Pharmacological support for the development of SGLT2 inhibitors comes from studies using phlorizin, a natural product discovered in 1835 from root bark of apple trees. Von Mering discovered that ingestion of phlorizin produced glucosuria in humans. Rossetti and DeFronzo et al found that in partially pancreatectomized rats, phlorizin normalized blood glucose levels. While this theoretical concept supported the idea that glucosuria could normalize fasting and fed plasma glucose levels (and reverse insulin resistance in animals), it did not immediately translate into pharmacotherapy due to phlorizin s multiple limitations: (1) low selectivity for SGLT2 over SGLT1 causing frequent gastrointestinal side effects, (2) degradation by the gut enzyme disaccharidase reducing the oral bioavailability, and (3) the interaction of one of its metabolites, phloretin, which inhibits GLUT2 and GLUT1 glucose reabsorption in the gut.