Metabolic Zonation in Liver of Diabetic Rats. Zonal Distribution of Phosphoenolpyruvate Carboxykinase, Pyruvate Kinase, Glucose-6-Phosphatase and Succinate Dehydrogenase

Abstract

The activities and zonal distribution of key enzymes of carbohydrate metabolism were studied in livers of diabetic rats. Forty-eight hours after alloxan treatment the following alterations were observed, intermediate values being reached after 24 h. Blood glucose, acetoacetate and .beta.-hydroxybutyrate were increased to more than 500%; liver glycogen was reduced to about 100%. Portal vein insulin was reduced to below 10%, portal glucagon was increased to almost 200%. The glucogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were enhanced to 320% and 150%, respectively. The glycolytic enzymes glucokinase and pyruvate kinase L (differentiated from the M2 isoenzyme with a specific anti-L-antibody) were lowered to 50% and 75%, respectively. The citrate cycle enzyme succinate dehydrogenase remained unchanged. The normal perivenous gradient of phosphoenolpyuvate carboxykinase of about 3:1, as measured in microdissected tissue samples, was enhanced to about 4:1 with activities elevated to 230% and 190%, respectively, in the 2 zones. The normal periportal to perivenous gradient of pyruvate kinase L of about 1:1.7, as determined with the microdissection technique, was reduced to about 1:1.4 with levels lowered to 55% and 45%, respectively, in the 2 zones. The even zonal distribution of pyruvate kinase M2 remained unaltered. The normal periportal to perivenous gradients of glucose-6-phosphatase and succinate dehydrogenase, demonstrated histochemically, remained unaffected. In insulin-deficient diabetes the gluconeogenic capacity was strongly elevated in the periportal zone while the glycolytic capacity was reduced in the perivenous area. Apparently in diabetes, in contrast to starvation, the glucostat function of the liver and the concomitant reciprocal distribution of glucogenic and glycolytic enzymes is not lost, but only impaired due to shifts of the zonal enzyme levels.