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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Sato, Yoshifumi¹  Rahman, Md Mostafizur¹  Haneda, Masaki¹  Tsuyama, Tomonori⁵  Mizumoto, Tomoya¹  Yoshizawa, Tatsuya¹  Kitamura, Tadahiro²  Gonzalez, Frank J.³  Yamamura, Ken-ichi⁴  Yamagata, Kazuya^1,5 

[1] Kumamoto Univ, Fac Life Sci, Dept Med Biochem, Kumamoto 8608556, Japan

[2] Gunma Univ, Metab Signal Res Ctr, Inst Mol & Cellular Regulat, Maebashi, Gunma, Japan

[3] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[4] Kumamoto Univ, Inst Resource Dev & Anal, Chuo Ku, 2-2-1 Honjo, Kumamoto 8600811, Japan

[5] Kumamoto Univ, Fac Life Sci, Ctr Metab Regulat Hlth Aging CMHA, Kumamoto 8608556, Japan

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

DOI  :  10.1016/j.bbadis.2020.165898

来源: Elsevier

【 摘 要 】

Hepatocyte nuclear factor 1 alpha (HNF1 alpha) is a transcription factor required for normal insulin secretion and maintenance of beta-cell number in the pancreas. HNF1 alpha 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 HNF1 alpha 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 HNF1 alpha 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 HNF1 alpha activated the Slc5a1 promoter in alpha TC1-6 cells. Inhibition of SGLT1 suppressed 1.1 mM glucose-stimulated glucagon secretion in islets and alpha TC1-6 cells, but SGLT1 inhibition had no additional inhibitory effect in HNF1 alpha-deficient cells. Our findings indicate that HNF1 alpha modulates glucagon secretion in alpha-cells through the regulation of Slc5a1.

【 授权许可】

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