Instead, our model formalizes the concept that a persistent hyperglycemic insult, determined by long-standing, possibly progressive degrees of insulin resistance, brings about a progressive decline of insulin sensitivity, and that the even mild glucose toxicity connected with persistent insulin resistance eventually damages pancreatic replication reserve, determines an eventual decline of β-cell mass and an eventual failure of compensating insulin hypersecretion, resulting finally in rapid acceleration of hyperglycemia and in the overt clinical picture of frank T2DM. This evidence concerns the gene INS and type 2 diabetes mellitus.