No direct effect of SGLT2 activity on glucagon secretion.
Alpha cells
Endogenous glucose production
Glucagon secretion
SGLT2
Sodium–glucose cotransporter 2 inhibitors
Sodium–glucose cotransporter-2
Type 2 diabetes
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
17
11
2018
accepted:
12
02
2019
pubmed:
25
3
2019
medline:
14
1
2020
entrez:
24
3
2019
Statut:
ppublish
Résumé
Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets. Glucagon output decreased three- to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells. Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucose-lowering effects.
Identifiants
pubmed: 30903205
doi: 10.1007/s00125-019-4849-6
pii: 10.1007/s00125-019-4849-6
pmc: PMC7212061
mid: EMS86318
doi:
Substances chimiques
Insulin
0
Sodium-Glucose Transporter 1
0
Sodium-Glucose Transporter 2
0
Somatostatin
51110-01-1
Glucagon
9007-92-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1011-1023Subventions
Organisme : Wellcome Trust
ID : 106262
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106263/Z/14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106262/Z/14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106263
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
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MRC_MC_UU_12012/3
Pays : United Kingdom
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