HNF1α controls glucagon secretion in pancreatic α-cells through modulation of SGLT1

Biochim Biophys Acta Mol Basis Dis. 2020 Nov 1;1866(11):165898. doi: 10.1016/j.bbadis.2020.165898. Epub 2020 Jul 22.


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.

Keywords: Glucagon; Hepatocyte nuclear factor (HNF) 1α; Maturity-onset diabetes of the young (MODY); Pancreatic α-cell; Sodium-glucose cotransporter (SGLT).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Blotting, Western
  • Body Weight / genetics
  • Body Weight / physiology
  • Cell Line
  • Chromatin Immunoprecipitation
  • Fluorescent Antibody Technique
  • Glucagon / blood
  • Glucagon-Secreting Cells / metabolism*
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Knockout
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium-Glucose Transporter 1 / genetics
  • Sodium-Glucose Transporter 1 / metabolism*


  • Blood Glucose
  • Hepatocyte Nuclear Factor 1-alpha
  • RNA, Small Interfering
  • Slc5a1 protein, mouse
  • Sodium-Glucose Transporter 1
  • Glucagon