A Variation on the Theme: SGLT2 Inhibition and Glucagon Secretion in Human Islets.

Abstract

Sodium-glucose cotransporter 2 (SGLT2), encoded by SLC5A2 , is primarily responsible for glucose resorption from the proximal tubule of the kidney. Selective inhibitors of SGLT2 (or SGLT2i), such as the gliflozins, are widely used for the treatment of type 2 diabetes (T2D), since they decrease blood glucose levels by increasing excretion of the sugar in the urine (1). These glucose-lowering effects might however be partially offset by the action of SGLT2i to increase circulating glucagon levels (2). Whether SGLT2i influence glucagon secretion via direct (3) or indirect/paracrine (4,5) mechanisms remains keenly debated. A number of studies have shown contrasting effects of SGLT2i on pancreatic α-cells, with increases (3,6–9), decreases (10), or no change (5,10) in glucagon secretion depending on the species, preparation, glucose concentration, and gliflozin used. Moreover, discordant results have been reported by different investigators regarding expression of SGLT2 and Slc5a1 / SLC5A1 in mouse, rat, and human islets, as well as sorted cell populations (3,5,8,10). In this issue of Diabetes , Saponaro et al. (11) shed further light on the complex issue of SGLT2i and glucagon secretion. Using a large number of donors, the authors show that responses of isolated human islets to SGLT2i are highly heterogeneous, with large variation in basal and secreted glucagon levels as well as responsiveness to treatment. This apparent heterogeneity was also reflected at the level of SGLT2/ SLC5A2 expression, shown using Western blotting with antibodies validated according to established guidelines, or interrogation of bulk islet data from 207 donors deposited in the Translational Human Pancreatic Islet Genotype Tissue-Expression Resource (TIGER) RNA-seq database. While SGLT2 was …