Progressive histopathological changes in pancreatic islets of Zucker Diabetic Fatty rats

Abstract

Thus far, histopathological changes in the pancreatic islets of Zucker Diabetic Fatty (ZDF) rats, an animal model of type 2 diabetes mellitus (or non-insulin-dependent diabetes mellitus), have only been studied in male rats and in 18-weeks old rats or younger. In this study, we have examined in both male and female ZDF rats the histopathological changes longitudinally, from 6 to 32 weeks of age. We studied islet architecture and cellular distribution of the various islet hormones both in ZDF and control rats. In the ZDF rats, aging was initially associated with an enlargement of the islets. From 18 weeks onwards, no further enlargement was noted but islet boundaries became increasingly irregular, leading to the appearance of projections of endocrine cells into the surrounding exocrine tissue. At the islet boundaries as well as within the islets progressive fibrosis was observed with increasing amounts of collagen and reticular fibers. In the islets, staining intensity of both insulin and islet amyloid polypeptide (IAPP) increased slightly till 10 weeks of age and thereafter decreased rapidly. In contrast, the staining intensities of glucagon, somatostatin, and pancreatic polypeptide (PP) did not change. Even at the age of 32 weeks, just the beta-cells and not the other endocrine islet cells appear to be affected. In control rats, aging evoked only minor changes. Thus, we observed that during prolonged development of diabetes mellitus in both male and female ZDF rats histopathological changes in the pancreatic islets became progressively more severe, eventually leading to disintegration of the islets.

Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats

“…2). The increased collagen mRNA is consistent with the collagen fibers found within diabetic ZDF islets (30) (Fig. 5).…”

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

“…We describe for the first time the attenuation of these changes after chronic blockade of the RAS. Previous studies have attributed progressive islet damage seen in this model to chronic hyperglycemia (glycotoxicity) (21). Although treatment with ACE inhibitors or AT 1 receptor antagonists improves peripheral insulin sensitivity and glucose disposal in ZDF rats (31), the beneficial effects on islet morphology described here were independent of any direct effects on glycemic control.…”

“…ZL rats were studied concurrently and acted as further controls. The end point of 20 weeks was selected as insulin resistance, hyperinsulinemia, hyperglycemia, and islet fibrosis all are observed in the ZDF model at this time point (21). All animal procedures were in accordance with guidelines set by the National Health and Medical Research Council of Australia.…”

A Review of Islet of Langerhans Degeneration in Rodent Models of Type 2 Diabetes

“…At this stage, insulin hypersecretion is apparent, although insulin mRNA levels remain normal (Tokuyama et al, 1995). After the onset of diabetes, as defined by severe, fasting hyperglycemia, islets are irregular with projections into the exocrine pancreas as a result of hyperplasia/hypertrophy and infiltration with inflammatory cells (Finegood et al, 2001;Janssen et al, 2001;Pickavance et al, 2003;Tokuyama et al, 1995). Following the onset of diabetes, insulin mRNA and insulin secretion are severely reduced (Tokuyama et al, 1995).…”