Stimulation of RNA synthesis in isolated nuclei by an insulin-induced factor in liver.

Abstract

Insulin stimulates the transport of small molecules as well as the synthesis of triglyceride, glycogen, DNA, RNA and protein. Although it is widely accepted that its differing actions are consequent to the binding to surface receptors, there is suggestive evidence that it may also act intracellularly. In 1975, we reported two well defined intracellular insulin binding sites in rat liver: the nucleus and the endoplasmic reticulum1. Specific binding sites for insulin on intact nuclei were shown by an immunofluorescent and autoradiographic technique, and the kinetics of insulin binding to isolated nuclear membranes were described2,3. Similar results have been obtained by other investigators4–6, and the more recent reports on the internalization of insulin7–9 give further support for an intracellular site of action of intact insulin or of its metabolic product. Investigation of the stimulatory effect of insulin on the synthesis of DNA and RNA in diabetic rats and isolated hepatocytes10–13 suggests that the stimulation of RNA synthesis precedes that of DNA, and is likely to be an early event in the stimulation of macromolecular synthesis. I report here evidence of a low molecular weight substance in rat liver perfused with insulin which can stimulate the synthesis of RNA in isolated nuclei. These results suggest that insulin may function by binding to the cell surface, initiating or enhancing endocytosis14 and entering the cell via a micropinocytotic route9. Once inside the cell, the active principle could be insulin itself, an intracellular degradation product of insulin, or a metabolic product of insulin action.