title: Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion.
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). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, 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 EGP 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 glycosuria; 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.
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonner
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France. [4] Université de Lille, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Université de Lille, Lille, France.
authors.forename: Valéry
authors.initials: V
authors.lastname: Gmyr
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Université de Lille, Lille, France.
authors.forename: Gurvan
authors.initials: G
authors.lastname: Queniat
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Université de Lille, Lille, France.
authors.forename: Ericka
authors.initials: E
authors.lastname: Moerman
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Université de Lille, Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Thévenet
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Beaucamps
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Université de Lille, Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delalleau
authors.affiliation: Laboratory of Experimental Hormonology, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Popescu
authors.affiliation: Laboratory of Experimental Hormonology, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Willy J
authors.initials: WJ
authors.lastname: Malaisse
authors.affiliation: Laboratory of Experimental Hormonology, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Sener
authors.affiliation: 1] Université de Lille, Lille, France. [2] INSERM UMR 1177, Lille, France. [3] Institut Pasteur de Lille, Lille, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] Université de Lille, Lille, France. [3] CNRS UMR 8199, Lille, France.
authors.forename: Amar
authors.initials: A
authors.lastname: Abderrahmani
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] Université de Lille, Lille, France. [3] Institut Pasteur de Lille, Lille, France. [4] INSERM UMR 1011, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: 1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France. [4] Université de Lille, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry*; D001786:Blood Glucose / Q000737:chemistry; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005943:Gluconeogenesis; D005960:Glucosides / Q000737:chemistry*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D034741:RNA, Small Interfering; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; C495675:Slc5a1 protein, mouse; C490299:Slc5a2 protein, mouse; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; C529054:dapagliflozin; D005934:Glucagon