The absolute differences in plasma glucagon concentrations between SGLT-2 inhibitor-treated and placebo-treated patients are small (1–1.5 pmol/L) [65,66], and although some have argued for a direct role of SGLT-2 on the alpha cells [67,68,69,70], current evidence, which includes the results of glucose clamping, seems to point toward an indirect mechanism by which SGLT-2 inhibition increases renal glucosuria, resulting in significant lowering of blood glucose concentrations that causes a slightly greater alpha cell secretion [71,72,73,74,75]. This evidence concerns the gene SLC5A2 and Glycosuria.