Protective effects of glucagon-like peptide-1 on beta-cells: preclinical data and clinical studies
Protective effects of glucagon-like peptide-1 on beta-cells: preclinical data and clinical studies
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DOI：
10.1714/985.10684
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发表时间：
2011-12-01
影响因子：
0.5
通讯作者：
Di Biagio, Rosamaria
中科院分区：
文献类型：
--
作者：
Consoli, Agostino;Di Biagio, Rosamaria
持续的β细胞质量和功能丧失代表了2型糖尿病发病机制和进展的关键机制。能够阻止β细胞损失并最终能够使β细胞功能接近恢复正常的药物将对2型糖尿病治疗有巨大的帮助。胰高血糖素样肽-1（GLP-1）受体激动剂依塞那肽和利拉鲁肽可刺激体外新生并防止β细胞样细胞系的凋亡。因此，在几种糖尿病动物模型中，GLP-1受体激动剂治疗可改善葡萄糖代谢，保留β细胞群并改善β细胞功能。例如，在db/db小鼠中，利拉鲁肽可保护β细胞免受氧化应激和内质网应激相关损伤。人体体内的数据不太确定，通常基于几乎不可靠的β细胞功能指标。然而，利拉鲁肽短期治疗（14周）以剂量-反应方式增加了β细胞最大反应能力。更长时间（1年）的艾塞那肽治疗也能够增加β细胞的最大反应能力，但在4周的洗脱期后效果不再存在。然而，在3年艾塞那肽治疗后的4周洗脱期后，观察到另一种β细胞功能指数（处置指数）的轻微改善，尽管与甘精胰岛素治疗相比具有显著性。最后，尽管目前没有足够长随访期的临床试验，但在利拉鲁肽单药治疗的2年期间获得了持久的血糖控制。由于良好控制的持久性严格依赖于β细胞功能没有进一步恶化，因此这些临床数据可能会带来希望，即GLP-1受体拮抗剂治疗可能有助于保护2型糖尿病患者的β细胞功能。
Continuing beta-cell mass and function loss represents the key mechanism for the pathogenesis and the progression of type 2 diabetes mellitus. Drugs capable of arresting beta-cell loss and eventually able to bring beta-cell function close to be back to normal would then be a formidable help in type 2 diabetes mellitus treatment. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide can stimulate in vitro neogenesis and prevent apoptosis in beta-cell-like cell lines. Consistently, treatment with GLP-1 receptor agonists ameliorates glucose metabolism, preserves beta-cell mass and improves beta-cell function in several animal models of diabetes. For instance, in the db/db mice, liraglutide protects the beta-cell from oxidative stress and endoplasmic reticulum stress-related damage. Data in humans, in vivo, are less definitive and often based on scarcely reliable indexes of beta-cell function. However, short-term treatment (14 weeks) with liraglutide increased beta-cell maximal response capacity in a dose-response fashion. A longer (1 year) exenatide treatment also was able to increase beta-cell maximal response capacity, but the effect was no longer there after a 4-week washout period. However, a marginal, although significant as compared to glargine treatment, improvement in another beta-cell function index (disposition index) was observed after a 4-week washout period following 3-year exenatide treatment. Finally, although no clinical trials with a long enough follow-up period are presently available, durable glucose control has been obtained during 2 years of liraglutide treatment in monotherapy. Since the durability of good control is strictly dependent upon a lack of further beta-cell function deterioration, these clinical data may foster hope that GLP-1 receptor antagonist treatment might help preserving beta-cell function also in individuals affected by type 2 diabetes mellitus.