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

• Published in: Nature medicine Vol. 21; no. 5; pp. 512 - 517
• Main Authors: Bonner, Caroline, Kerr-Conte, Julie, Gmyr, Valéry, Queniat, Gurvan, Moerman, Ericka, Thévenet, Julien, Beaucamps, Cédric, Delalleau, Nathalie, Popescu, Iuliana, Malaisse, Willy J, Sener, Abdullah, Deprez, Benoit, Abderrahmani, Amar, Staels, Bart, Pattou, François
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Nature Publishing Group
• Subjects: 14; 14/19; 38/1; 38/109; 38/39; 38/89; 692/699/2743/137/773; 82; Administration, Oral; Adult; Animals; Benzhydryl Compounds - chemistry; Biomedicine; Blood Glucose - chemistry; Cancer Research; Carrier proteins; Cell Separation; Dapagliflozin; Dosage and administration; Drug therapy; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Gene Silencing; Glucagon; Glucagon - blood; Glucagon - metabolism; Glucagon-Secreting Cells - metabolism; Gluconeogenesis; Glucose; Glucosides - chemistry; Health aspects; Hepatocyte Nuclear Factor 4 - metabolism; Humans; Infectious Diseases; Insulin Resistance; letter; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Molecular Medicine; Neurosciences; Pancreas; RNA, Small Interfering - metabolism; Sodium-Glucose Transporter 1 - metabolism; Sodium-Glucose Transporter 2 - metabolism; Type 2 diabetes
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3828

The recently approved drug dapagliflozin is now shown to increase glucagon secretion by acting on pancreatic alpha cells, which has implications for the potency of its antidiabetic effects 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 kidney 2 , 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 EGP 6 , 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 glycosuria 6 , 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 K ATP 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.