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?

Abstract

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.

Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages

“…In this study, we observed no changes in plasma glucagon levels with liraglutide and/or ipragliflozin treatments in either the DIO or the db/db mice, although glucagon levels in the db/db mice in the Combo group tended to increase. The effect of SGLT2is on glucagon secretion is a matter of debate [ 15 ]. Earlier studies [ 16 , 17 ], including ours [ 18 ] demonstrated that SGLT2is increase plasma glucagon levels.…”

SGLT2 inhibitors and AMPK: The road to cellular housekeeping?

“…These metabolic changes collectively promote ketogenesis. 94 Some studies have suggested that SGLT2 inhibitors may have a direct stimulatory effect on alpha cells. However, this finding is controversial and has not been consistently replicated in all studies.…”

“…The lower plasma glucose level stimulates the secretion of glucagon and suppresses insulin production, resulting in an elevated glucagon‐to‐insulin ratio. These metabolic changes collectively promote ketogenesis 94 …”