, and this effect was equally well abolished by previous administration of exendin(9-39). A profound increase in diuresis was observed after intravenous administration of both 100 and 500 mug/kg GLP-1. Using a novel long-acting injectable GLP-1 derivative, NN2211, the acute and subchronic anorectic potentials of GLP-1 and derivatives were studied in both normal rats and rats made obese by neonatal monosodium glutamate treatment (MSG). We showed previously that MSG-treated animals are insensitive to the anorectic effects of centrally administered GLP-1(7-37). Both normal and MSG-lesioned rats were randomly assigned to groups to receive NN2211 or vehicle. A single bolus injection of NN2211 caused profound dose-dependent inhibition of overnight food and water intake and increased diuresis in both normal and MSG-treated rats. Subchronic multiple dosing of NN2211 (200 mug/kg) twice daily for 10 days to normal and MSG-treated rats caused profound inhibition of food intake. The marked decrease in food intake was accompanied by reduced body weight in both groups, which at its lowest stabilized at similar to 85% of initial body weight. Initial excursions in water intake and diuresis were transient as they were normalized within a few days of treatment. Lowered plasma levels of triglycerides and leptin were observed during NN2211 treatment in both normal and MSG-treated obese rats. In a subsequent study, a 7-day NN2211 treatment Period of normal rats ended with measurement of energy expenditure (EE) and body composition determined by indirect calorimetry and dual energy X-ray absorptiometry, respectively. Compared with vehicle-treated rats, NN2211 and pair-fed rats decreased their total EE corresponding to the observed weight loss, such that EE per weight unit of lean body mass was unaffected. Despite its initial impact on body fluid balance, NN2211 had no debilitating effects on body water homeostasis as confirmed by analysis of body composition, plasma electrolytes, and hematocrit. This is in contrast to pair-fed animals, which displayed hemoconcentration and tendency toward increased percentage of fat mass. The present series of experiments show that GLP-1 is fully capable of inhibiting food intake in rats via a peripherally accessible site. The loss in body weight is accompanied by decreased levels of circulating leptin indicative of loss of body fat. The profound weight loss caused by NN2211 treatment was without detrimental effects on body water homeostasis. Thus, long-acting GLP-1 derivatives may prove efficient as weight-reducing therapeutic agents for overweight patients with type 2 diabetes.