Insulin Metabolism and Degradation*

INSULIN degradation is a complex and incompletely, understood process at present. In terms of overall clearance and metabolism, the liver is responsible for more than half of the total insulin degradation, with kidney responsible for most of the rest. The peripheral tissues, fat and muscle, probably degrade the remainder of the insulin in the body, but the absolute contribution of these tissues to insulin turnover is uncertain. It now appears that peripheral tissues can serve as a reservoir for insulin, presumably by the hormone binding reversibly to membrane receptors. The function of this remains to be established. At a cellular level in most tissues, insulin degradation is initiated by the hormone binding to specific receptors. The hormone-receptor complex is processed, including internalization and degradation of at least some of the hormone-receptor complexes. The enzyme or enzymes involved in the degradative process have not been established, but three systems have been implicated: insulin protease, glutathione insulin transhydrogenase (GIT), and lysosomal enzymes.