From the *Department of Physiology, University of Toronto, Toronto, Ontario, Canada; †Centre for Neuroscience, UC Davis, Davis, CA; ‡iBV, INSERM U1091, CNRS UMR7277, University of Nice Sophia-Antipolis, UFR Sciences, F-06108 Nice, France; and §Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada.
Pancreas. 2014 Jan;43(1):93-102. doi: 10.1097/MPA.0b013e3182a70bfb.
The cWnt activator, R-spondin1 (Rspo1), regulates β-cell growth, function, and neogenesis, although its role in conditions such as streptozotocin (STZ)-induced diabetes is unknown. We hypothesized that Rspo1 deficiency enhances β-cell neogenesis in STZ-induced diabetes.
Wild-type (Rspo1) and knockout (Rspo1) mice were injected with STZ (40 mg/kg) for 5 days, followed by analysis of oral glucose and insulin tolerance, and were killed on day 6 (acute; 9-11 mice) or 32 (chronic; 11-16 mice). Immunohistochemistry was performed for β-cell apoptosis, proliferation, neogenesis, and markers of β-cell maturity.
There was no difference in oral glucose handling between STZ-induced Rspo1 and Rspo1 mice, although Rspo1 mice demonstrated increased insulin sensitivity. β-cell mass, islet number, and islet size distribution did not differ between STZ-induced Rspo1 and Rspo1 mice, but Rspo1 animals had reduced β-cell apoptosis and increased numbers of insulin-positive ductal cells, indicating β-cell neogenesis. Furthermore, the increased β-cell regeneration observed in the Rspo1 animals was associated with a more differentiated/mature β-cell phenotype as assessed by increased immunopositivity for Nkx6.1, MafA, and GLUT2.
These findings indicate that Rspo1 is a negative regulator of β-cell neogenesis, development, and survival in the face of STZ-induced diabetes, providing a therapeutic target for the enhancement of β-cell mass.
卷曲相关蛋白 1（Rspo1）是 cWnt 激活剂，它可调节β细胞的生长、功能和新生，但其在链脲佐菌素（STZ）诱导的糖尿病等疾病中的作用尚不清楚。我们假设 Rspo1 缺乏可增强 STZ 诱导的糖尿病中的β细胞新生。
野生型（Rspo1）和敲除型（Rspo1）小鼠连续 5 天腹腔注射 STZ（40mg/kg），然后分析口服葡萄糖和胰岛素耐量，并于第 6 天（急性组；9-11 只小鼠）或第 32 天（慢性组；11-16 只小鼠）处死。进行β细胞凋亡、增殖、新生和β细胞成熟标志物的免疫组织化学检测。
STZ 诱导的 Rspo1 和 Rspo1 小鼠的口服葡萄糖处理无差异，尽管 Rspo1 小鼠表现出胰岛素敏感性增加。β细胞质量、胰岛数量和胰岛大小分布在 STZ 诱导的 Rspo1 和 Rspo1 小鼠之间无差异，但 Rspo1 动物的β细胞凋亡减少，胰岛素阳性导管细胞数量增加，表明β细胞新生。此外，在 Rspo1 动物中观察到的β细胞再生增加与β细胞表型分化/成熟增加相关，表现为 Nkx6.1、MafA 和 GLUT2 的免疫阳性率增加。
这些发现表明，Rspo1 是 STZ 诱导的糖尿病中β细胞新生、发育和存活的负调节因子，为增强β细胞质量提供了一个治疗靶点。
