Subcutaneous administration of insulin, with the contribution of reduced clearance, abolishes the diurnal fluctuations of plasma insulin levels establishing an inflexible hyperinsulinemia (141), and reverses the distribution of insulin in the systemic circulation resulting in higher peripheral than portal levels increasing dramatically the risk for hypoglycemia and fat storage/weight gain, and inducing or aggravating insulin resistance in the liver and peripheral tissues (137) (Fig. 4). Here, INS is linked to Insulin resistance.