Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

No direct effect of SGLT2 activity on glucagon secretion

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. White coat hypertension in early pregnancy in women with pre-existing diabetes: prevalence and pregnancy outcomes

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Effects of dapagliflozin, metformin or exercise on glucose metabolism and glycaemic variability in individuals with prediabetes: The PRE-D trial

    Publikation: Bidrag til tidsskriftKonferenceabstrakt i tidsskriftForskningpeer review

  1. Effect of the incretin hormones on the endocrine pancreas in end-stage renal disease

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Investigating Intestinal Glucagon after Roux-en-Y Gastric Bypass Surgery

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Methods and guidelines for measurement of glucagon in plasma

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

  4. The Liver-α-Cell Axis and Type 2 Diabetes

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

  • 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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind62
Udgave nummer6
Sider (fra-til)1011-1023
Antal sider13
ISSN0012-186X
DOI
StatusUdgivet - jun. 2019

ID: 58217736