The first controlled trial in diabetes was the University Group Diabetes Program (UGDP) (1960–1970), which compared the effects of diet alone, tolbutamide, fixed-dose insulin, variable-dose insulin, and phenformin in reducing large vessel disease or death in recently diagnosed type 2 diabetes patients.50 The study resulted in a series of controversies as excessive deaths were reported in the phenformin group because of lactic acidosis and in the tolbutamide group because of cardiovascular events. This evidence concerns the gene INS and type 2 diabetes mellitus.