INSR and obesity due to melanocortin 4 receptor deficiency: Since these key pathways are activated by the IR signal, the balance between molecular discriminants in terms of circumstantial co-expression (by both protein stability and gene transcription) and isoform expression (affecting sensitivity to the same signals) can play a consistent part in the qualitative response exerted by hypoxia under hyper-insulinemic states (obesity and type 2 diabetes) as well as by IGF-I and II paracrine-stimuli and IGF-II autocrine loop during cancer progression and malignant transformation.