Evolution of metabolic and renal changes in the ZDF/Drt-fa rat model of type II diabetes

Studies of the pathophysiology of renal disease in non-insulin-dependent diabetes mellitus (NIDDM) have been hindered by the lack of an appropriate experimental model. We examined the natural history of metabolic and renal changes in the partially inbred Zucker Diabetic Fatty Rat (ZDF/Drt-fa), a model that closely mimics the metabolic abnormalities of NIDDM. Lean nondiabetic littermates served as controls. Body weights in the obese rats were higher initially, but thereafter stabilized at values similar to those in lean controls. Blood glucose levels rose to overtly hyperglycemic levels in the obese group, stabilizing in the 300 to 400 mg/dL range. Serum insulin, cholesterol, and triglyceride levels were all elevated in the obese group, though insulin levels declined later in life. Values for systolic blood pressure rose slightly with age in both groups, but remained within the normal range, and did not differ between groups. Urinary albumin excretion values were higher in the obese group at all time points, and rose progressively throughout the study. Morphologic examination revealed the presence of severe hydronephrosis in almost all animals, affecting lean as well as obese rats. In some cases, complications were found, including tubular dilation, necrotizing granulomas, inflammatory changes, and pyelonephritis, some of which were fungal. Accordingly, the ZDF/Drt-fa rat appears to be an excellent model of the metabolic changes that characterize NIDDM. Unfortunately, the utility of this model for study of diabetic renal disease is compromised by the ubiquitous presence of other, nondiabetic renal lesions.