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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.

Author information

1
INSERM, U1190, 59000 Lille, France.
2
University of Lille, 59000 Lille, France.
3
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
4
Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
5
European Genomic Institute for Diabetes (EGID), 59000 Lille, France.
6
INSERM, U1011, 59000 Lille, France.
7
Institut Pasteur de Lille, 59000 Lille, France.
8
CHU Lille, Chirurgie Endocrinienne et Métabolique, 59000 Lille, France.
9
INSERM, U1190, 59000 Lille, France caroline.bonner@univ-lille.fr.

Abstract

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.

PMID:
31896553
DOI:
10.2337/db19-0888

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