Age-Related Pancreatic Islet Changes in Sprague-Dawley Rats

Abstract

To characterize the clinical pathologic and morphologic features of spontaneous age-related changes in pancreatic islets observed in Crl:CDR(SD)BR rats, I reviewed data from rats used as controls in 10 toxicity studies from 1987 to 1992. Rats were 3.5–26 mo old at necropsy. At necropsy, rats were weighed, and serum, urine, and pancreas samples were collected. Serum was analyzed for glucose, triglyceride, and cholesterol concentrations; urine was analyzed for glucose and ketones; and samples of pancreas were stained with hematoxylin and eosin, Masson's trichrome stain, or for insulin by an immunoperoxidase method with a Masson's trichrome counterstain and examined microscopically. Male rats gained weight more rapidly than females and were visibly obese by 5 mo. Weight gain was accompanied by increased fasting triglyceride and cholesterol concentrations. Triglyceride increased more than cholesterol: from 3.5 to 17 mo of age, triglyceride concentrations increased 3.4-fold in males and 3.1-fold in females. By 14 mo of age, rats generally had fasting triglyceride concentrations >200 mg/dl (2.2 μM). Fasting glucose concentrations generally were slightly (<30%) greater in males than females. More males than females had glucose >200 mg/dl (11 mM); several males had glucose >300 mg/dl (16.5 mM). Glucosuria was not detected in any rat. Ketonuria was much more common in males than in females, but its incidence did not parallel that of obesity and hypertriglyceridemia; instead, ketonuria was most common in young males and decreased with age. Morphologic islet changes were observed in rats as young as 3.5 mo old, and their incidence increased with age. They were much more common in males than in females at all ages. Islet changes began as β-cell hyperplasia causing enlarged islets. With time, fibrosis gradually dissected islets into discreet nests of cells separated by bands of collagenous tissue so that they resembled cirrhotic liver. As the process continued, the ratio of fibrous tissue to islet cells increased until some islets were reduced to scattered β cells imbedded in a mass of scar tissue. By the time rats were 26 mo old, enlarged islets were rare; instead, remaining islets generally were small. Islet cell neoplasia did not occur in rats 17 mo of age or younger. In 26-mo-old rats, neoplasms were more common in males than in females (incidence of 20% vs 10%, respectively). The pathogenesis of these abnormalities is unclear, but they suggest that male Sprague-Dawley rats fed ad libitum are a less than ideal system in which to conduct long-term toxicity/safety assessment studies or any other research studies that could be influenced by altered metabolism. These results also reveal that male and female Sprague-Dawley rats differ metabolically and that the differences may predispose males to islet cell neoplasms.