The relationship between the severity of diabetes and the hepatic accumulation of triglycerides in the streptozotocin-diabetic rat was studied. A consistent increase in hepatic triglyceride content was observed only in the ketotic diabetic state. Insulin treatment of the ketotic diabetic rat resulted in the reversal of increased plasma concentrations of glucose, free fatty acids, β-hydroxybutyric acid, and triglycerides to those observed in nondiabetic controls. Insulin treatment of the ketotic rats, however, did not completely eliminate the accumulation of the hepatic triglycerides.
To determine whether increased triglyceride synthesis was a contributory factor to the hepatic triglyceride accumulation, triglyceride synthesis was studied in vitro using nuclear-free homogenates of liver. Triglyceride synthesis increased in ketotic diabetes. Insulin treatment of the ketotic rats partially reversed the increased diglyceride synthesis observed in ketosis but had no effect on the accelerated triglyceride synthesis. The effects of ketotic diabetes and insulin treatment of the diabetic rat on the activities of two key enzymes of the triglyceride biosynthetic pathway were examined next. The maximal velocities (Vmax) of liver-soluble phosphatidate phosphohydrolase and of microsomal diglyceride acyltransferase increased in ketosis. Insulin treatment of the diabetic rats reverted the activity of these two enzymes to control values.
The results of our study demonstrate that hepatic triglyceride synthesis in ketotic rats accelerates at a time when hepatic triglyceride content increases, the increased synthesis of triglycerides was associated with increases in the activities of two key enzymes of triglyceride biosynthesis. There was a correlation between hepatic triglyceride content and triglyceride synthesis in control, ketotic diabetic, and insulin-treatedrats. These observations suggest a physiologic role for the observed changes in the accumulation of hepatic triglycerides in ketotic diabetes.