Assessment of diabetogenic drug activity in the rat: Diphenylhydantoin

Abstract

An animal model is described that can be used to detect drugs that may exacerbate or ameliorate diabetes. The design of this model is based upon the finding that hyperglycemia caused by intravenous administration of streptozotocin to rats is inversely correlated with pancreatic insulin concentration when expressed as total pancreatic insulin (ng) per body weight (g). Drugs that alter this relationship may be classified, in a preliminary manner, as ameliorative or diabetogenic.

The diabetogenic activity of diphenylhydantoin (DPH) via oral administration was assessed in both normal and streptozotocin diabetic rats. Rats were fed powdered chow diet, with or without 0.2% (w/w) DPH, for 19 days. Food consumption and rat weight were recorded daily; whole blood glucose concentrations were determined at the start of the study and at the midpoint. At sacrifice liver and pancreas were excised and blood samples were collected. Protein, glycogen, and lipid levels were determined in liver; insulin in pancreas; and insulin, ketone bodies, glucose, and Iipid in blood. DPH treatment did not affect growth or food consumption. The drug dose, calculated from the food consumption data, was 139 mg/kg‐day for the normal rats and 311 mg/kg‐day for the diabetic rats. DPH increased liver weight and lipid content in both normal and diabetic rats and lowered blood serum triglyceride concentration in normal rats. However, the concentrations of whole blood glucose, blood serum insulin, and pancreatic insulin were not altered by DPH treatment. The results indicate that the diabetogenic side effect of DPH cannot be observed in rats when the drug is administered orally.