This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Molon-Noblot, S. Articles by Laroque, P. Search for Related Content PubMed PubMed Citation Articles by Molon-Noblot, S. Articles by Laroque, P. Social Bookmarking                         What's this?

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

References

• Ahuja SK, Manickavel V., Amy RM, Russell JC (1987). Age-related qualitative and quantitative changes in the endocrine pancreas of the LA/N-corpulent rat. Diabetes Res 6: 137—144.[Web of Science][Medline] [Order article via Infotrieve]
• Anver MR, Cohen BJ (1979). Lesions associated with aging. In: The Laboratory Rat, Vol. I, Baker HJ, Lindsey JR, Weisbroth SH (eds). Academic Press, New York, pp 377—399.
• Burek JD (1978). Pathology of aging rats. CRC Press, Boca Raton, FL. 4. Burek JD (1990). Survival experience with the Sprague—Dawley-derived rat. The Toxicology Forum, Transcript of 1990 Annual Meeting, Aspen, CO, pp 506—518.
• Chapin RE, Gulati DK, Barnes LH, Teague JL (1993). The effects of feed restriction on reproductive function in Sprague—Dawley rats. Fund Appl Toxicol 20: 23—29.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Cornwell GG, Thomas BP, Snyder DL (1991). Myocardial fibrosis in aging germ-free and conventional Lobund-Wistar rats: The protective effect of diet restriction. J Gerontol 46: B167—169.[Abstract]
• Crawford JM (1997). The pancreas. In Basic Pathology, 6th edition, Kumar V, Cotran RS, Robbins S (eds). W. B. Saunders Company, Philadelphia, PA, pp 563—575.
• Dillberger JE (1994). Age-related pancreatic islet changes in Sprague— Dawley rats. Toxicol Pathol 21(6): 48—54.
• Feuers RJ, Duffy PH, Chen F., Desai V., Oriaku E., Shaddock JG, Pipkin JW, Weinruch R., Hart RW ( 1995). Intermediary metabolism and antioxidant systems. In: Dietary restriction: implication for the design and interpretation of toxicity and carcinogenicity studies. Hart RW, Neumann DA and Robertson RT editors, ILSI Press, Washington, DC, pp 181—195.
• Finch CE (1990). Longevity, Senescence and the Genome. The University of Chicago Press, Chicago, IL.
• Fishbein L (ed). (1991). Biological Effects of Dietary Restriction. Springer Verlag, New York.
• Gepts W., LeCompte PM (1981). The pancreatic islets in diabetes. Am J Med 70: 105—115.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Gomez Dumm CLA, Semino MC, Gagliardino JJ (1989). Quantitative morphological changes in endocrine pancreas of rats with spontaneous diabetes mellitus. Virchows Arch B Cell Pathol 57: 375—381.[Web of Science][Medline] [Order article via Infotrieve]
• Gomez Dumm CLA, Semino MC, Gagliardino JJ (1990). Sequential morphological changes in pancreatic islets of spontaneously diabetic rats. Pancreas 5: 533—539.[Web of Science][Medline] [Order article via Infotrieve]
• Gonet AE, Stauffacher W., Pictet R., Renold AE, Mougin J. (1965). Obesity and diabetes mellitus with striking congenital hyperplasia of the islets of Langerhans in Spiny mice (Acomys cahirinus). I. Histological findings and preliminary metabolic observations. Diabetologia 1: 162—171.[CrossRef]
• Gumprecht LA, Long CR, Soper KA, Smith PF, Hascheck-Hock WM, Keenan KP (1993). The early effects of dietary restriction on the pathogenesis of chronic renal disease in Sprague—Dawley rats at 12 months. Toxicol Pathol 21(6): 528—537.[Abstract/Free Full Text]
• Hadju A., Herr F., Rona G. ( 1968). The functional significance of a spontaneous pancreatic islet changes in rats. Diabetologia 4: 44—47.[Medline] [Order article via Infotrieve]
• Hadju A., Rona G. ( 1967). Morphological observations on spontaneous pancreatic islet changes in rats. Diabetes 16: 108—110.[Medline] [Order article via Infotrieve]
• Hart RW, Keenan KP, Turturo A., Abdo KM, Leaky J., LynCook L. (1995). Caloric restriction and toxicology. Fund Appl Toxicol 25: 184—195.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Haseman JK, Arnold J., Eustis SL (1990). Tumor incidences in Fisher 344 rats: NTP historical data. In: Pathology of the Fisher rat: Reference and atlas, Boorman GA, Eustis SL, Elwell MR, Montgomery CA, McKenzie WF (eds). Academic Press, San Diego, pp 555—564.
• Iwasaki K., Gleiser CA, Masoro EJ, McMahan CA, Seo EJ, Yu BP (1988). The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol 43: B5—B12.[Abstract]
• Keenan KP, Coleman JB, McCoy CL, Chao-Min Hoe, Soper KA, Laroque L. (2000). Chronic nephropathy in ad libitum overfed Sprague—Dawley rats and its early attenuation by increasing degrees of dietary (caloric) restriction to control growth. Tox Path 28: 788—798.
• Keenan KP, Smith PF, Ballam GC, Soper KA, Bokelman DL (1992). The effect of diet and dietary optimization (caloric restriction) on rat survival in carcinogenicity studies. An industrial viewpoint. In Centre for Medicines Research Worshop. The carcinogenicity debate, McAuslane JAN, Lumley CF, Walker SR (eds). Butler and Tanner, London, pp 77—102.
• Keenan KP, Ballam GC, Soper KA, Laroque P., Coleman JB, Dixit R. (1999). Diet, caloric restriction and the rodent bioassay. Toxicol Sci52 (supplement): 24—34.[Abstract]
• Keenan KP, Laroque P., Ballam GC, Soper KA, Dixit R., Mattson BA, Adams SP, Coleman JB (1996). The effects of diet, ad libitum overfeeding, and moderate dietary restriction on the rodent bioassay: The uncontrolled variable in safety assessment. Toxicol Pathol 24(6): 757—768.[Abstract/Free Full Text]
• Keenan KP, Smith PF, Soper KA (1994). The effects of dietary (caloric) restriction on rat aging, survival, pathology and toxicology. In: Pathobiology of the Aging Rat, Vol. II, Mohr U, Dungworth DL, Capen CC (eds). ILSI Press, Washington, DC, pp 609—628.
• Keenan KP, Smith PF, Hertzog P., Soper KA, Ballam GG, Clark RL (1994). The effects of overfeeding and dietary restriction on Sprague—Dawley rat survival and early pathology biomarkers of aging. Toxicol Pathol 22(3): 300—315.[Abstract/Free Full Text]
• Keenan KP, Soper KA, Smith PF, Ballam GC, Clark RL (1995). Diet, overfeeding and moderate dietary restriction in control Sprague—Dawley rats: I. Effects on spontaneous neoplasms. Toxicol Pathol 23: 269—286.[Abstract/Free Full Text]
• Koizumi A., Wada Y., Tsukada M., Hasegawa J., Walford RL (1989). Low blood glucose levels and small islets of Langerhans in the pancreas of calorie-restricted mice. Age 12: 93—96.[CrossRef][Web of Science]
• Kritchevsky D. (1993). Energy restriction and carcinogenesis. Food Res Internat 26: 289—295.[CrossRef]
• Laganiere S., Yu B. (1989). Effect of chronic food restriction in aging rats. I. Liver subcellular membranes. Mech Ageing & Dev 48: 207—219.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Laroque P., Keenan K., Soper K., Dorian C., Hubert MF, Duprat P. (1997). Effect of initial body weight and moderate dietary restriction on survival in Sprague—Dawley rats. Exper Toxicol Pathol 49: 459—465.
• Larsson L-I., Boder GB, Shaw WN ( 1977). Changes in the islets of Langerhan s in the obese Zucker rat. Lab Invest 36: 593—598.[Web of Science][Medline] [Order article via Infotrieve]
• Lu MH, Hinson WG, Turturro A., Anson J., Hart RW ( 1991). Cell cycle analysis in bone marrow and kidney tissues of dietary restricted rats. Mech Ageing Dev 59: 111—121.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Maeda H., Gleiser CA, Masoro EJ, Murata I., McMahan CA, Yu BP (1985). Nutrional influences on aging of Fisher 344 rats. II. Pathology. J Gerontol 40: 671—688.[Abstract/Free Full Text]
• Marshall S., Garvey WT, Traxinger RR (1991). Insights into the metabolic regulation of insulin action and insulin resistance: Role of glucose and amino acids. FASEB J 5: 3031—3036.[Abstract]
• Masoro EJ (1991). Biology of aging: Facts, thoughts, and experimental approaches. Lab Invest 65: 500—510.[Web of Science][Medline] [Order article via Infotrieve]
• Masoro EJ, McCarter RJ, Katz MS, McMahan CA (1992). Dietary restriction alters characteristics of glucose fuel use. J Gerontology 47(6): B202— B208.
• Masoro EJ (1996). Possible mechanisms underlying the antiaging actions of caloric restriction. Toxicol Pathol 24(6): 738—741.[Abstract/Free Full Text]
• Masoro EJ, Eustad SD (1996). The evolution of the antiaging action of dietary restriction: A hypothesis. J Gerontology 51A: B387—B391.
• Masoro EJ, McCarter RJM (1991). Aging as a consequence of fuel utilization. Aging 3: 117—128.[Medline] [Order article via Infotrieve]
• Masoro EJ, Iwasaki K., Gleiser CA, McMahan CA, Seo EJ, Yu BP (1989). Dietary modulation of the progression of nephropathy in aging rats: An evaluation of the importance of protein. Am J Clin Nutr 49: 1217—1227.[Abstract/Free Full Text]
• Masoro EJ, Shimokawa I., Yu BP (1991). Retardation of the aging process in rats by food restriction. Ann NY Acad Sci 621: 337—352.[Web of Science][Medline] [Order article via Infotrieve]
• Nakama K., Shichinoe K., Koàbayashi K., Naito K., Ushida O., Yasuhara K., Tobe M. ( 1985). Spontaneous diabetes-like syndrome in WBN/KOB rats. Acta Diabetol Lat: 22: 335—342.[Web of Science][Medline] [Order article via Infotrieve]
• Owen RA, Heywood R. (1986). Age-related variations in renal structure and function in Sprague—Dawley rats. Toxicol Pathol 14: 158—167.[Medline] [Order article via Infotrieve]
• Rao GN, Edmondson J., Elwell MR (1993). Influence of dietary protein concentration on severity of nephropathy in Fischer-344 (F-344/N) rats. Toxicol Pathol 21: 353—361.[Web of Science][Medline] [Order article via Infotrieve]
• Reaven EP, Gold G., Reaven GM (1979). Effect of age on glucose-stimulated insulin release by the beta cell of the rat. J Clin Invest 64: 591— 599.
• Reaven E., Wright D., Mondon CE, Solomon R., Ho H., Reaven GM (1983). Effect of age and diet on insulin secretion and insulin action in the rat. Diabetes 32: 175—180.[Abstract]
• Reaven GM, Reaven E. (1981). Prevention of age-related hypertriglyceridemia by caloric restriction and exercise training in the rat. Metabolism 30: 982—986.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Remacle C., Hauser N., Jeanjean M., Gommers A. (1977). Morphometric analysis of endocrine pancreas in old rats. Exp Gerontol 12: 207— 214.
• Roe FJC, Lee PN, Conybeare G., Kelly D., Matter B., Prentice D., Tobin G. (1995). The biosure study: Influence of composition of diet and food consumption on longevity, degenerative disease and neoplasi a in Wistar rats studies for up to 30 months post weaning. Food and Chem Toxicol 33 (suppl 1): 1S—100S.
• Ross MH ( 1976). Nutrition and longevity in experimental animals. In: Nutrition and Aging, Winick M (ed). Wiley, New York.
• Shino A., Matsuo T., Iwatsuka H., Suzuoki Z. (1973). Structural changes of pancreatic islets in genetically obese rats. Diabetologia 9: 413—421.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Tapp DC, Wortham WG, Addison JF, Hammonds DN, Barnes JL, Venkatachalam MA (1989). Food restriction retards body growth and prevents end-stage renal pathology in remnant kidneys of rats regardless of protein intake. Lab Invest 60: 184—185.[Web of Science][Medline] [Order article via Infotrieve]
• Tukey JW, Cinimera JL, Heyse JF (1985). Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 41: 295—301.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Turturro A., Duffy P., Hart RW ( 1995). The effect of caloric modulation on toxicity studies. In: Dietary restriction: Implications for the design and interpretation of toxicity and carcinogenicity studies. Hart RW, Neumann DA, Robertson RT (eds). ILSI Press, Washington, DC. pp 79— 97.
• Weibel ER (1979). Practical methods for biological morphometry. In: Stereological methods. Vol. 1, Academic Press, San Diego, CA. pp 101—162.
• Weindruch R., Walford RL (1988). The retardation of aging and disease by dietary restriction. Charles C Thomas, Springfield, IL.
• Weindruch R. (1996). The retardation of aging by caloric restriction: Studies in rodents and primates. Toxicol Pathol 24(6): 742—745.[Abstract/Free Full Text]
• Wolf N., Pendergrass W. (1995). In vivo cell replication rates and in vitro cell replication capacity are modulated by caloric intake. In: Dietary restriction: Implications for the design and interpretation of toxicity and carcinogenicity studies. Hart RW, Neumann DA, Robertson RT (eds). ILSI Press, Washington, DC, pp 229—310.
• Yu BP (ed). (1995). Modulation of Aging Processes by Dietary Restriction. CRC Press, Boca Raton, FL.

Toxicologic Pathology, Vol. 29, No. 3, 353-362 (2001)
DOI: 10.1080/019262301316905318


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Imaoka, H. Satoh, and K. Furuhama Age- and Sex-Related Differences in Spontaneous Hemorrhage and Fibrosis of the Pancreatic Islets in Sprague-Dawley Rats Toxicol Pathol, April 1, 2007; 35(3): 388 - 394. [Abstract] [Full Text] [PDF]

				K. P. Keenan, C.-M. Hoe, L. Mixson, C. L. Mccoy, J. B. Coleman, B. A. Mattson, G. A. Ballam, L. A. Gumprecht, and K. A. Soper Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague-Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction Toxicol Pathol, October 1, 2005; 33(6): 650 - 674. [Abstract] [Full Text] [PDF]

				S. Molon-Noblot, M.-F. Hubert, C.-M. Hoe, K. Keenan, and P. Laroque The Effects of Ad Libitum Feeding and Marked Dietary Restriction on Spontaneous Skeletal Muscle Pathology in Sprague-Dawley Rats Toxicol Pathol, August 1, 2005; 33(5): 600 - 608. [Abstract] [Full Text] [PDF]

				S. Molon-Noblot, P. Laroque, J. B. Coleman, C.-M. Hoe, and K. P. Keenan The Effects of Ad Libitum Overfeeding and Moderate and Marked Dietary Restriction on Age-Related Spontaneous Pituitary Gland Pathology in Sprague--Dawley Rats Toxicol Pathol, April 1, 2003; 31(3): 310 - 320. [Abstract] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Molon-Noblot, S. Articles by Laroque, P. Search for Related Content PubMed PubMed Citation Articles by Molon-Noblot, S. Articles by Laroque, P. Social Bookmarking                         What's this?