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Nils Wierup

Nils Wierup

Senior lecturer

Nils Wierup

No direct effect of SGLT2 activity on glucagon secretion

Author

  • Rune E. Kuhre
  • Seyed M. Ghiasi
  • Alice E. Adriaenssens
  • Nicolai J. Wewer Albrechtsen
  • Daniel B. Andersen
  • Alexander Aivazidis
  • Lihua Chen
  • Thomas Mandrup-Poulsen
  • Cathrine Ørskov
  • Fiona M. Gribble
  • Frank Reimann
  • Nils Wierup
  • Björn Tyrberg
  • Jens J. Holst

Summary, in English

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.

Department/s

  • Neuroendocrine Cell Biology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2019

Language

English

Pages

1011-1023

Publication/Series

Diabetologia

Volume

62

Issue

6

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes
  • Cell and Molecular Biology

Keywords

  • Alpha cells
  • Endogenous glucose production
  • Glucagon secretion
  • SGLT2
  • Sodium–glucose cotransporter 2 inhibitors
  • Sodium–glucose cotransporter-2
  • Type 2 diabetes

Status

Published

Research group

  • Neuroendocrine Cell Biology

ISBN/ISSN/Other

  • ISSN: 0012-186X