Inter-Individual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets

Studies implicating sodium-glucose-cotransporter-2 (SGLT2) inhibitors in glucagon secretion by pancreatic alpha cells reported controversial results. We hypothesized that inter-individual heterogeneity in SGLT2 expression and regulation may impact on glucagon secretion by human alpha cells in response to SGLT2 inhibitors. An unbiased RNA-seq analysis of 207 donors revealed an unprecedented level of heterogeneity of SLC5A2 expression. To determine heterogeneity of SGLT2 expression at the protein level, the anti-SGLT2 antibody was first rigorously evaluated for specificity, followed by Western blot and immunofluorescence analysis on islets from 10-12 donors. The results revealed a high inter-donor variability of SGLT2 protein expression. Quantitative analysis of 665 human islets reaffirmed SGLT2 protein co-localization with glucagon-positive cells, but not with insulin or somatostatin. Moreover, glucagon secretion by islets from 31 donors at low-glucose (1 mM) was also heterogeneous, and correlated with dapagliflozin-induced glucagon secretion at 6 mM glucose. Intriguingly, islets from 3 donors did not secrete glucagon in response to either 1 mM glucose or dapagliflozin, indicating a functional impairment of the islets of these donors to glucose-sensing and SGLT2 inhibition. Collectively, these data indicate that heterogeneous expression of SGLT2 protein and corresponding variability in glucagon secretory responses contribute to inter-individual differences in response to SGLT2 inhibitors.