A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin

Abstract

Aim: To investigate whether changes in endogenous glucose production (EGP) and insulin and glucagon levels are elicited by the decrease in plasma glucose (PG) levels induced by the sodium-glucose co-transporter-2 (SGLT2) inhibitor tofogliflozin. Materials and Methods:We evaluated EGP in 12 Japanese patients with type 2 diabetes under the conditions of no drugs administered (CON), single administration of the SGLT2 inhibitor tofogliflozin (TOF), and single administration of TOF with adjustment of PG levels with exogenous glucose infusion to mimic changes in PG levels observed with CON (TOF + G). We evaluated changes in EGP and levels of C-peptide and glucagon from baseline to 180 minutes after drug administration.Results: Endogenous glucose production decreased in the CON (−0.22 ± 0.11 mg/ kgÁmin) and TOF + G experiments (−0.31 ± 0.24 mg/kgÁmin), but not in the TOF experiment (+0.

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

“…To assess the effect of tofogliflozin on EGP at 180 min after a single-dose administration of tofogliflozin, EGP and other related parameters during −180 to 180 min of the baseline and acute effect studies were evaluated; results have been reported elsewhere [ 38 ]. Some of the previous data are presented again in the present study to show the participants’ metabolic status before the hyperinsulinemic euglycemic clamp study.…”

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?

“…The strongest support for this argument comes from the observation that the stimulatory effect on glucagon secretion is absent when blood glucose concentrations are kept constant by clamping. 21,35,80,81 This is the case both in mice and in humans, and speaks against a proposed direct effect of SGLT2is on the alpha cell, because a direct effect would be expected to increase glucagon secretion independently of fasting glucose levels. Further analysis, using larger sample cohorts from both SLGT2i-naïve individuals and from individuals who have been treated chronically with SGLT2is, are needed to determine whether, to what extent and under what circumstances, alpha cells express SLC5A2 at levels that may translate into effects on alpha-cell function.…”

“…Although current evidence does not allow us to provide definitive answers, we argue that the underlying mechanism(s) involved are more probable to result from events secondary to SGLT2i‐induced increased glucosuria and/or the resultant blood glucose lowering rather than from direct inhibition of alpha‐cell SGLT2 activity. The strongest support for this argument comes from the observation that the stimulatory effect on glucagon secretion is absent when blood glucose concentrations are kept constant by clamping 21,35,80,81 . This is the case both in mice and in humans, and speaks against a proposed direct effect of SGLT2is on the alpha cell, because a direct effect would be expected to increase glucagon secretion independently of fasting glucose levels.…”

“…The most compelling support for this hypothesis comes from clamp studies, which have been carried out in mice and rats, as well as in humans. Here, plasma glucagon concentrations increased when blood glucose was allowed to decrease as a consequence of SGLT2i administration, whereas there was no acute effect on plasma glucagon levels in rats or humans when the fall in glucose was prevented under clamped isoglycaemic conditions 21,35,80,81 . However, as these were acute studies on drug‐naïve individuals, it remains to be investigated whether clamping of blood glucose also prevents an increase in plasma glucagon after prolonged SGLT2i therapy.…”

“…Here, plasma glucagon concentrations increased when blood glucose was allowed to decrease as a consequence of SGLT2i administration, whereas there was no acute effect on plasma glucagon levels in rats or humans when the fall in glucose was prevented under clamped isoglycaemic conditions. 21,35,80,81 However, as these were acute studies on drugnaïve individuals, it remains to be investigated whether clamping of blood glucose also prevents an increase in plasma glucagon after prolonged SGLT2i therapy. Furthermore, the physiological relevance of clamping can be debated, as it disrupts the normal connection between blood glucose and endocrine signalling.…”