SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels.
Animals
Benzhydryl Compounds
/ pharmacology
Blood Glucose
/ metabolism
Canagliflozin
/ pharmacology
Diabetes Mellitus
/ metabolism
Diet, High-Fat
Disease Models, Animal
Gastric Inhibitory Polypeptide
/ metabolism
Glucagon
/ blood
Glucagon-Like Peptide 1
/ metabolism
Glucagon-Secreting Cells
/ metabolism
Glucose
/ metabolism
Glucosides
/ pharmacology
Glycosuria
/ metabolism
Hypoglycemic Agents
/ pharmacology
Insulin
/ metabolism
Male
Mice
Mice, Inbred C57BL
Sodium-Glucose Transporter 1
/ metabolism
Sodium-Glucose Transporter 2
/ metabolism
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Alpha cell
Diabetes
Phloretin
SGLT
Sodium glucose cotransporter
Sotagliflozin
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
20
09
2018
revised:
19
10
2018
accepted:
23
10
2018
pubmed:
13
11
2018
medline:
7
1
2020
entrez:
13
11
2018
Statut:
ppublish
Résumé
It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic α cells. The role of SGLT1 in α cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight. Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin. RT-PCR, RNA sequence, and immunohistochemistry were conducted to test the expression of SGLT1 and SGLT2 in α cells. We also used αTC1 cells and mouse islets to investigate the molecular mechanism by which SGLT1 modulates glucagon secretion. Dapagliflozin, but not canagliflozin, increased plasma glucagon levels in HFHSD fed mice. SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells, mouse islets and human islets. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. Canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. SGLT1 effect on glucagon secretion depended on glucose transport, but not glucose metabolism. Islets from HFHSD and db/db mice displayed higher SGLT1 mRNA levels and lower GLUT1 mRNA levels than the islets from control mice. These expression levels were associated with higher glucagon secretion. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets. These data suggested that a novel mechanism regulated glucagon secretion through SGLT1 in α cells. This finding possibly explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.
Identifiants
pubmed: 30416006
pii: S2212-8778(18)30937-2
doi: 10.1016/j.molmet.2018.10.009
pmc: PMC6323192
pii:
doi:
Substances chimiques
Benzhydryl Compounds
0
Blood Glucose
0
Glucosides
0
Hypoglycemic Agents
0
Insulin
0
Slc5a1 protein, mouse
0
Slc5a2 protein, mouse
0
Sodium-Glucose Transporter 1
0
Sodium-Glucose Transporter 2
0
Sodium-Glucose Transporter 2 Inhibitors
0
Canagliflozin
0SAC974Z85
dapagliflozin
1ULL0QJ8UC
Gastric Inhibitory Polypeptide
59392-49-3
Glucagon-Like Peptide 1
89750-14-1
Glucagon
9007-92-5
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-12Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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