No direct effect of SGLT2 activity on glucagon secretion

Rune E Kuhre; Seyed M Ghiasi; Alice E. Adriaenssens; Nicolai Jacob 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

doi:10.1007/s00125-019-4849-6

No direct effect of SGLT2 activity on glucagon secretion

Rune E Kuhre, Seyed M Ghiasi, Alice E. Adriaenssens, Nicolai Jacob 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

40 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	62
Udgave nummer	6
Sider (fra-til)	1011-1023
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-019-4849-6
Status	Udgivet - 1 jun. 2019

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10.1007/s00125-019-4849-6

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title = "No direct effect of SGLT2 activity on glucagon secretion",

abstract = "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.",

author = "Kuhre, {Rune E} and Ghiasi, {Seyed M} and Adriaenssens, {Alice E.} and Albrechtsen, {Nicolai Jacob Wewer} and Andersen, {Daniel B.} and Alexander Aivazidis and Lihua Chen and Thomas Mandrup-Poulsen and Cathrine {\O}rskov and Gribble, {Fiona M.} and Frank Reimann and Nils Wierup and Bj{\"o}rn Tyrberg and Holst, {Jens J}",

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doi = "10.1007/s00125-019-4849-6",

language = "English",

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journal = "Diabetologia",

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T1 - No direct effect of SGLT2 activity on glucagon secretion

AU - Kuhre, Rune E

AU - Ghiasi, Seyed M

AU - Adriaenssens, Alice E.

AU - Albrechtsen, Nicolai Jacob Wewer

AU - Andersen, Daniel B.

AU - Aivazidis, Alexander

AU - Chen, Lihua

AU - Mandrup-Poulsen, Thomas

AU - Ørskov, Cathrine

AU - Gribble, Fiona M.

AU - Reimann, Frank

AU - Wierup, Nils

AU - Tyrberg, Björn

AU - Holst, Jens J

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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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DO - 10.1007/s00125-019-4849-6

M3 - Journal article

C2 - 30903205

SN - 0012-186X

VL - 62

SP - 1011

EP - 1023

JO - Diabetologia

JF - Diabetologia

IS - 6

ER -

No direct effect of SGLT2 activity on glucagon secretion

Abstract

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