Autoregulatory System of Insulin Degradation in Liver

I. Decreased¹³¹I-Insulin Degradation in the Liver of Insulin Deficient Rats

Abstract

The adaptive capacity of the liver to metabolize insulin in response to the fluctuation of blood level of insulin was studied with normally fed, fasted, and alloxan diabetic rats. The degradation of insulin in the livers of fasted or alloxan diabetic rats was decreased compared with that in the livers of normally fed control rats. The hepatic proteolytic activities to hydrolyze casein, α-N-benzoyl-DL-arginine-β-naphthylamide, and L-leucyl-β-naphthylamide were not altered under the same conditions of fasting or alloxan diabetes. The rate of insulin degradation in the liver correlated well with the hepatic level of reduced glutathione. However, even when the decreased level of reduced glutathione in diabetic liver was restored to the con-trol value by the addition of crystalline reduced glutathione to the incubation mixture, the degradation of insulin did not return to the control value. On the other hand, the administration of insulin to the diabetic rats restored the decreased insulin degradation to the control level. In addition, increasing insulin concentration in incubation media (human sera) enhanced the insulin degradation in liver slices and homogenates. These findings indicate that a specific insulin degradation system is responsible for the decreased insulin degradation in insulin deficiency and the enhanced insulin degradation in increased insulin level in the body. The present study, therefore, suggests that the liver possesses an autoregulatory mechanism for
the control of insulin degradation, the changing the rate of insulin metabolism in response to the fluctuation of the blood level of insulin. This system may operate in controlling the concentration of insulin in blood supplementary to the regulation of insulin secretion.