Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents
Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents
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DOI：
10.1016/j.bbrc.2009.10.054
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发表时间：
2009-12-18
影响因子：
3.1
通讯作者：
Watada, Hirotaka
中科院分区：
文献类型：
--
作者：
Arakawa, Masayuki;Ebato, Chie;Watada, Hirotaka
β细胞的增殖受各种代谢需求的调节，包括外周胰岛素抵抗、肥胖和高血糖。除了促进葡萄糖诱导的胰岛素分泌外，胰升糖素样肽-1受体激动剂(GLP-1R)还能刺激胰岛β细胞的增殖和抑制其凋亡，从而可能维持胰岛细胞的质量。为了评价GLP-1R激动剂对胰岛β细胞的保护作用，我们研究了exendin-4在不同条件下对C57BL/6J小鼠胰岛细胞增殖、质量和糖耐量的急性和慢性影响。短期服用高剂量exendin-4会短暂刺激β细胞的增殖。比较转录分析显示，IGF-1受体及其下游效应因子在胰岛表达上调。长期服用exendin-4和高脂饲料治疗4周后，小鼠体重增加和糖耐量显著降低，胰岛素分泌和胰岛β细胞质量减少。这些发现表明，长期的GLP-1治疗导致了外周器官的胰岛素敏化，而不是增强了β细胞的增殖和功能。特别是当动物被喂食高脂肪食物的时候。因此，exendin-4对葡萄糖耐量、胰岛素分泌和β细胞增殖的影响在很大程度上取决于治疗剂量、治疗时间和膳食含量。虽然GLP-1在某些糖尿病小鼠模型中促进了β细胞的增殖，但我们的结果表明，只有在需要扩大β细胞质量以满足代谢需求的情况下，GLP-1才能刺激β细胞的生长。(C)2009 Elsevier Inc.保留所有权利。
Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently Stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function. particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, Our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands. (C) 2009 Elsevier Inc. All rights reserved.