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Keywords:

  • Goto-Kakizaki rats;
  • liraglutide;
  • pancreatic beta cells
  • Goto-Kakizaki大鼠,利拉鲁肽,胰腺β细胞

Abstract

Background

Glucagon-like peptide-1 (GLP-1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP-1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP-1 analogue, liraglutide in Gato-Kakizaki (GK) rats and explored the underlying mechanisms.

Methods

The effects of liraglutide on glucose tolerance were evaluated by intraperitoneal glucose tolerance test (IPGTT) and insulin release tests (IRT). Ki67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) immunostaining, Western blots and real-time polymerase chain reaction were applied to evaluate cell proliferation, apoptosis and related gene expressions.

Results

Our results demonstrated that early use of liraglutide improved glucose tolerance during liraglutide treatment in GK rats. Liraglutide increased pancreatic insulin contents and markedly reduced beta cell apoptosis. Liraglutide also downregulated pro-apoptotic gene expressions and reduced intra-islet macrophage infiltration.

Conclusions

This experiment reported for the first time that early use of liraglutide could protect beta cell failure in pre-diabetic GK rats through reduction of beta cell apoptosis and ameliorating islet inflammation.

摘要

背景

胰高血糖素样肽-1(GLP-1)类似物作为胰岛素促泌剂的出现,在2型糖尿病患者中得到了广泛应用。目前在啮齿类动物中还证实了GLP-1类似物可以促进β细胞的增殖并且减少凋亡。本研究中,我们在Gato-Kakizaki (GK)大鼠身上,通过早期(在2周龄时)使用GLP-1类似物—利拉鲁肽来观察它对胰腺β细胞的保护作用,并且探讨了其潜在的作用机制。

方法

通过腹腔内葡萄糖耐量以及胰岛素释放试验来评估利拉鲁肽对葡萄糖耐量的影响。使用Ki67与脱氧核糖核苷酸末端转移酶介导的dUTP缺口末端标记、蛋白电泳以及实时聚合酶链反应来评估细胞增殖、凋亡以及相关的基因表达。

结果

我们的结果证实,在GK大鼠中早期使用利拉鲁肽可以改善葡萄糖耐量。利拉鲁肽可以增加胰腺的胰岛素含量并且显著地减少β细胞的凋亡。利拉鲁肽还可以下调促凋亡基因的表达并且减少胰岛内的巨噬细胞浸润。

结论

本研究首次报道了在糖尿病前期的GK大鼠中早期使用利拉鲁肽可以通过减少β细胞凋亡以及改善胰岛炎症来防止β细胞衰竭。