The mechanisms responsible for the obesity-associated increase in plasma insulin have been a matter of interest for a long time and it has been debated whether hyperinsulinemia is due to insulin hypersecretion or reduced insulin clearance or both, whether the alterations in insulin kinetics are due to excess adiposity per se or secondary to insulin resistance, whether alterations in insulin kinetics are indeed a consequence and not a cause of insulin resistance, and whether increased insulin clearance is a primary cause for the insulin deficiency of T2D [4,7,41,140,141,142,143]. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.