All these observations indicate the occurrence of a multistep resistance to antiaggregation in obesity and in obese type 2 diabetes mellitus, including the ability of insulin to increase NO, the ability of NO to increase cGMP, the ability of cGMP to reduce platelet calcium and consequently aggregation, and, similarly, the ability of PGI2 to increase cAMP and the cAMP ability to reduce platelet function [34, 141]. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.