Insulin degradation. VI. Feedback control by insulin of liver glutathione-insulin transhydrogenase in rat.

Abstract

The changes in the hepatic levels of glutathione-insulin transhydrogenase (GIT) in response to changes in the blood levels of insulin in rats under a variety of conditions have been determined by quantitative specific immunochemical titrations using antiserum to purified rat liver GIT. The GIT concentration was consistently lower in decreased insulin states brought about by starvation and by alloxan diabetes than in normally fed rats. Subsequent refeeding of starved rats with standard laboratory chow restored the loss in GIT content. Treatment of alloxandiabetic rats with insulin for two days increased concentration of GIT greatly above normal; administration of the A chain or B chain of insulin in the same manner was ineffective and did not augment or inhibit the effect of insulin. The insulin-mediated increase of GIT in diabetic rats was nullified by concomitant administration of either actinomycin D (an inhibitor of RNA synthesis) or cycloheximide (an inhibitor of protein synthesis). Thus, the data indicate that insulin induces synthesis of GIT protein via RNA synthesis. The biological significance of the induction of the GIT protein by insulin is interpreted as a feedback mechanism to regulate the insulin levels in the body. The results provide further evidence that GIT activity is the primary determinant of the rate of hepatic insulin metabolism. It must be assumed, however, that other factors are also involved in the regulatory process of insulin degradation, and some possibilities are suggested.