Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor required for normal insulin secretion and maintenance of β-cell number in the pancreas. HNF1α is also expressed in pancreatic α-cells, but its role in these cells is unknown. The aim of this study was to clarify the role of HNF1α in α-cells. Male Hnf1a+/− mice with a mixed background were backcrossed to outbred ICR mice. Glucose tolerance, glucagon and insulin secretion, islet histology, and gene expression were investigated in ICR Hnf1a−/− and Hnf1a+/+ mice. Regulation of Slc5a1 (encoding sodium glucose cotransporter 1 [SGLT1]) expression by HNF1α and the effect of SGLT1 inhibition on glucagon secretion were also explored. ICR Hnf1a−/− mice were glucose intolerant and exhibited impaired glucose-stimulated insulin secretion. The β-cell area of ICR mice was decreased in Hnf1a−/− mice, but the α-cell area in the pancreas was similar between Hnf1a−/− and Hnf1a+/+ mice. Hnf1a−/− mice showed higher fasting glucagon levels and exhibited inadequate suppression of glucagon after glucose load. In addition, glucagon release in response to hypoglycemia was impaired in Hnf1a−/− mice, and glucagon secretion after 1.1 mM glucose administration, was also decreased in Hnf1a−/− islets. Slc5a1 expression was decreased in Hnf1a−/− islets, while HNF1α activated the Slc5a1 promoter in αTC1-6 cells. Inhibition of SGLT1 suppressed 1.1 mM glucose-stimulated glucagon secretion in islets and αTC1-6 cells, but SGLT1 inhibition had no additional inhibitory effect in HNF1α-deficient cells. Our findings indicate that HNF1α modulates glucagon secretion in α-cells through the regulation of Slc5a1.

肝细胞核因子 1α (HNF1α) 是正常胰岛素分泌和维持胰腺中 β 细胞数量所必需的转录因子。HNF1α也在胰腺α细胞中表达，但其在这些细胞中的作用尚不清楚。本研究的目的是阐明 HNF1α 在 α 细胞中的作用。将具有混合背景的雄性Hnf1a +/- 小鼠回交至远交 ICR 小鼠。在 ICR Hnf1a -/- 和Hnf1a +/+ 小鼠中研究了葡萄糖耐量、胰高血糖素和胰岛素分泌、胰岛组织学和基因表达。还探讨了 HNF1α对Slc5a1（编码钠葡萄糖协同转运蛋白 1 [SGLT1]）表达的调节以及 SGLT1 抑制对胰高血糖素分泌的影响。ICR Hnf1a-/- 小鼠不耐受葡萄糖并且表现出葡萄糖刺激的胰岛素分泌受损。ICR小鼠的β细胞面积在Hnf1a -/- 小鼠中减少，但胰腺中的α细胞面积在Hnf1a -/- 和Hnf1a +/+ 小鼠之间相似。Hnf1a -/- 小鼠表现出更高的空腹胰高血糖素水平，并且在葡萄糖负荷后表现出对胰高血糖素的不充分抑制。此外，在Hnf1a -/- 小鼠中，响应于低血糖的胰高血糖素释放受损，在Hnf1a -/- 胰岛中，给予 1.1 mM 葡萄糖后胰高血糖素分泌也减少。Slc5a1在Hnf1a -/- 胰岛中的表达降低，而 HNF1α 激活了αTC1-6 细胞中的 Slc5a1启动子。SGLT1 的抑制抑制了胰岛和 αTC1-6 细胞中 1.1 mM 葡萄糖刺激的胰高血糖素分泌，但 SGLT1 抑制对 HNF1α 缺陷细胞没有额外的抑制作用。我们的研究结果表明，HNF1α 通过调节 Slc5a1 调节 α 细胞中胰高血糖素的分泌。