Mechanisms of up-regulation of the liver insulin receptor in chronically hypoinsulinemic rats: assessment of receptor endocytosis.

Chronic hypoinsulinemic states in rodents are known to cause an increase in the number of insulin receptors at the hepatocyte surface. To assess whether this change results from a reduced endocytosis of the receptors, the effects of streptozotocin treatment and fasting on the number and the subcellular distribution of hepatic insulin receptors have been evaluated in the rat. In streptozotocin-treated rats, insulin receptor number was increased by 25-40% in plasma membrane and total cellular membrane fractions, and by 60-130% in the light Golgi-endosomal (GE) fraction. In contrast, receptor number was unaffected in the intermediate GE fraction and decreased by 25-35% in the heavy GE fraction. Such changes were detectable at 12 h in GE fractions and at 2 days in other subcellular fractions, and lasted for at least 8 days. Streptozotocin treatment also led to a 3- to 4-fold decrease in the insulin content of GE fractions, indicating reduced hormone endocytosis. Fasting for 16 h elicited changes in receptor and ligand concentration in cell fractions comparable to those induced by streptozotocin. It is concluded that, although endocytosis of hepatic insulin receptors is reduced in chronic hypoinsulinemic states, changes in receptor synthesis and/or degradation also occur in these states.