If the enhancement in PM HGU caused by hyperinsulinemia in the morning depends on insulin’s direct effects (favored by portal vein insulin delivery), then the disrupted distribution of insulin to the liver caused by AM peripheral delivery could impair the improved PM response, emphasizing the necessity of restoring the normal physiologic insulin gradient through therapeutic approaches such as delivering hepatopreferential or oral insulin analogs (22). The gene discussed is INS; the disease is Hyperinsulinemia.