In metabolically unhealthy persons with obesity and/or diabetes, insulin/insulin receptor/insulin receptor substrate/phosphoinositide 3-kinase/Akt signaling is down-regulated in vascular cells, while insulin receptor/son of sevenless/growth factor receptor bound protein/mitogen-activated protein kinase (MAPK) signaling is enhanced. This evidence concerns the gene INSR and obesity due to melanocortin 4 receptor deficiency.