Diabetes-prone BioBreeding (BBdp) rats often present an enteropathy that may precede the onset of autoimmune insulitis. The aim of the present study was to assess the influence of sex, the time course, the strain specificity, the distribution along the intestinal tract and the effect of diet for the changes in the activity of gut invertase, maltase and lactase found in BBdp rats, as compared with both Wistar–Furth (WF) and diabetes-resistant BioBreeding (BBc) rats. These hydrolases were measured, therefore, at day 10, 30, 45, 70, 95 and 120 in three intestinal segments of WF, BBc and BBdp rats fed, after weaning, either a protective high-casein diet, which decreases the incidence of diabetes in the BBdp rats, or one of two diabetogenic diets (National Toxicology Program; NTP or wheat-gluten-based; WG). Except for a somewhat lower lactase activity in the BBdp rats, no obvious difference in hydrolyase activity between the three strains of rats was observed at day 10. Between days 30 and 120, however, the activity of the hydrolases, especially that of invertase and lactase, was lower in the BBdp rats than in either the WF or BBc rats, at least when considering the animals fed either the NTP or WG diet. These findings support the view that BBdp rats exposed to a diabetogenic diet develop an enteropathy well before the onset of autoimmune insulitis, in a manner somehow comparable with the situation found in some type 1 diabetic patients, in whom coeliac disease may be diagnosed before diabetes onset.