Moreover, HGF has at least four characteristics that suggest a pathophysiological link between insulin-resistance and islet hyperplasia/hyperinsulinemia: (1) HGF is mainly produced by the liver; (2) it is under the regulation of the ERK pathway; (3) HGF stimulates insulin secretion and increased islet mass both in vitro and in vivo; and (4) circulating levels are elevated in obesity associated-insulin-resistance. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.