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The Effects of Ad Libitum Overfeeding and Moderate and Marked Dietary Restriction on Age-Related Spontaneous Pancreatic Islet Pathology in Sprague—Dawley Rats

Laboratoires Merck Sharp & Dohme-Chibret, Department of Safety Assessment, route de Marsat, Riom 63963 Clermont-Ferrand Cedex 9, France, sylvain_molonnoblot{at}merck.com

Kevin P. Keenan

Merck Research Laboratories, Department of Safety Assessment and Biometrics, West Point, PA 19486, USA

John B. Coleman

Merck Research Laboratories, Department of Safety Assessment and Biometrics, West Point, PA 19486, USA

Chao-Min Hoe

Merck Research Laboratories, Department of Safety Assessment and Biometrics, West Point, PA 19486, USA

Philippe Laroque

Laboratoires Merck Sharp & Dohme-Chibret, Department of Safety Assessment, route de Marsat, Riom 63963 Clermont-Ferrand Cedex 9, France

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-deoxyuridin e (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.

Key Words: Aging • dietary restriction • endocrine pancreas • insulin • islet fibrosis • islet hyperplasia • islet cell tumors

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