INS and Hyperglycemia: 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.