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

Abstract

ObjectivesIt 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.MethodsPlasma 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.ResultsDapagliflozin, 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.ConclusionsThese 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.

Delayed intervention with a novel SGLT2 inhibitor NGI001 suppresses diet‐induced metabolic dysfunction and non‐alcoholic fatty liver disease in mice

“…Previous studies have shown that canagliflozin (10 and 30 mg·kg −1 ) and dapagliflozin (10 mg·kg −1 ) decreased blood glucose to almost the same level in HFHSD mice (Suga et al, 2019). Taken together, NGI001, as well as dapagliflozin and canagliflozin, were effective in inhibiting hyperglycaemia at a dose between 10 and 30 mg·kg −1 in HFD mice.…”

Effect of Combination Therapy of Canagliflozin Added to Teneligliptin Monotherapy in Japanese Subjects with Type 2 Diabetes Mellitus: A Retrospective Study

“…On the contrary, there are some reports which suggest that canagliflozin does not increase the serum glucagon level during meal tolerance test [8,16]. In addition, it is also presented that SGLT1 but not SGLT2 is expressed in the murine αTC1 cell line and human and murine pancreatic islets and that canagliflozin reduced glucagon secretion from αTC1 cells in an SGLT1-dependent manner [17]. On the other hand, it is also reported that SGLT2 but not SGLT1 is expressed in glucagon-secreting alpha cells of human and murine pancreatic islets and dapagliflozin triggers glucagon secretion [18].…”

Glucose transporters in pancreatic islets

“…This finding suggests that GLUT1 in rodent α-cells might fulfill a similar function as GLUT2 does in rodent β-cells. Blocking of GLUT1 with phloretin resulted in an increase in glucagon secretion, emphasizing the idea that GLUT1 mediates a direct glucosedependent effect on glucagon secretion [141].…”

“…A recent study suggested that Slc2a1 is regulated in a nutrientdependent manner in mouse islets [141]. High fat, highsucrose fed C57BL/6 as well as db/db mice exhibited lower levels of Slc2a1 transcripts than control mice, which was accompanied by an enhanced secretion of glucagon [141].…”

“…A recent study suggested that Slc2a1 is regulated in a nutrientdependent manner in mouse islets [141]. High fat, highsucrose fed C57BL/6 as well as db/db mice exhibited lower levels of Slc2a1 transcripts than control mice, which was accompanied by an enhanced secretion of glucagon [141]. Phloretin treatment of isolated mouse islets led to a reduction of Slc2a1 expression and an increased glucagon secretion, indicating a potential direct link between GLUT1-mediated glucose uptake and the regulation of glucagon release [141].…”