1740-P: The Effects of SGLT2 Inhibitor Canagliflozin on Glucagon Secretion in SUR1 Knockout Mice

Studies have showed that some of SGLT2 inhibitors increased the release of glucagon. But the selective SGLT2 inhibitors, such as canagliflozin, don't directly stimulate glucagon secretion due to its low SGLT1 potency. Congenital hyperinsulinism due to KATP channels loss-of-function mutations have suppressed glucagon secretion. We therefore applied canagliflozin to SUR1 knockout (SUR1-/- mice to investigate if SGLT2i could affect glucagon secretion when both β- and α-cells are constantly depolarized. Single dose of canagliflozin (30 mg/Kg) were orally administered to wildtype mice (WT) and SUR1-/- mice, then followed by an oral glucose challenge. Glucose, insulin, and glucagon were measured. Glucagon secretion was also studied in isolated islets. Compared to vehicle controls, canagliflozin significantly lowered glucose levels and improved glucose tolerance in WT mice without altering insulin and glucagon secretion. Ratios of insulin and glucagon to glucose were unchanged after 30 min of glucose challenge. In SUR1-/- mice, canagliflozin did not affect glucose and insulin levels, but it significantly increased glucagon secretion. Canagliflozin also enhanced glucose tolerance in SUR1-/- mice with improved insulin/glucose ratio and elevated ratio of glucagon/glucose. In isolated islets, canagliflozin (10 µM) has no effects on amino acid mixture (AAM) stimulated glucagon secretion and glucose mediated suppression of glucagon secretion in WT islets. SUR1-/- islets are sensitive to AAM stimulated insulin secretion, but lack of glucose suppression of glucagon secretion, and canagliflozin does not change such pattern. However, canagliflozin induced a 2-fold increase of basal glucagon secretion in SUR1-/- islets. This study showed that when α-cells were depolarized by KATP channel deletion, canagliflozin stimulated glucagon secretion both in vivo and in isolated islets, suggesting that SGLT2 inhibitors have intrinsic effects on α-cells.