SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels

Takayoshi Suga, Osamu Kikuchi, Masaki Kobayashi, Sho Matsui, Hiromi Yokota-Hashimoto, Eri Wada, Daisuke Kohno, Tsutomu Sasaki, Kazusane Takeuchi, Satoru Kakizaki, Masanobu Yamada, Tadahiro Kitamura

Pancreatic α cells secrete glucagon, which controls blood glucose levels. In patients with type 1 or type 2 diabetes, hyperglycemia is often associated with hyperglucagonemia. However, the mechanism underlying excessive glucagon secretion is not fully understood. A recent report described the expression of sodium glucose cotransporters (SGLT) 1 and 2 in α cells. Suga et al. suggest that a novel mechanism regulates glucagon secretion through SGLT1 in α cells. Their findings might have implications for the classification and selection of SGLT2 inhibitors in the treatment of diabetes.

Objectives: It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic α cells. The role of SGLT1 in α cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight.

Methods: Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin. RT-PCR, RNA sequence, and immunohistochemistry were conducted to test the expression of SGLT1 and SGLT2 in α cells. We also used αTC1 cells and mouse islets to investigate the molecular mechanism by which SGLT1 modulates glucagon secretion.

Results: Dapagliflozin, but not canagliflozin, increased plasma glucagon levels in HFHSD fed mice. SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells, mouse islets and human islets. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. Canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. SGLT1 effect on glucagon secretion depended on glucose transport, but not glucose metabolism. Islets from HFHSD and db/db mice displayed higher SGLT1 mRNA levels and lower GLUT1 mRNA levels than the islets from control mice. These expression levels were associated with higher glucagon secretion. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets.

Conclusions: These data suggested that a novel mechanism regulated glucagon secretion through SGLT1 in α cells. This finding possibly explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.