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Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion

Nature Medicine volume 21, pages 512–517 (2015)Cite this article

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Abstract

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP)1. Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney2,3,4,5, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP6,7 by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria6,7; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through KATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue.

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Figure 1: SGLT1 and SGLT2 are specifically expressed in human pancreatic alpha cells.
Figure 2: SLC5A1 and SLC5A2 gene expression is regulated in obesity and by hyperglycemia.
Figure 3: SGLT2 inhibition induces glucagon secretion in vitro from human islets.
Figure 4: Dapagliflozin treatment of healthy C57BL/6 mice increases plasma glucagon concentrations.

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Acknowledgements

We thank the Agence de la Biomedecine and Lille University core facilities for biotherapy, experimental research, and histology; R. Boutry for excellent technical assistance; and L. Schäffer (Novo Nordisk, Bagsvaerd, Denmark) for providing the S961 insulin receptor antagonist. We are grateful to J. Girard (Institut Cochin, Paris, France) and J.-C. Henquin (Université de Louvain, Brussels, Belgium) for their comments and stimulating discussions. This work was presented in part at the 2014 annual meetings of the American Diabetes Association and the European Association to Study Diabetes. This work was supported by grants from the Conseil Régional Nord-Pas-de-Calais and the European Commission (FEDER 12003944 to F.P.), the Fondation de l'Avenir (Matmut Award to F.P.), and the European Genomic Institute for Diabetes (ANR-10-LABX-46 to F.P.). The European Consortium for Islet Transplantation is funded by the Juvenile Diabetes Research Foundation International. B.S. is a member of the Institut Universitaire de France. International.

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Author notes

  1. Bart Staels and François Pattou: These authors contributed equally to this work.

Authors and Affiliations

  1. European Genomic Institute for Diabetes, Lille, France

    Caroline Bonner, Julie Kerr-Conte, Valéry Gmyr, Gurvan Queniat, Ericka Moerman, Julien Thévenet, Cédric Beaucamps, Nathalie Delalleau, Amar Abderrahmani, Bart Staels & François Pattou

  2. INSERM UMR 1190, Lille, France

    Caroline Bonner, Julie Kerr-Conte, Valéry Gmyr, Gurvan Queniat, Ericka Moerman, Julien Thévenet, Cédric Beaucamps, Nathalie Delalleau & François Pattou

  3. Centre Hospitalier Régional Universitaire, Lille, France

    Caroline Bonner, Julie Kerr-Conte, Cédric Beaucamps & François Pattou

  4. Université de Lille, Lille, France

    Julie Kerr-Conte, Valéry Gmyr, Gurvan Queniat, Ericka Moerman, Julien Thévenet, Nathalie Delalleau, Benoit Deprez, Amar Abderrahmani, Bart Staels & François Pattou

  5. Laboratory of Experimental Hormonology, Medical School, Université Libre de Bruxelles, Brussels, Belgium

    Iuliana Popescu, Willy J Malaisse & Abdullah Sener

  6. INSERM UMR 1177, Lille, France

    Benoit Deprez

  7. Institut Pasteur de Lille, Lille, France

    Benoit Deprez & Bart Staels

  8. CNRS UMR 8199, Lille, France

    Amar Abderrahmani

  9. INSERM UMR 1011, Lille, France

    Bart Staels

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Contributions

C. Bonner designed and performed experiments, analyzed the data, and wrote the manuscript. I.P., A.S. and W.J.M. conceived some experiments. V.G., G.Q., E.M., J.T., N.D., C. Beaucamps and B.D. performed specific experiments. J.K.-C. and A.A. participated in experimental design, analyzed data and wrote the manuscript. F.P. and B.S. supervised the project and wrote the manuscript.

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Correspondence to Bart Staels or François Pattou.

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Bonner, C., Kerr-Conte, J., Gmyr, V. et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 21, 512–517 (2015). https://doi.org/10.1038/nm.3828

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