SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans.
Animals
Benzhydryl Compounds
/ pharmacology
Blood Glucose
/ metabolism
Glucagon
/ drug effects
Glucagon-Like Peptide 1
/ metabolism
Glucagon-Secreting Cells
/ metabolism
Glucose
/ metabolism
Glucosides
/ pharmacology
Humans
Insulin
/ metabolism
Insulin Secretion
/ drug effects
Insulin-Secreting Cells
/ metabolism
Islets of Langerhans
/ metabolism
Mice
Pancreas
/ metabolism
Rats
Sodium-Glucose Transporter 2
/ metabolism
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Diabetes
Gliflozins
Glucagon
Insulin
SGLT2 inhibitor
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
30
07
2020
revised:
13
08
2020
accepted:
25
08
2020
pubmed:
9
9
2020
medline:
8
9
2021
entrez:
8
9
2020
Statut:
ppublish
Résumé
Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria, but they also stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. This study verified whether or not SGLT2i affect glucagon and insulin secretion by a direct action on islet cells in three species, using multiple approaches. We tested the in vivo effects of two selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on various biological parameters (glucosuria, glycemia, glucagonemia, insulinemia) in mice. mRNA expression of SGLT2 and other glucose transporters was assessed in rat, mouse, and human FACS-purified α- and β-cells, and by analysis of two human islet cell transcriptomic datasets. Immunodetection of SGLT2 in pancreatic tissues was performed with a validated antibody. The effects of dapagliflozin, empagliflozin, and sotagliflozin on glucagon and insulin secretion were assessed using isolated rat, mouse and human islets and the in situ perfused mouse pancreas. Finally, we tested the long-term effect of SGLT2i on glucagon gene expression. SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a decline in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and the in situ perfused mouse pancreas did not identify any direct effect of dapagliflozin, empagliflozin or sotagliflozin on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets. The data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells.
Identifiants
pubmed: 32896668
pii: S2212-8778(20)30145-9
doi: 10.1016/j.molmet.2020.101071
pmc: PMC7554656
pii:
doi:
Substances chimiques
Benzhydryl Compounds
0
Blood Glucose
0
Glucosides
0
Insulin
0
SLC5A2 protein, human
0
Slc5a2 protein, mouse
0
Slc5a2 protein, rat
0
Sodium-Glucose Transporter 2
0
Sodium-Glucose Transporter 2 Inhibitors
0
dapagliflozin
1ULL0QJ8UC
Glucagon-Like Peptide 1
89750-14-1
Glucagon
9007-92-5
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101071Subventions
Organisme : NIDDK NIH HHS
ID : UC4 DK098085
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK098085
Pays : United States
Organisme : Wellcome Trust
ID : 106263/Z/14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106262/Z/14/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/3
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/3
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.
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