For instance, when intra-portal insulin levels are increased [e.g., obesity, Cushing’s syndrome or due to treatment with glucocorticoids and glucagon-like peptide-1 receptor agonists (GLP-1RA)] or decreased (e.g., anorexia nervosa and T1D) in disease states, these secondary changes (“secondary association”) alters hepatic GH sensitivity resulting in discordant GH and IGF-I levels (high GH/low IGF-I levels and low GH/high IGF-I levels, respectively). The gene discussed is GH1; the disease is obesity due to melanocortin 4 receptor deficiency.