*4.2.3.2 Functions of SGLT2 in pancreatic alpha cells*

During fasting when blood glucose level is low, several counter-regulatory responses are generated to increase and maintain blood glucose within normal range. Pancreatic alpha cells secrete glucagon which stimulates glycogenolysis and gluconeogenesis in the liver. Conversely, glucagon secretion is inhibited when blood glucose level increases after taking food [51]. Inhibition of glucagon secretion is mediated by paracrine effect of insulin and direct glucose-mediated regulation of glucagon secretion. In alpha cells, SGLT2-mediated glucose uptake is a critical step involved in direct regulation of glucagon secretion [31].

The expression of SGLT2 at mRNA level increases in alpha cells in obesity and prediabetes. Once T2DM develops, the glucotoxicity leads to decrease in its expression. The glucagon secretion blockage which normally occurs at high plasma glucose levels gets blunted due to downregulation of SGLT2 causing enhanced endogenous glucose production in the liver which further aggravates hyperglycemia [31].
