Pancreatic α-cell sodium-glucose cotransporter 1 (SGLT1) does not appear to contribute to hyperglucagonemia and glucose intolerance in diabetic mice.

Pancreatic α-cells secrete glucagon, a hormone that elevates blood glucose levels. In type 2 diabetes, high plasma glucagon levels are associated with hyperglycemia. However, the underlying mechanisms of increasing glucagon secretion remain unclear. We focused on the intrinsic regulatory mechanisms of glucagon secretion in α-cells, in particular sodium-glucose cotransporter 1 (SGLT1), which is involved in the early steps of glucose sensing. We previously demonstrated that SGLT1 is expressed in α-cells and is significantly upregulated in diabetic mice compared with non-diabetic mice. In isolated islets from diabetic mice, SGLT1 knockdown attenuated glucagon hypersecretion, and in αTC1 cells, SGLT-specific substrates promoted glucagon secretion by raising intracellular calcium. On the basis of these findings, we hypothesized that SGLT1 upregulation in α-cells under diabetic conditions impairs the suppression of glucagon secretion, thereby contributing to hyperglycemia. However, a previous study showed that systemic SGLT1 knockout (KO) mice exhibit a higher proportion of α-cells in the islets and atypically high plasma glucagon levels. To clarify the roles of SGLT1 specifically in α-cells, we generated α-cell-specific SGLT1 KO mice using a tamoxifen-inducible Cre-loxP system and analyzed these mice fed a high-fat, high-sucrose diet. The results clearly showed that, inconsistent with the results from the systemic SGLT1 KO mice, SGLT1 deficiency specifically in α-cells did not affect glucagon secretion, glucose tolerance, or α-cell proportion in the islets under diabetic conditions. Thus, though SGLT1 is upregulated in diabetic α-cells, this does not appear to contribute to hyperglucagonemia and impaired glucose tolerance in diabetic mice.