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.