SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans.

Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria. However, they stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. Here, we aimed to verify whether or not SGLT2i affect glucagon and insulin secretion by direct action on islet cells in three species using multiple approaches. Methods and results SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a drop in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but a moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and with the in situ perfused mouse pancreas did not reveal any direct effect of selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets. Conclusions These data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells.