Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia

AimsGlucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse.MethodsC57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices.ResultsWhereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice.ConclusionsLiraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.

研究背景与目的：胰高血糖素样肽-1（GLP-1）受体激动剂与二肽基肽酶-4（DPP4）抑制剂可改善葡萄糖耐量，但其具体作用机制尚未完全阐明。此前已有研究提出，每一类降糖药物均可能增加胰腺炎发病风险。本研究系统比较了两种临床常用GLP-1类似物——利拉鲁肽（liraglutide）与艾塞那肽（exendin-4），以及DPP4抑制剂西格列汀（sitagliptin）在小鼠模型中的作用效果。

方法：将C57BL/6小鼠正常饲养131天，分为普通饮食（normal diet, ND）组与60%脂肪含量高脂饮食（high fat diet, HFD）组，随后检测其空腹血糖、空腹胰岛素水平及腹腔葡萄糖耐量。通过免疫组化分析胰腺切片，检测β细胞与α细胞体积，以及Reg3b免疫反应性。

结果：利拉鲁肽（200 μg/kg）与艾塞那肽（10 μg/kg）给药可降低小鼠体重并/或改善葡萄糖耐量，而西格列汀（10 mg/kg）对上述两项指标均无显著影响。利拉鲁肽可使普通饮食与高脂饮食小鼠的β细胞质量均显著降低，而艾塞那肽则无此作用。与之相反，西格列汀可暴露高脂饮食对β细胞质量的促进作用。在普通饮食喂养的小鼠中，三种药物均可增加Reg3B阳性区域面积；而在高脂饮食小鼠中，西格列汀与艾塞那肽可影响该参数，利拉鲁肽则无此效果。相应地，西格列汀可使普通饮食与高脂饮食小鼠的循环淀粉酶水平升高，而GLP-1类似物无此作用。

结论：利拉鲁肽可改善小鼠葡萄糖耐量，同时对胰腺炎风险的影响相对轻微。与之相反，艾塞那肽与西格列汀在分别仅对代谢指标产生轻度影响或无影响的给药剂量下，即可引发胰腺炎相关体征。