Degradation of intra- and extrahepatic protein by livers of normal and diabetic mice: differential responses to starvation

Abstract Rates of total hepatic proteolysis were measured in normal and streptozotocin-diabetic mice during feeding and over 48 hr of starvation, during which livers in the two groups lost 37% and 54% of their protein content, respectively. Measurements were made in 15-min in situ cyclic perfusions from the linear accumulation of free valine in the presence of cycloheximide; rates were corrected for turnover of short-lived proteins because these components contribute negligibly to alterations in liver protein content. During deprivation, corrected rates, expressed on a per liver basis, remained constant in normal mice but increased markedly in the diabetic group, attaining twice prestarvation values by 48 hr. By contrast, degradation rates of long-lived intracellular proteins, calculated from the sum of their synthesis and the linear decrease in protein content, decreased predictably in both groups and in parallel with absolute rates of protein synthesis. The extra proteolysis, representing the difference between total and long-lived protein degradation, was small in fed animals but increased progressively during starvation. With diabetic mice, however, the increase was approximately 5 times that of the normal and, in absolute terms, roughly equaled the total loss of liver protein. We suggest that this fraction arose from intrahepatic breakdown of proteins that were ultimately derived from sources outside the liver. Acceleration of this novel process could play an important interim role in providing endogenous glucogenic substrate under conditions in which the demand for this substrate is high.