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

Animals Blood Glucose / metabolism Blotting, Western Body Weight / genetics Cell Line Chromatin Immunoprecipitation Fluorescent Antibody Technique Glucagon / blood Glucagon-Secreting Cells / metabolism Hepatocyte Nuclear Factor 1-alpha / genetics 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
Glucagon Hepatocyte nuclear factor (HNF) 1α Maturity-onset diabetes of the young (MODY) Pancreatic α-cell Sodium-glucose cotransporter (SGLT)

Journal

Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730

Informations de publication

Date de publication:
01 11 2020
Historique:
received: 17 01 2020
revised: 30 06 2020
accepted: 15 07 2020
pubmed: 28 7 2020
medline: 15 12 2020
entrez: 26 7 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.bbadis.2020.165898 PMID: 32711050 PMC: PMC8865093
pubmed: 32711050
pii: S0925-4439(20)30246-5
doi: 10.1016/j.bbadis.2020.165898
pmc: PMC8865093
mid: NIHMS1774938
pii:
doi:

Substances chimiques

Blood Glucose 0
Hepatocyte Nuclear Factor 1-alpha 0
RNA, Small Interfering 0
Slc5a1 protein, mouse 0
Sodium-Glucose Transporter 1 0
Glucagon 9007-92-5

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

165898

Subventions

Organisme : Intramural NIH HHS
ID : ZIA BC005708
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

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Auteurs

Yoshifumi Sato (Y)

Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Md Mostafizur Rahman (MM)

Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Masaki Haneda (M)

Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Tomonori Tsuyama (T)

Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Tomoya Mizumoto (T)

Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Tatsuya Yoshizawa (T)

Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Tadahiro Kitamura (T)

Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.

Frank J Gonzalez (FJ)

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Ken-Ichi Yamamura (KI)

Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.

Kazuya Yamagata (K)

Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: k-yamaga@kumamoto-u.ac.jp.

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Classifications MeSH

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