ABSTRACT

Previous studies indicated that ductal cells can contribute to endocrine neogenesis in adult rodents after alpha cells convert into beta cells. This can occur through Pax4 mis-expression in alpha cells or through long-term administration of gamma-aminobutyric acid (GABA) to healthy mice. GABA has also been reported to increase the number of beta cells through direct effects on their proliferation, but only in specific genetic mouse backgrounds. To test whether GABA induces neogenesis of beta cells from ductal cells or affects pancreatic cell proliferation, we administered GABA or saline over 2 or 6 months to Sox9CreER;R26R^YFP mice in which 60–80% of large or small ducts were efficiently lineage labeled. We did not observe any increases in islet neogenesis from ductal cells between 1 and 2 months of age in saline treated mice, nor between 2 and 6 months of saline treatment, supporting previous studies indicating that adult ductal cells do not give rise to new endocrine cells during homeostasis. Unlike previous reports, we did not observe an increase in beta cell neogenesis after 2 or 6 months of GABA administration. Nor did we observe a significant increase in the pancreatic islet area, the number of insulin and glucagon double positive cells, or cell proliferation in the pancreas. This indicates that the effect of long term GABA administration on the pancreas is minimal or highly context dependent.

摘要

先前的研究表明，在α细胞转化为β细胞后，导管细胞可以促进成年啮齿动物的内分泌新生。这可以通过 α 细胞中 Pax4 的错误表达或通过对健康小鼠长期施用 γ-氨基丁酸 (GABA) 来实现。据报道，GABA 还可以通过直接影响 β 细胞的增殖来增加其数量，但仅限于特定的遗传小鼠背景。为了测试 GABA 是否诱导导管细胞新生 β 细胞或影响胰腺细胞增殖，我们向Sox9CreER;R26R ^YFP施用 GABA 或盐水超过 2 或 6 个月其中 60-80% 的大小导管被有效谱系标记的小鼠。我们没有观察到盐水处理小鼠 1 至 2 个月龄期间以及盐水处理 2 至 6 个月期间导管细胞的胰岛新生增加，这支持了先前的研究，表明成年导管细胞不会产生新的内分泌细胞体内平衡期间。与之前的报告不同，我们没有观察到 GABA 给药 2 或 6 个月后 β 细胞新生的增加。我们也没有观察到胰岛面积、胰岛素和胰高血糖素双阳性细胞数量或胰腺细胞增殖的显着增加。这表明长期给予 GABA 对胰腺的影响很小或高度依赖于环境。