Atypical hyperplasia of choledocho‐pancreatic duct epithelium in an Otsuka Long Evans Tokushima Fatty strain of rats

Abstract

Epithelial papillary hyperplasia of choledocho-pancreatic duct, associated with cellular atypism, was observed in Otsuka Long Evans Tokushima Fatty (OLETF) rats, a strain originally established as an animal model for non-insulin-dependent diabetes mellitus (NIDDM). To investigate the potential feasibility of OLETF rats as an animal model for pancreatic ductal carcinoma, we examined the pathological characteristics of ductal lesions in OLETF rats aged from 5 to 50 weeks. Hyperplastic lesions in OLETF rats became apparent after 10 weeks of age and increased in severity and frequency of atypical changes in hyperplastic epithelium appearing after 20 weeks. We compared ductal lesions from OLETF rats with those from age-matched Long Evans Tokushima Otsuka (LETO) rats, which share a similar genetic background with OLETF rats but do not develop NIDDM. While LETO rats also display a tendency toward ductal hyperplasia, lesions from OLETF rats were more numerous and larger in size than those from age-matched LETO rats. In addition, lesions from OLETF rats contained a significantly higher number of proliferating cell nuclear antigen-positive cells than those from LETO rats. Finally, lesions in OLETF rats were accompanied by inflammation, and the observed morphological alteration of lesions correlated well with the grade of inflammation.

Genetic analysis of pancreatic duct hyperplasia in Otsuka Long–Evans Tokushima Fatty rats: Possible association with a region on rat chromosome 14 that includes the disrupted cholecystokinin‐A receptor gene

“…For two‐point linkage analysis and association study, we treated this phenotype as a qualitative trait by dividing animals to two groups, affected (grade 1 and grade 2) and unaffected (grade 0). As reported previously, 14 hyperplastic proliferation in affected animals (grade 2) was observed in the main choledocho‐pancreatic duct and was characterized by the appearance of many crypts within thickened ductal walls (Fig. 1a).…”

“…The Long–Evans Tokushima Otsuka (LETO) rat shares a similar genetic background with the OLETF rat but does not develop T2DM 12 . As we previously reported, LETO rats occasionally develop hyperplasia in the pancreatic duct epithelium; 50% of the male rats bear hyperplasia at the age of 30 weeks, however, these lesions are mild and not atypical 14 . The observation that LETO rats contain intact Cckar suggests that additional loci contribute to the susceptibility to hyperplasia.…”

“…It is likely that a deficiency of Cckar influences the T2DM phenotype, but this effect might be subtle enough to be masked by genetic background; otherwise, BN rats would be expected to harbor one or more strong protective alleles. Furthermore, hyperplasia of the pancreatic duct epithelium in OLETF rats occurs prior to the development of diabetic phenotypes such as glucose intolerance 14 …”

“…Further examination revealed that both male and female OLETF rats exhibited hyperplasia by 15 weeks of age. In almost every case, hyperplasia was accompanied by papillary proliferation, frequently with cellular atypia 14 …”

Contribution of animal models to diabetes research: Its history, significance, and translation to humans

“…Diet restriction or exercise in juvenile stages or shortly after the onset of diabetes postpones the onset of diabetes or an improvement of diabetes. It is of note that atypical hyperplasia of bile and pancreatic ducts is often encountered in this model which may provide some clues to the increased frequencies of atypical growth of ductal neoplasms 136 .…”