Section of Investigative Medicine, Imperial College London, London, U.K.
Diabetes. 2014 Nov;63(11):3711-20. doi: 10.2337/db14-0242. Epub 2014 Jun 17.
Obesity is a growing epidemic, and current medical therapies have proven inadequate. Endogenous satiety hormones provide an attractive target for the development of drugs that aim to cause effective weight loss with minimal side effects. Both glucagon and GLP-1 reduce appetite and cause weight loss. Additionally, glucagon increases energy expenditure. We hypothesized that the combination of both peptides, administered at doses that are individually subanorectic, would reduce appetite, while GLP-1 would protect against the hyperglycemic effect of glucagon. In this double-blind crossover study, subanorectic doses of each peptide alone, both peptides in combination, or placebo was infused into 13 human volunteers for 120 min. An ad libitum meal was provided after 90 min, and calorie intake determined. Resting energy expenditure was measured by indirect calorimetry at baseline and during infusion. Glucagon or GLP-1, given individually at subanorectic doses, did not significantly reduce food intake. Coinfusion at the same doses led to a significant reduction in food intake of 13%. Furthermore, the addition of GLP-1 protected against glucagon-induced hyperglycemia, and an increase in energy expenditure of 53 kcal/day was seen on coinfusion. These observations support the concept of GLP-1 and glucagon dual agonism as a possible treatment for obesity and diabetes.
肥胖是一种日益严重的流行疾病，而目前的医学疗法已被证明效果不足。内源性饱腹感激素为开发旨在通过最小化副作用实现有效减肥的药物提供了一个有吸引力的目标。胰高血糖素和 GLP-1 均可降低食欲并导致体重减轻。此外，胰高血糖素还能增加能量消耗。我们假设，以个体亚厌食剂量联合施用这两种肽，将降低食欲，而 GLP-1 将防止胰高血糖素的高血糖作用。在这项双盲交叉研究中，将每种肽的亚厌食剂量、两种肽的组合或安慰剂单独输注到 13 名人类志愿者体内 120 分钟。在 90 分钟后提供随意进食的餐食，并确定热量摄入。通过间接测热法在基线和输注期间测量静息能量消耗。单独给予亚厌食剂量的胰高血糖素或 GLP-1 并未显著减少食物摄入。以相同剂量同时输注导致食物摄入量显著减少 13%。此外，添加 GLP-1 可防止胰高血糖素引起的高血糖，并在同时输注时观察到每天增加 53 卡路里的能量消耗。这些观察结果支持 GLP-1 和胰高血糖素双重激动剂作为肥胖和糖尿病治疗的一种可能方法的概念。
