Tamura Kanako, Minami Kohtaro, Kudo Maya, Iemoto Keisuke, Takahashi Harumi, Seino Susumu
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
PLoS One. 2015 May 4;10(5):e0126003. doi: 10.1371/journal.pone.0126003. eCollection 2015.
Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice.
胰高血糖素样肽-1（GLP-1）受体激动剂可增强葡萄糖诱导的胰岛素分泌。此外，据报道它们可增加糖尿病啮齿动物的胰腺β细胞量。然而，GLP-1受体激动剂的确切作用方式仍有待阐明。在此，我们通过使用基于诱导型Cre/loxP的胰腺β细胞追踪系统和四氧嘧啶诱导的糖尿病小鼠，阐明了人GLP-1类似物利拉鲁肽对β细胞命运和功能的影响。利拉鲁肽每天皮下注射一次，持续30天。检测β细胞量的变化以及葡萄糖耐量和胰岛素分泌情况。我们发现，长期使用利拉鲁肽治疗可改善葡萄糖耐量以及胰岛素对口服葡萄糖负荷的反应。利拉鲁肽治疗30天导致胰腺β细胞量比载体组高2倍。利拉鲁肽增加了胰腺β细胞的增殖率，并防止β细胞发生凋亡性细胞死亡。然而，利拉鲁肽治疗前后YFP标记的β细胞相对于总β细胞的相对丰度没有差异，这表明新生对β细胞量增加的贡献不大或几乎没有贡献。利拉鲁肽降低了四氧嘧啶诱导的糖尿病小鼠胰岛细胞中的氧化应激。此外，停药两周后，利拉鲁肽对这些小鼠的有益作用仍然存在。总之，长期使用利拉鲁肽治疗可通过改善四氧嘧啶诱导的糖尿病小鼠的β细胞量和功能来改善高血糖症。
