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No direct effect of...
No direct effect of SGLT2 activity on glucagon secretion
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- Kuhre, Rune E. (författare)
- University of Copenhagen
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- Ghiasi, Seyed M. (författare)
- University of Copenhagen
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- Adriaenssens, Alice E. (författare)
- University of Cambridge
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- Wewer Albrechtsen, Nicolai J. (författare)
- Copenhagen University Hospital,University of Copenhagen
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- Andersen, Daniel B. (författare)
- University of Copenhagen
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- Aivazidis, Alexander (författare)
- AstraZeneca, Sweden
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- Chen, Lihua (författare)
- AstraZeneca, Sweden
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- Mandrup-Poulsen, Thomas (författare)
- University of Copenhagen
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- Ørskov, Cathrine (författare)
- University of Copenhagen
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- Gribble, Fiona M. (författare)
- University of Cambridge
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- Reimann, Frank (författare)
- University of Cambridge
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- Wierup, Nils (författare)
- Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups
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- Tyrberg, Björn (författare)
- AstraZeneca, Sweden
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- Holst, Jens J. (författare)
- University of Copenhagen
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(creator_code:org_t)
- 2019-03-22
- 2019
- Engelska.
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 62:6, s. 1011-1023
- Relaterad länk:
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http://dx.doi.org/10...
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https://link.springe...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- Alpha cells
- Endogenous glucose production
- Glucagon secretion
- SGLT2
- Sodium–glucose cotransporter 2 inhibitors
- Sodium–glucose cotransporter-2
- Type 2 diabetes
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Kuhre, Rune E.
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Ghiasi, Seyed M.
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Adriaenssens, Al ...
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Wewer Albrechtse ...
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Andersen, Daniel ...
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Aivazidis, Alexa ...
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visa fler...
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Chen, Lihua
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Mandrup-Poulsen, ...
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Ørskov, Cathrine
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Gribble, Fiona M ...
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Reimann, Frank
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Wierup, Nils
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Tyrberg, Björn
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Holst, Jens J.
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Cell och molekyl ...
- Artiklar i publikationen
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Diabetologia
- Av lärosätet
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Lunds universitet