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

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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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References

  1. Kahn, S.E., Cooper, M.E. & Del Prato, S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383, 1068–1083 (2014).

    Article  CAS  Google Scholar 

  2. Demaris, K.M. & White, J.R. Dapagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes. Drugs Today (Barc) 49, 289–301 (2013).

    Article  CAS  Google Scholar 

  3. Jabbour, S.A. & Goldstein, B.J. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int. J. Clin. Pract. 62, 1279–1284 (2008).

    Article  CAS  Google Scholar 

  4. Komoroski, B. et al. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 85, 513–519 (2009).

    Article  CAS  Google Scholar 

  5. Nair, S. & Wilding, J.P. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J. Clin. Endocrinol. Metab. 95, 34–42 (2010).

    Article  CAS  Google Scholar 

  6. Merovci, A. et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 124, 509–514 (2014).

    Article  CAS  Google Scholar 

  7. Ferrannini, E. et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124, 499–508 (2014).

    Article  CAS  Google Scholar 

  8. Biddinger, S.B. & Kahn, C.R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006).

    Article  CAS  Google Scholar 

  9. DeFronzo, R.A., Simonson, D. & Ferrannini, E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 23, 313–319 (1982).

    Article  CAS  Google Scholar 

  10. Campbell, P.J., Mandarino, L.J. & Gerich, J.E. Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. Metabolism 37, 15–21 (1988).

    Article  CAS  Google Scholar 

  11. Consoli, A. Role of liver in pathophysiology of NIDDM. Diabetes Care 15, 430–441 (1992).

    Article  CAS  Google Scholar 

  12. Dinneen, S., Alzaid, A., Turk, D. & Rizza, R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia 38, 337–343 (1995).

    Article  CAS  Google Scholar 

  13. Baron, A.D., Schaeffer, L., Shragg, P. & Kolterman, O.G. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36, 274–283 (1987).

    Article  CAS  Google Scholar 

  14. Unger, R.H., Aguilar-Parada, E., Muller, W.A. & Eisentraut, A.M. Studies of pancreatic alpha cell function in normal and diabetic subjects. J. Clin. Invest. 49, 837–848 (1970).

    Article  CAS  Google Scholar 

  15. Alford, F.P. et al. Glucagon control of fasting glucose in man. Lancet 2, 974–977 (1974).

    Article  CAS  Google Scholar 

  16. Gargani, S. et al. Adaptive changes of human islets to an obesogenic environment in the mouse. Diabetologia 56, 350–358 (2013).

    Article  CAS  Google Scholar 

  17. Yi, P., Park, J.S. & Melton, D.A. Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell 153, 747–758 (2013).

    Article  CAS  Google Scholar 

  18. Stoffel, M. & Duncan, S.A. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc. Natl. Acad. Sci. USA 94, 13209–13214 (1997).

    Article  CAS  Google Scholar 

  19. Rhee, J. et al. Regulation of hepatic fasting response by PPARgamma coactivator-1α (PGC-1): requirement for hepatocyte nuclear factor 4α in gluconeogenesis. Proc. Natl. Acad. Sci. USA 100, 4012–4017 (2003).

    Article  CAS  Google Scholar 

  20. Love-Gregory, L.D. et al. A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4α gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an Ashkenazi Jewish population. Diabetes 53, 1134–1140 (2004).

    Article  CAS  Google Scholar 

  21. Weedon, M.N. et al. Common variants of the hepatocyte nuclear factor-4α P2 promoter are associated with type 2 diabetes in the U.K. population. Diabetes 53, 3002–3006 (2004).

    Article  CAS  Google Scholar 

  22. Han, S. et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57, 1723–1729 (2008).

    Article  CAS  Google Scholar 

  23. Leibiger, B. et al. Glucagon regulates its own synthesis by autocrine signaling. Proc. Natl. Acad. Sci. USA 109, 20925–20930 (2012).

    Article  CAS  Google Scholar 

  24. Gylfe, E. & Gilon, P. Glucose regulation of glucagon secretion. Diabetes Res. Clin. Pract. 103, 1–10 (2014).

    Article  CAS  Google Scholar 

  25. Zhang, Q. et al. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 18, 871–882 (2013).

    Article  CAS  Google Scholar 

  26. Mueckler, M. & Thorens, B. The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med. 34, 121–138 (2013).

    Article  CAS  Google Scholar 

  27. Fujimori, Y. et al. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J. Pharmacol. Exp. Ther. 327, 268–276 (2008).

    Article  CAS  Google Scholar 

  28. Jurczak, M.J. et al. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes 60, 890–898 (2011).

    Article  CAS  Google Scholar 

  29. Kojima, N., Williams, J.M., Takahashi, T., Miyata, N. & Roman, R.J. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J. Pharmacol. Exp. Ther. 345, 464–472 (2013).

    Article  CAS  Google Scholar 

  30. Powell, D.R. et al. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am. J. Physiol. Endocrinol. Metab. 304, E117–E130 (2013).

    Article  CAS  Google Scholar 

  31. Tahara, A. et al. Antidiabetic effects of SGLT2-selective inhibitor ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice. J. Pharmacol. Sci. 120, 36–44 (2012).

    Article  CAS  Google Scholar 

  32. Suzuki, M. et al. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J. Pharmacol. Exp. Ther. 341, 692–701 (2012).

    Article  CAS  Google Scholar 

  33. Liang, Y. et al. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS ONE 7, e30555 (2012).

    Article  CAS  Google Scholar 

  34. Luippold, G., Klein, T., Mark, M. & Grempler, R. Empagliflozin, a novel potent and selective SGLT-2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin-induced diabetic rats, a model of type 1 diabetes mellitus. Diabetes Obes. Metab. 14, 601–607 (2012).

    Article  CAS  Google Scholar 

  35. Yamaguchi, K. et al. In vitro-in vivo correlation of the inhibition potency of sodium-glucose cotransporter inhibitors in rat: a pharmacokinetic and pharmacodynamic modeling approach. J. Pharmacol. Exp. Ther. 345, 52–61 (2013).

    Article  CAS  Google Scholar 

  36. Devenny, J.J. et al. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring) 20, 1645–1652 (2012).

    Article  CAS  Google Scholar 

  37. Nagata, T. et al. Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats. Am. J. Physiol. Endocrinol. Metab. 304, E414–E423 (2013).

    Article  CAS  Google Scholar 

  38. Cryer, P.E., Davis, S.N. & Shamoon, H. Hypoglycemia in diabetes. Diabetes Care 26, 1902–1912 (2003).

    Article  CAS  Google Scholar 

  39. DeFronzo, R.A., Ferrannini, E. & Simonson, D.C. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38, 387–395 (1989).

    Article  CAS  Google Scholar 

  40. Jurysta, C. et al. Glucose transport by acinar cells in rat parotid glands. Cell. Physiol. Biochem. 29, 325–330 (2012).

    Article  CAS  Google Scholar 

  41. Magen, D., Sprecher, E., Zelikovic, I. & Skorecki, K. A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney Int. 67, 34–41 (2005).

    Article  CAS  Google Scholar 

  42. Kerr-Conte, J. et al. Upgrading pretransplant human islet culture technology requires human serum combined with media renewal. Transplantation 89, 1154–1160 (2010).

    Article  Google Scholar 

  43. Dorrell, C. et al. Transcriptomes of the major human pancreatic cell types. Diabetologia 54, 2832–2844 (2011).

    Article  CAS  Google Scholar 

  44. Lukowiak, B. et al. Identification and purification of functional human beta-cells by a new specific zinc-fluorescent probe. J. Histochem. Cytochem. 49, 519–528 (2001).

    Article  CAS  Google Scholar 

  45. Schulthess, F.T. et al. CXCL10 impairs beta cell function and viability in diabetes through TLR4 signaling. Cell Metab. 9, 125–139 (2009).

    Article  CAS  Google Scholar 

  46. Lefebvre, B. et al. Efficient gene delivery and silencing of mouse and human pancreatic islets. BMC Biotechnol. 10, 28 (2010).

    Article  Google Scholar 

  47. Obermeier, M. et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab. Dispos. 38, 405–414 (2010).

    Article  CAS  Google Scholar 

  48. Cheng-Xue, R. et al. Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from both alpha-cells and delta-cells. Diabetes 62, 1612–1622 (2013).

    Article  Google Scholar 

  49. Abderrahmani, A. et al. Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells. Diabetologia 50, 1304–1314 (2007).

    Article  CAS  Google Scholar 

  50. de Jonge, H.J. et al. Evidence based selection of housekeeping genes. PLoS ONE 2, e898 (2007).

    Article  Google Scholar 

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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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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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