Analysis of the endocrine pancreas in adulthood in rats born with intrauterine growth restriction

Authors

DOI:

https://doi.org/10.33448/rsd-v14i7.49197

Keywords:

Intrauterine growth restriction, Pancreatic islets, Oxidative stress, Diabetes.

Abstract

Uncontrolled maternal hyperglycemia can negatively program fetal development, resulting in growth restriction and increased risk of metabolic diseases in adulthood. Severe diabetes (uncontrolled) was induced by streptozotocin (a beta-cytotoxic drug) as a model to cause fetal growth restriction. The aim of this study was to evaluate the functional characteristics of the pancreatic islets of these adult SGA rats at the end of pregnancy, to understand the role of major endocrine–pancreatic hormones in reproductive dysfunctions. For this purpose, non-diabetic and severely diabetic Sprague Dawley rats were used to obtain female offspring (F1), which were classified as appropriate (AGA) or small (SGA) for gestational age, generating two groups: AGA from non-diabetic mothers (Control) and SGA from severely diabetic mothers (SGA group) (n = 10 animals/group. No differences were observed in insulin-, glucagon-, proliferation-, or apoptosis-positive cells. Decompensated maternal diabetes led to intrauterine growth restriction in the offspring and is associated with glucose intolerance, hyperinsulinemia, and oxidative stress in adult females. Although no significant changes were observed in the proportion of insulin-positive cells, the increase in somatostatin-immunoreactive cells suggests that glycemic dysfunction may involve alterations in non-β cells, affecting insulin signaling and secretion. These findings highlight the need for further studies to explore the cellular mechanisms involved in this process.

References

Aerts, L., & Van Assche, F. A. (1977). Rat foetal endocrine pancreas in experimental diabetes. J Endocrinol.73, 339-46.

Aerts, L., & Van Assche, F. A. (2006). Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol. 38(5-6), 894-903.

Akamine, C T & Yamamoto, R K (2009). Estudo dirigido: estatística descritiva. (3ed). Editora Érica. Bekman, OR & Costa Neto, PLO (2009). Análise estatística da decisão. (2ed). Ed. Edgar Blucher.

Atkinson, M .A., Campbell-Thompson, M., Kusmartseva, I., & Kaestner, K. H. (2020). Organisation of the human pancreas in health and in diabetes. Diabetologia. 63(10), 1966-1973.

Barker, D. J. P., Osmond, C., Golding, J., Kuh, D., & Wadsworth, M. E. J. (1989). Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ.298, 564–7.

Benediktsson, R., Lindsay, R. S., Noble, J., Seckl, J. R., & Edwards, C. R. (1993) Glucocorticoid exposure in utero: new model for adult hypertension. Lancet. 341(8841), 339e41.

Berends, L. M., Dearden, L., Tung, Y. C. L., Voshol, P., Fernandez-Twinn, D. S., & Ozanne, S. E. (2018). Programming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice. Diabetologia. 61, 2225–34.

Brereton, M. F., Vergari, E., Zhang, Q., & Clark, A. (2015). Alpha-, Delta- and PP-cells: Are They the Architectural Cornerstones of Islet Structure and Co-ordination? J Histochem Cytochem. 63(8), 575-91.

Burgos-Morón, E., Abad-Jiménez, Z., Marañón, A. M., Iannantuoni, F., Escribano-López, I., López-Domènech, S., Salom, C., Jover, A., Mora, V., Roldan, I., Solá, E., Rocha, M., & Víctor, V. M. (2019). Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues. J Clin Med. 4;8(9), 1385.

Chew, L. C., & Verma, R. P. (2021). Fetal growth restriction. In: StatPearls. StatPearls Publishing: Treasure Island (FL). 1–16.

Corvino, S. B., Netto, A. O., Sinzato, Y. K., Campos, K. E., Calderon, I. M., Rudge, M. V., et al. (2015a). Intrauterine growth restricted rats exercised at pregnancy. Reprod Sci. 22, 991–99.

Corvino, S. B., Volpato, G. T., Rudge, M. V., & Damasceno, D. C. (2015b). Intrauterine Growth Restricted Rats Exercised before and during Pregnancy: Maternal and Perinatal Repercussions. Evid Based Complement Alternat Med. 2015, 294850.

Cruz, L. L., Barco, V. S., Paula, V. G., Gallego, F. Q., Souza, M. R., Corrente, J. E., Zambrano, E., Volpato, G. T., & Damasceno, D. C. (2023). Severe Diabetes Induction as a Generational Model for Growth Restriction of Rat. Reprod Sci. 30(8), 2416-2428.

Fernandez-Twinn, D. S., & Ozanne, S. E. (2006). Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Phys Behav. 88(3), 234-243.

Gatford, K. L., Kaur, G., Falcão-Tebas, F., Wadley, G. D., Wlodek, M. E., Laker, R. C., Ebeling, P. R., & McConell, G. K. (2014). Exercise as an intervention to improve metabolic outcomes after intrauterine growth restriction. Am J Physiol Endocrinol Metab. 1;306(9), E999-1012.

Girard, J. R., Ferre, P., Gilbert, M., Kervran, A., Assan, R., & Marliss, E. B. (1977). Fetal metabolic response to maternal fasting in the rat. Am J Physiol. 232(5): E456e63.

Gluckman, P. D., & Hanson, M. A. (2007). Developmental plasticity and human disease: research directions. J Intern Med. 261(5), 461–471.

Gluckman, P. D., Hanson, M. A., & Buklijas, T. (2010). A conceptual framework for the developmental origins of health and disease. J Dev Orig Health Dis. 1(1), 6-18.

Guzman, C., Cabrera, R., Cardenas, M., Larrea, F., Nathanielsz, P. W., & Zambrano, E. (2006) Protein restriction during fetal and neonatal development in the rat alters reproductive function and accelerates reproductive ageing in female progeny. J Physiol. 572, 97-108.

Hales, C .N., & Barker, D .J. (2001). The thrifty phenotype hypothesis. Br Med Bull. 60, 5–20.

Harris, R. B. S. (1998). Acute and chronic effects of leptin on glucose utilization in lean mice. Biochem Biophys Res Commun. 245, 502–9.

Holemans, K., Aerts, L., & Van Assche, F. A. (2003). Fetal growth restriction and consequences for the offspring in animal models. J Soc Gynecol Investig.10, 392–99.

Holemans, K., Aerts, L., & Van Assche, F. A. (2003). Fetal growth restric tion and consequences for the ofspring in animal models. J Soc Gynecol Investig. 10:392–9.

Kordowich, S., Mansouri A., & Collombat, P. (2009). Reprogramming into pancreatic endocrine cells based on developmental cues Mol. Cell. Endocrinol. 315, 11-18.

Lai, L. L., Lu, H. Q., Li, W. N., Huang, H. P., Zhou, H. Y., Leng, E. N., & Zhang, Y. Y. (2021). Protective effects of quercetin and crocin in the kidneys and liver of obese Sprague-Dawley rats with Type 2 diabetes: Effects of quercetin and crocin on T2DM rats. Hum Exp Toxicol. 40, 661-672.

Melamed, N., Baschat, A., Yinon, Y., Athanasiadis, A., Mecacci, F., Figueras, F., et al. (2021). FIGO (International Federation of Gynecology and obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction. Int J Gynaecol Obstet. 152, 3–57.

Moraes-Souza, R. Q., Soares, T. S., Carmo, N. O., Damasceno, D. C., Campos, K. E., & Volpato, G. T. (2017). Adverse effects of Croton urucurana B. exposure during rat pregnancy. J. Ethnopharmacol. 199, 328–333,

Müller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D., & Tschöp, M. H. (2017). The New Biology and Pharmacology of Glucagon. Physiol Rev. 97(2), 721-766.

Nassar, A. H., Masrouha, K. Z., Itani, H., Nader, K. A., & Usta, I. M. (2012). Effects of sildenafil in nomega-nitro-L-arginine methyl ester-induced intrauterine growth restriction in a rat model. Am J Perinatol 29(6), 429e34.

Nathanielsz, P. W. (2006). Animal models that elucidate basic principles of the developmental origins of adult diseases. ILAR J. 47(1), 73-82.

Nazari, Z., Nabiuni, M., Ghaffari, S., Saeidi, M., Shahriyari, A., & Golalipour, M .J. (2017). Gestational Diabetes Induces Pancreatic Beta-Cells Apoptosis in Adult Rat Offspring. Int. J. Morphol. 35(1), 16-20, 2017.

Ozanne, S. E., & Hales, C. N. (2004). Lifespan: catch-up growth and obesity in male mice. Nature. 427(6973), 411-412.

Paula, V. G., Sinzato, Y. K., Moraes-Souza, R. Q., Soares, T. S., Souza, F Q G, Karki B, Andrade Paes A M, et al. (2022). Metabolic changes in female rats exposed to intrauterine hyperglycemia and post-weaning consumption of high-fat diet. Biol Reprod. 106, 200–12.

Pereira A. S. et al. (2018). Metodologia da pesquisa científica. [e-book gratuito]. Ed.UAB/NTE/UFSM. Shitsuka et al. (2014). Matemática fundamental para a tecnologia. São Paulo: Ed. Érica.

Petersen, M. C., & Shulman, G. I. (2018). Mechanisms of insulin action and insulin resistance, Physiol. Rev. 98 (4), 2133–2223.

Petersen, M. C., Vatner, D. F., & Shulman, G. I. (2017). Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 3(10), 572-587.

Pfeifer, C. R., Shomorony, A., Aronova, M. A., Zhang, G., Cai, T., Xu, H., Notkins, A. L., & Leapman, R. D. (2015). Quantitative analysis of mouse pancreatic islet architecture by serial block-face SEM. J Struct Biol.189(1), 44-52.

Ravelli, A. C., Van Der Meulen, J. H., Osmond, C., Barker, D. J., & Bleker, O. P. (1999). Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr. 70(5), 811-816.

Ravishankar, V., Buhimschi. C. S., Booth, C. J., Bhandari, V., Norwitz, E., Copel, J., et al. (2007). Fetal nucleated red blood cells in a rat model of intrauterine growth restriction induced by hypoxia and nitric oxide synthase inhibition. Am J Obstet Gynecol. 196(5). 482 e1e482 e8.

Resnick, O., Morgane, P. J., Hasson, R., & Miller, M. (1982). Overt and hidden forms of chronic malnutrition in the rat and their relevance to man. Neurosci Biobehav Rev. 6(1), 55e75.

Roseboom, T. J., Van der Meulen, J. H., Ravelli, A. C., et al. (1999). Blood pressure in adults after prenatal exposure to famine. J Hypertens. 17(3), 325-330.

Simpson, J., & Kelly, J. P. (2011). The impact of environmental enrichment in laboratory rats-Behavioural and neurochemical aspects. Behav Brain Res. 222(1), 246-64.

Sinzato, Y. K., Gelaleti, R. B., Volpato, G. T., Rudge, M. V. C., Herrera, E., & Damasceno, D. C. (2020). Streptozotocin-induced leukocyte DNA damage in rats. Drug Chem Toxicol. 43(2), 165-168.

Sinzato, Y. K., Klöppel, E., Miranda, C. A., Paula, V. G., Alves, L. F., Nascimento, L. L. S., et al. (2021). Comparison of streptozotocin-induced diabetes at different moments of the life of female rats for translational studies. Lab Anim Res.55, 329–40.

Sinzato, Y. K., Paula, V. G., Gallego, F. Q., Moraes-Souza, R. Q., Corrente, J. E., Volpato, G. T., & Damasceno, D. C. (2022). Maternal diabetes and postnatal high-fat diet on pregnant offspring. Front Cell Dev Biol.10, 818621.

Tai, M. A. (1994). Mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes Care.17, 152–4.

Tanaka, M., Natori, M., Ishimoto, H., Miyazaki, T., Kobayashi, T., & Nozawa, S. (1994). Experimental growth retardation produced by transient period of uteroplacental ischemia in pregnant Sprague-Dawley rats. Am J Obstet Gynecol. 171(5), 1231e4.

Tentor, L., & Salvati, A. M.(1981). Hemoglobinometry in human blood. Methods Enzymol. 1981;76, 707–15.

Volpato, G. T., Damasceno, D. C., Sinzato, Y. K., Ribeiro, V. M., Rudge, M. V., & Calderon, I. M. (2015). Oxidative stress status and placental implications in diabetic rats undergoing swimming exercise after embryonic implantation. Reprod Sci. 22(5), 602-8.

White, V., Jawerbaum, A., Mazzucco, M. B., Gauster, M., Desoye, G., & Hiden, U. (2015). Diabetes-associated changes in the fetal insulin/insulin-like growth factor system are organ specific in rats. Pediatr Res.77, 48-55.

Wigglesworth, J. S. (1974). Fetal growth retardation. Animal model: uterine vessel ligation in the pregnant rat. Am J Pathol. 77(2), 347e50.

Woodall, S. M., Breier, B. H., Johnston, B. M., Bassett, N. S., Barnard, R., & Gluckman, P. D. (1999). Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring. J Endocrinol. 163(1), 69e77.

Woodall, S. M., Breier, B. H., Johnston, B. M., & Gluckman, P. D. (1996). A model of intrauterine growth retardation caused by chronic maternal undernutrition in the rat: effects on the somatotrophic axis and postnatal growth. J Endocrinol. 150(2), 231e42.

Yaribeygi, H., Atkin, S. L., & Sahebkar, A. (2019). Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function. Journal of Cellular Physiology. 234 (6), 8402–8410.

Zambrano, E. (2009). The transgenerational mechanisms in developmental programming of metabolic diseases. Rev Invest Clin. 1(1), 41-52.

Zhou, W., & YE, S. (2018). Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol Int. 42, 1282-1291.

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Published

2025-07-10

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Health Sciences

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Analysis of the endocrine pancreas in adulthood in rats born with intrauterine growth restriction . Research, Society and Development, [S. l.], v. 14, n. 7, p. e3414749197, 2025. DOI: 10.33448/rsd-v14i7.49197. Disponível em: https://rsdjournal.org/rsd/article/view/49197. Acesso em: 5 dec. 2025.