INS and obesity due to melanocortin 4 receptor deficiency: Under chronic hyperinsulinema (e.g., obesity and type II diabetes) or prolonged treatment with insulin, GH resistance at the hepatic level is commonly observed, which can be attributed to the inhibitory effects of insulin on JAK2/STATs signaling (16, 17) and GHR gene transcription via the MEK/ERK and PI3K/Akt pathways (18, 19).