Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

Do sodium-glucose co-transporter-2 inhibitors increase plasma glucagon by direct actions on the alpha cell? And does the increase matter for the associated increase in endogenous glucose production?

Research output: Contribution to journalReviewResearchpeer-review

DOI

  1. Plasma GDF15 levels are similar between subjects after bariatric surgery and matched controls and are unaffected by meals

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Neprilysin inhibition increases glucagon levels in humans and mice with potential effects on amino acid metabolism

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Factors associated with favorable changes in food preferences after bariatric surgery

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. On premises and principles for measurement of gastrointestinal peptide hormones

    Research output: Contribution to journalReviewResearchpeer-review

View graph of relations

Sodium-glucose co-transporter-2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha-cell sodium-glucose co-transporter-1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.

Original languageEnglish
JournalDiabetes, Obesity and Metabolism
Volume23
Issue number9
Pages (from-to)2009-2019
Number of pages11
ISSN1462-8902
DOIs
Publication statusPublished - Sep 2021

    Research areas

  • Benzhydryl Compounds, Blood Glucose, Diabetes Mellitus, Type 2/drug therapy, Glucagon, Glucose, Glucosides, Humans, Pharmaceutical Preparations, Sodium, Sodium-Glucose Transporter 2 Inhibitors/therapeutic use, alpha-cell glucose transporters, renal glucose reabsorption, glucose-regulated glucagon secretion, sodium-glucose co-transporter-2 inhibitors, alpha-cell glucose metabolism, hepatic glucose output

ID: 67244540