Insulin degradation. XVIII. On the regulation of glutathione-insulin transhydrogenase in the hyperglycemic obese (ob/ob) mouse.
The occurrence of insulin-degrading activity in the liver of the obese hyperglycemic mouse (ob/ob) and its litter mate has been studied. The trichloroacetic acid-soluble product formed from insulin upon incubation with liver homogenate was identified as the A chain of insulin. In Ouchterlony double-diffusion experiments with antibody to purified rat liver glutathione-insulin transhydrogenase, mouse liver homogenate and the microsomal fraction each gave a single precipitation band of identity with the purified rat liver enzyme. These results indicate that the insulin-degrading activity present in the mouse liver is, in fact, glutathione-insulin transhydrogenase. Subcellular distribution studies of glutathione-insulin transhydrogenase and marker enzymes indicate that the transhydrogenase is located primarily in the microsomal fraction of mouse liver homogenate. The ob/ob mouse, which is a genetic mutant characterized by obesity, hyperinsulinism and resistance to the hypoglycemic action of insulin, contains hepatic glutathione-insulin transhydrogenase activity (per mg microsomal protein) markedly higher (40--60%) than its lean litter mates. However, a major portion of the increased hepatic enzyme in the ob/ob mouse occurs in a latent state; the increased amount of enzyme either is unavailable or is nonfunctional, although the ob/ob mouse still contains more of the functional form than the lean mouse. Thus, the results are consistent with the suggestion that the hepatic glutathione-insulin transhydrogenase is probably under a feedback control by circulating insulin.
D000818:Animals; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D005779:Immunodiffusion; D007328:Insulin / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000201:enzymology; D009132:Muscles / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011490:Protein Disulfide Reductase (Glutathione) / Q000276:immunology / Q000378:metabolism*; D013045:Species Specificity; D013347:Subcellular Fractions / Q000201:enzymology; D013385:Succinate Dehydrogenase / Q000378:metabolism
D007328:Insulin; D011092:Polyethylene Glycols; D010088:Oxidoreductases; D013385:Succinate Dehydrogenase; D011490:Protein Disulfide Reductase (Glutathione); D005952:Glucose-6-Phosphatase