| First Author | Sato Y | Year | 2020 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1866 |
| Issue | 11 | Pages | 165898 |
| PubMed ID | 32711050 | Mgi Jnum | J:301444 |
| Mgi Id | MGI:6490858 | Doi | 10.1016/j.bbadis.2020.165898 |
| Citation | Sato Y, et al. (2020) HNF1alpha controls glucagon secretion in pancreatic alpha-cells through modulation of SGLT1. Biochim Biophys Acta Mol Basis Dis 1866(11):165898 |
| abstractText | Hepatocyte nuclear factor 1alpha (HNF1alpha) is a transcription factor required for normal insulin secretion and maintenance of beta-cell number in the pancreas. HNF1alpha is also expressed in pancreatic alpha-cells, but its role in these cells is unknown. The aim of this study was to clarify the role of HNF1alpha in alpha-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 HNF1alpha 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 beta-cell area of ICR mice was decreased in Hnf1a-/- mice, but the alpha-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 HNF1alpha activated the Slc5a1 promoter in alphaTC1-6 cells. Inhibition of SGLT1 suppressed 1.1 mM glucose-stimulated glucagon secretion in islets and alphaTC1-6 cells, but SGLT1 inhibition had no additional inhibitory effect in HNF1alpha-deficient cells. Our findings indicate that HNF1alpha modulates glucagon secretion in alpha-cells through the regulation of Slc5a1. |
