Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.
Diabetes Metab J. 2021 Jan;45(1):86-96. doi: 10.4093/dmj.2019.0160. Epub 2020 Feb 26.
Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS).
Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and β-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion.
NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and β-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice.
Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and β-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in β-cell mass determination and diabetes.
Notch 信号通路在胰腺发育过程中对调节胰腺内分泌和外分泌细胞命运起着重要作用。Notch 信号在成年胰腺中也有表达。关于 Notch 对成年胰腺的影响的研究较少。在这里，我们使用 Notch1 反义转基因 (NAS) 研究了 Notch 在成年胰腺胰岛质量和葡萄糖稳态中的作用。
对 8 周龄雄性 NAS 小鼠的肝脏进行 Western blot 分析。我们还对 8 周龄雄性 NAS 小鼠和雄性 C57BL/6 小鼠（对照）进行了腹腔内葡萄糖耐量试验 (IPGTT) 和腹腔内胰岛素耐量试验。在两组中进行了胰岛和β细胞的形态学观察。通过葡萄糖刺激胰岛素分泌 (GSIS) 和灌注测量胰岛的胰岛素分泌能力。
NAS 小鼠的 IPGTT 血糖水平较高，胰岛素分泌较低。胰岛素抵抗无明显差异。NAS 小鼠的总胰岛和β细胞质量减少。大胰岛（≥250 µm）的数量减少，而小胰岛（<250 µm）的数量增加。GSIS 和灌注观察到胰岛素分泌减少。NAS 小鼠的神经基因 3、神经发生和 MAF bZIP 转录因子 A 水平增加。
我们的研究表明 Notch1 抑制减少了胰岛素分泌和胰岛及β细胞质量。据认为，Notch1 抑制抑制胰岛增殖并诱导小胰岛分化。总之，Notch 信号通路可能在β细胞质量的确定和糖尿病中起重要作用。
