INS and diabetes mellitus: The monogenic disorders provide particular insights that (1) there are clear biological driven origins of obesity affecting appetite, which predisposes to insulin resistance and type 2 diabetes, (2) specific defects in pancreatic beta cell function predispose to diabetes in absence of either obesity or insulin resistance, and (3) specific defects in insulin signaling or fat storage capacity can lead to severe insulin resistance in absence of obesity, which leads to diabetes through pancreatic exhaustion.