Does insulin need a second messenger?

It is well established that specific binding sites for insulin are present on the plasma membranes of target tissues. In order to explain how insulin regulates a wide variety of biologic functions both on the surface of the cell as well as in its interior, it has been postulated that insulin generates a second messenger at the cell surface. To date, however, no second messenger for insulin has been identified that can carry out all of insulin's known actions. Recent studies have demonstrated that, in addition to the plasma membrane, other subcellular organelles, such as the nucleus, have specific binding sites for insulin. There is also evidence indicating that large serum proteins such as albumin, large protein hormones such as prolactin, and small protein hormones such as insulin can enter intact cells. It is hypothesized, therefore, that insulin has at least two mechanisms of action on target tissues. One mechanism entails the direct binding of insulin to the plasma membrane, which in turn leads to its well-known effects on membrane transport. The other mechanism requires the entry of insulin itself into the interior of the cell and its subsequent direct binding to subcellular organelles. This latter process then serves to mediate many of the known intracellular functions of insulin.