This Article Full Text Full Text (PDF) 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 Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petrik, J. Articles by Hill, D. J. Search for Related Content PubMed PubMed Citation Articles by Petrik, J. Articles by Hill, D. J.

A Low Protein Diet Alters the Balance of Islet Cell Replication and Apoptosis in the Fetal and Neonatal Rat and Is Associated with a Reduced Pancreatic Expression of Insulin-Like Growth Factor-II¹

Lawson Research Institute (J.P., E.A., C.C., D.J.H.), St. Joseph’s Health Centre, London, Ontario N6A 4V2, Canada; Departments of Physiology (J.P., C.C., D.J.H.), Medicine (E.A., D.J.H.), and Paediatrics (J.P., D.J.H.), University of Western Ontario, London, Ontario N6A 5A5, Canada; and Laboratoire de Biologie Cellulaire (B.R., C.R., J.J.H.), World Health Organization Collaborating Centre for the Development of the Biology of the Endocrine Pancreas, Université Catholique de Louvain, B-1348 Louvain-La-Neuve, Belgium

Address all correspondence and requests for reprints to: Dr. D. J. Hill, Lawson Research Institute, St. Joseph’s Health Centre, 268 Grosvenor Street, London, Ontario, Canada, N6A 4V2. E-mail: dhill{at}lri.stjosephs.london.on.ca

A programmed turnover of pancreatic ß cells occurs in the neonatal rat involving a loss of ß cells by apoptosis, and their replacement by islet cell replication and neogenesis. The timing of apoptosis is associated with a loss of expression of a survival factor, insulin-like growth factor-II (IGF-II), in the pancreatic islets. Offspring from rats chronically fed a low protein isocalorific diet (LP) exhibit a reduced pancreatic ß cell mass at birth and a reduced insulin secretion in later life. This study therefore investigated the impact of LP on islet cell ontogeny in the late fetal and neonatal rat, and any associated changes in the presence of IGFs and their binding proteins (IGFBPs). Pregnant Wistar rats were fed either LP (8% protein) or normal (C) (20% protein) chow from shortly after conception until the offspring were 21 days postnatal (PN). Bromo-deoxyuridine (BrdU) was administered 1 h before rats were killed and pancreata removed from animals between 19.5 days fetal life and postnatal day 21. Offspring of rats given LP diet had reduced birthweight, pancreatic ß cell mass, and pancreas insulin content, with smaller islets compared with control fed animals, which persisted to weaning. Histological analysis showed that islets from pups given LP diet had a lower nuclear labeling index with BrdU in the ß cells, although, paradoxically, more ß cells showed immunoreactivity for proliferating cell nuclear antigen (PCNA). Because PCNA is present in G1 as well as S phase of the cell cycle, we quantified the number of ß cells immunopositive for cyclin D1, a marker of G1, and NEK2, an indicator of cells in G2 and mitosis. More ß cells in islets from LP-fed animals contained cyclin D1, but less contained NEK2 than did those in controls. This suggests that the ß cell cycle may have a prolonged G1 phase in LP-fed animals in vivo. Offspring of rats given C diet had a low rate of islet cell apoptosis detected by the TUNEL method in fetal and neonatal life (1–2%), with a transient increase to 8% at PN day 14. Offspring of rats receiving LP diet demonstrated a significantly greater level of islet cell apoptosis at every age, rising to 15% at PN 14. IGF-II mRNA was quantified in whole pancreas and was significantly reduced in LP-fed animals at ages up to PN day 10. IGF-II immunoreactivity within the islets of LP-fed rats was also less apparent, but no changes were seen in immunoreactive IGF-I or IGFBPs-2 to -5. These findings show that LP diet changes the balance of ß cell replication and apoptosis in fetal and neonatal neonatal life, which may involve an altered length of ß cell cycle, and contribute to the smaller islet size and impaired insulin release seen in later life. A reduced pancreatic expression of IGF-II may contribute to the lower ß cell proliferation rate and increased apoptosis seen in the fetus and neonate after feeding LP diet.

This article has been cited by other articles:

				A. Chamson-Reig, E. J Arany, K. Summers, and D. J Hill A low protein diet in early life delays the onset of diabetes in the non-obese diabetic mouse J. Endocrinol., May 1, 2009; 201(2): 231 - 239. [Abstract] [Full Text] [PDF]

				J. L. Tarry-Adkins, J. H. Chen, N. S. Smith, R. H. Jones, H. Cherif, and S. E. Ozanne Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets FASEB J, May 1, 2009; 23(5): 1521 - 1528. [Abstract] [Full Text] [PDF]

				K. L. Gatford, S. N. B. Mohammad, M. L. Harland, M. J. De Blasio, A. L. Fowden, J. S. Robinson, and J. A. Owens Impaired {beta}-Cell Function and Inadequate Compensatory Increases in {beta}-Cell Mass after Intrauterine Growth Restriction in Sheep Endocrinology, October 1, 2008; 149(10): 5118 - 5127. [Abstract] [Full Text] [PDF]

				K. Yang, H. Guan, E. Arany, D. J. Hill, and X. Cao Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor FASEB J, July 1, 2008; 22(7): 2452 - 2464. [Abstract] [Full Text] [PDF]

				S. W. Limesand, P. J. Rozance, D. Smith, and W. W. Hay Jr. Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1716 - E1725. [Abstract] [Full Text] [PDF]

				I. Ueki and M. H. Stipanuk Enzymes of the Taurine Biosynthetic Pathway Are Expressed in Rat Mammary Gland J. Nutr., August 1, 2007; 137(8): 1887 - 1894. [Abstract] [Full Text] [PDF]

				J. E Bruin, L. D Kellenberger, H. C Gerstein, K. M Morrison, and A. C Holloway Fetal and neonatal nicotine exposure and postnatal glucose homeostasis: identifying critical windows of exposure J. Endocrinol., July 1, 2007; 194(1): 171 - 178. [Abstract] [Full Text] [PDF]

				S. P. Bagby Developmental Hypertension, Nephrogenesis, and Mother's Milk: Programming the Neonate J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1626 - 1629. [Full Text] [PDF]

				G. Guillemain, G. Filhoulaud, G. Da Silva-Xavier, G. A. Rutter, and R. Scharfmann Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation J. Biol. Chem., May 18, 2007; 282(20): 15228 - 15237. [Abstract] [Full Text] [PDF]

				E. Fernandez, M. A. Martin, S. Fajardo, F. Escriva, and C. Alvarez Increased IRS-2 content and activation of IGF-I pathway contribute to enhance beta-cell mass in fetuses from undernourished pregnant rats Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E187 - E195. [Abstract] [Full Text] [PDF]

				A. Chamson-Reig, S. M Thyssen, E. Arany, and D. J Hill Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. J. Endocrinol., October 1, 2006; 191(1): 83 - 92. [Abstract] [Full Text] [PDF]

				I. El Khattabi, C. Remacle, and B. Reusens The regulation of IGFs and IGFBPs by prolactin in primary culture of fetal rat hepatocytes is influenced by maternal malnutrition Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E835 - E842. [Abstract] [Full Text] [PDF]

				P. M. Vuguin, M. H. Kedees, L. Cui, Y. Guz, R. W. Gelling, M. Nejathaim, M. J. Charron, and G. Teitelman Ablation of the Glucagon Receptor Gene Increases Fetal Lethality and Produces Alterations in Islet Development and Maturation Endocrinology, September 1, 2006; 147(9): 3995 - 4006. [Abstract] [Full Text] [PDF]

				S. R. de Rooij, R. C. Painter, D. I.W. Phillips, C. Osmond, R. P.J. Michels, I. F. Godsland, P. M.M. Bossuyt, O. P. Bleker, and T. J. Roseboom Impaired Insulin Secretion After Prenatal Exposure to the Dutch Famine Diabetes Care, August 1, 2006; 29(8): 1897 - 1901. [Abstract] [Full Text] [PDF]

				M. H. Vickers, P. D. Gluckman, A. H. Coveny, P. L. Hofman, W. S. Cutfield, A. Gertler, B. H. Breier, and M. Harris Neonatal Leptin Treatment Reverses Developmental Programming Endocrinology, October 1, 2005; 146(10): 4211 - 4216. [Abstract] [Full Text] [PDF]

				E Zambrano, P. M Martinez-Samayoa, C. J Bautista, M Deas, L Guillen, G. L Rodriguez-Gonzalez, C Guzman, F Larrea, and P. W Nathanielsz Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation J. Physiol., July 1, 2005; 566(1): 225 - 236. [Abstract] [Full Text] [PDF]

				M. Thamotharan, B.-C. Shin, D. T. Suddirikku, S. Thamotharan, M. Garg, and S. U. Devaskar GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E935 - E947. [Abstract] [Full Text] [PDF]

				S. W. Limesand, J. Jensen, J. C. Hutton, and W. W. Hay Jr. Diminished {beta}-cell replication contributes to reduced {beta}-cell mass in fetal sheep with intrauterine growth restriction Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1297 - R1305. [Abstract] [Full Text] [PDF]

				I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]

				T. Sparre, M. R. Larsen, P. E. Heding, A. E. Karlsen, O. N. Jensen, and F. Pociot Unraveling the Pathogenesis of Type 1 Diabetes with Proteomics: Present And Future Directions Mol. Cell. Proteomics, April 1, 2005; 4(4): 441 - 457. [Abstract] [Full Text] [PDF]

				H. Guan, E. Arany, J. P. van Beek, A. Chamson-Reig, S. Thyssen, D. J. Hill, and K. Yang Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E663 - E673. [Abstract] [Full Text] [PDF]

				M. A Martin, P. Serradas, S. Ramos, E. Fernandez, L. Goya, M. N. Gangnerau, M. Lacorne, A. M. Pascual-Leone, F. Escriva, B. Portha, et al. Protein-Caloric Food Restriction Affects Insulin-Like Growth Factor System in Fetal Wistar Rat Endocrinology, March 1, 2005; 146(3): 1364 - 1371. [Abstract] [Full Text] [PDF]

				J. A Armitage, I. Y Khan, P. D Taylor, P. W Nathanielsz, and L. Poston Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J. Physiol., December 1, 2004; 561(2): 355 - 377. [Abstract] [Full Text] [PDF]

				S. P. Bagby Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease? J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2775 - 2791. [Full Text] [PDF]

				L. Banaei-Bouchareb, V. Gouon-Evans, D. Samara-Boustani, M. C. Castellotti, P. Czernichow, J. W. Pollard, and M. Polak Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice J. Leukoc. Biol., August 1, 2004; 76(2): 359 - 367. [Abstract] [Full Text] [PDF]

				E. A. Joanette, B. Reusens, E. Arany, S. Thyssen, R. C. Remacle, and D. J. Hill Low-Protein Diet during Early Life Causes a Reduction in the Frequency of Cells Immunopositive for Nestin and CD34 in Both Pancreatic Ducts and Islets in the Rat Endocrinology, June 1, 2004; 145(6): 3004 - 3013. [Abstract] [Full Text] [PDF]

				V. Delghingaro-Augusto, F. Ferreira, S. Bordin, M. E. C. do Amaral, M. H. Toyama, A. C. Boschero, and E. M. Carneiro A Low Protein Diet Alters Gene Expression in Rat Pancreatic Islets J. Nutr., February 1, 2004; 134(2): 321 - 327. [Abstract] [Full Text] [PDF]

				S. Boujendar, E. Arany, D. Hill, C. Remacle, and B. Reusens Taurine Supplementation of a Low Protein Diet Fed to Rat Dams Normalizes the Vascularization of the Fetal Endocrine Pancreas J. Nutr., September 1, 2003; 133(9): 2820 - 2825. [Abstract] [Full Text] [PDF]

				K Holemans, L Aerts, and F A Van Assche Lifetime consequences of abnormal fetal pancreatic development J. Physiol., February 15, 2003; 547(1): 11 - 20. [Abstract] [Full Text] [PDF]

				V. C. Arantes, V. P. A. Teixeira, M. A. B. Reis, M. Q. Latorraca, A. R. Leite, E. M. Carneiro, A. T. Yamada, and A. C. Boschero Expression of PDX-1 Is Reduced in Pancreatic Islets from Pups of Rat Dams Fed a Low Protein Diet during Gestation and Lactation J. Nutr., October 1, 2002; 132(10): 3030 - 3035. [Abstract] [Full Text] [PDF]

				B. Duvillie, C. Currie, T. Chrones, D. Bucchini, J. Jami, R. L. Joshi, and D. J. Hill Increased Islet Cell Proliferation, Decreased Apoptosis, and Greater Vascularization Leading to {beta}-Cell Hyperplasia in Mutant Mice Lacking Insulin Endocrinology, April 1, 2002; 143(4): 1530 - 1537. [Abstract] [Full Text] [PDF]

				C. E Bertram and M. A Hanson Animal models and programming of the metabolic syndrome: Type 2 diabetes Br. Med. Bull., November 1, 2001; 60(1): 103 - 121. [Abstract] [Full Text] [PDF]

				A. L Fowden and D. J Hill Intra-uterine programming of the endocrine pancreas Br. Med. Bull., November 1, 2001; 60(1): 123 - 142. [Abstract] [Full Text] [PDF]

				S. E Ozanne Metabolic programming in animals: Type 2 diabetes Br. Med. Bull., November 1, 2001; 60(1): 143 - 152. [Abstract] [Full Text] [PDF]

				R. A. Simmons, L. J. Templeton, and S. J. Gertz Intrauterine Growth Retardation Leads to the Development of Type 2 Diabetes in the Rat Diabetes, October 1, 2001; 50(10): 2279 - 2286. [Abstract] [Full Text]

				F. Song, M. Srinivasan, R. Aalinkeel, and M. S. Patel Use of a cDNA Array for the Identification of Genes Induced in Islets of Suckling Rats by a High-Carbohydrate Nutritional Intervention Diabetes, September 1, 2001; 50(9): 2053 - 2060. [Abstract] [Full Text] [PDF]

				P. D. Gluckman Editorial: Nutrition, Glucocorticoids, Birth Size, and Adult Disease Endocrinology, May 1, 2001; 142(5): 1689 - 1691. [Full Text]

				A. GAROFANO, P. CZERNICHOW, and B. BRÉANT Impaired {beta}-cell regeneration in perinatally malnourished rats: a study with STZ FASEB J, December 1, 2000; 14(15): 2611 - 2617. [Abstract] [Full Text]

				D. J. Hill, B. Strutt, E. Arany, S. Zaina, S. Coukell, and C. F. Graham Increased and Persistent Circulating Insulin-Like Growth Factor II in Neonatal Transgenic Mice Suppresses Developmental Apoptosis in the Pancreatic Islets Endocrinology, March 1, 2000; 141(3): 1151 - 1157. [Abstract] [Full Text] [PDF]