Defect in Insulin Binding to Receptor on Liver Plasma Membrane in Liver Injury Rat

Summary

In this study we measured insulin degrading activity in both purified liver plasma membranes and liver homogenates and insulin binding to purified liver plasma membranes in rats treated with CCI₄ (liver injury rats).

GSH-independent insulin degrading activity per mg protein per min in the 27,000 × g supernate of liver homogenate in the liver injury rats (9.96 ± 0.71) was significantly lower (p < 0.01) than that of the normal rats (13.40 ± 0.52). However, GSH-dependent insulin degrading activity was not significantly more elevated than that in the normal rats (36.01 ± 1.57 vs. 34.23 ± 1.34).

The liver plasma membranes of the liver injury rats showed a considerably greater decrease in the specific binding of ¹²⁵I-insulin per 100 μg protein as compared with those of the normal rats (5.46 ± 0.71% vs. 11.34 ± 0.25%; p < 0.001). Scatchard analysis using a negative cooperative model for insulin-receptor interaction indicated that a decrease in insulin binding to the liver plasma membranes of the liver injury rats were most likely due to a conspicuous decrease in receptor affinity, with no change in receptor concentration.

The amount of insulin degraded by the liver plasma membranes in the liver injury rats was also markedly decreased. According to the kinetic analysis of insulin degradation, there was a significant difference (p < 0.001) in apparent Km between the liver injury rats and the normal rats and, furthermore, as compared to the normal rats there was a sharp decrease in apparent Vmax in the liver injury rats.

These results suggested that the insulin binding to receptors might be an important factor of insulin degradation and that the failure of insulin degradation by liver in liver disease might be due to a decreased insulin binding to receptor and/or a decreased proteolytic enzyme activity, like an insulin protease.

Key-Words:

Liver Disease - Hyperinsulinism - Insulin Degrading Activity - Insulin Binding - Receptor