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

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2020-11, Vol.1866 (11), p.165898-165898, Article 165898
• Main Authors: Sato, Yoshifumi, Rahman, Md Mostafizur, Haneda, Masaki, Tsuyama, Tomonori, Mizumoto, Tomoya, Yoshizawa, Tatsuya, Kitamura, Tadahiro, Gonzalez, Frank J., Yamamura, Ken-ichi, Yamagata, Kazuya
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - metabolism; Blotting, Western; Body Weight - genetics; Body Weight - physiology; Cell Line; Chromatin Immunoprecipitation; Fluorescent Antibody Technique; Glucagon; Glucagon - blood; Glucagon-Secreting Cells - metabolism; Hepatocyte nuclear factor (HNF) 1α; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Islets of Langerhans - metabolism; Maturity-onset diabetes of the young (MODY); Mice; Mice, Knockout; Pancreatic α-cell; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; Sodium-glucose cotransporter (SGLT); Sodium-Glucose Transporter 1 - genetics; Sodium-Glucose Transporter 1 - metabolism
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2020.165898

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. •HNF1α is expressed in pancreatic α-cells, but its role in these cells is unknown.•We demonstrate that glucagon secretion at low glucose is impaired in Hnf1a−/− islets.•HNF1α activates transcription of Slc5a1 (encoding SGLT1) in α-cells.•SGLT1 inhibition suppresses glucagon secretion at low glucose conditions.•HNF1α controls glucagon secretion in α-cells through regulation of SGLT1 expression.