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No direct effect of SGLT2 activity on glucagon secretion.
Kuhre, Rune E; Ghiasi, Seyed M; Adriaenssens, Alice E; Wewer Albrechtsen, Nicolai J; Andersen, Daniel B; Aivazidis, Alexander; Chen, Lihua; Mandrup-Poulsen, Thomas; Ørskov, Cathrine; Gribble, Fiona M; Reimann, Frank; Wierup, Nils; Tyrberg, Björn; Holst, Jens J.
Afiliación
  • Kuhre RE; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
  • Ghiasi SM; Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Adriaenssens AE; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
  • Wewer Albrechtsen NJ; Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
  • Andersen DB; Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
  • Aivazidis A; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
  • Chen L; Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Mandrup-Poulsen T; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
  • Ørskov C; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
  • Gribble FM; Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Reimann F; Translational Science, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
  • Wierup N; Translational Science, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
  • Tyrberg B; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
  • Holst JJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
Diabetologia ; 62(6): 1011-1023, 2019 06.
Article en En | MEDLINE | ID: mdl-30903205
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Páncreas / Islotes Pancreáticos / Transportador 2 de Sodio-Glucosa Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Diabetologia Año: 2019 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Páncreas / Islotes Pancreáticos / Transportador 2 de Sodio-Glucosa Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Diabetologia Año: 2019 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Alemania