title: The effects of ad libitum overfeeding and moderate and marked dietary restriction on age-related spontaneous pancreatic islet pathology in Sprague-Dawley rats.
abstract: This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on aged-related degenerative and proliferative changes of the endocrine pancreas in Sprague-Dawley (SD) rats. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72-79% of AL (group 2), DR at 68-72% of AL (group 3) or DR at 47-48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Before each necropsy, glucose and serum insulin levels were measured. In addition to the routine histopathologic examination performed in both sexes, determination of 9 pancreatic islet stereologic parameters was done in males at 13, 26, and 53 weeks. In AL-fed rats, early changes in the islet morphology occurred, which resulted in a high incidence of islet fibrosis, focal hyperplasias and adenomas by two years. DR was dose-proportionally associated with decreased glucose and serum insulin levels, and delayed the onset, and decreased the incidence and severity of islet fibrosis and hyperplasia. Results of the stereology supported the histopathologic and clinical chemistry findings. It demonstrated that, compared to AL-fed rats, DR-fed rats had smaller pancreas, smaller pancreatic islets, smaller insulin secreting cell volumes, a lower degree of islet fibrosis and a lower islet cell BrdU labeling index, which correlated with a lower incidence of islet adenoma and carcinoma at study termination. Moderate and marked degrees of DR delayed the onset and severity of islet hyperplasia and fibrosis in a temporal- and dose-related manner. In contrast to marked DR, which dramatically prevented these changes, moderate DR delayed but not prevented onset of islet tumors. These findings support the concept that moderate DR results in a better-controlled animal model with a lower incidence or delayed onset of chronic spontaneous endocrine diseases in the rat bioassay.
authors.affiliation: Laboratoires Merck Sharp & Dohme-Chibret, Department of Safety Assessment, Clermont-Ferrand, France. sylvain_molonnoblot@merck.com
authors.forename: S
authors.initials: S
authors.lastname: Molon-Noblot
authors.forename: K P
authors.initials: KP
authors.lastname: Keenan
authors.forename: J B
authors.initials: JB
authors.lastname: Coleman
authors.forename: C M
authors.initials: CM
authors.lastname: Hoe
authors.forename: P
authors.initials: P
authors.lastname: Laroque
mesh_terms: D007516:Adenoma, Islet Cell / Q000473:pathology* / Q000503:physiopathology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001973:Bromodeoxyuridine / Q000378:metabolism; D018273:Carcinoma, Islet Cell / Q000473:pathology* / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000473:pathology; D005508:Food Deprivation; D006963:Hyperphagia / Q000503:physiopathology*; D007091:Image Processing, Computer-Assisted; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007328:Insulin; D001973:Bromodeoxyuridine