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Diabetes. 2020 Jan 2. pii: db190888. doi: 10.2337/db19-0888. [Epub ahead of print]

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

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INSERM, U1190, 59000 Lille, France.
University of Lille, 59000 Lille, France.
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
European Genomic Institute for Diabetes (EGID), 59000 Lille, France.
INSERM, U1011, 59000 Lille, France.
Institut Pasteur de Lille, 59000 Lille, France.
CHU Lille, Chirurgie Endocrinienne et Métabolique, 59000 Lille, France.
INSERM, U1190, 59000 Lille, France


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.


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