Effect of Diabetes on Circulating Pancreatic Hormones in Pregnant Rats and Their Offspring

Abstract

The aim of the study was to investigate the role of diabetic intrauterine environment on circulating insulin, glucagon, and somatostatin levels in pregnant rats, fetuses, and offspring. Diabetes was induced in female Wistar rats by streptozotocin at birth or as adult and the animals were assigned into: control (C); mildly diabetic (MD); and severely diabetic (SD). The rats were mated and distributed into 2 subgroups: euthanasia at day 21 of pregnancy and at day 10 postpartum. Both MD and SD dams showed impaired oral glucose tolerance. SD dams had lower body weight and insulin levels compared to C and MD dams. SD fetuses presented hyperglycemia and reduction of insulin and glucagon levels compared to C and MD fetuses. SD newborns had diminished total pancreatic insulin and plasma somatostatin compared to the other groups. MD dams and fetuses had lower glucagon and somatostatin levels compared to C dams. MD offspring had maintained lower somatostatin levels to neonatal period. Diabetes causes alterations in circulating levels of pancreatic hormones in the mother and offspring.

Key words

diabetes - glucagon - insulin - somatostatin - pregnancy - streptozotocin

• References

• 1 World Health Organization (WHO) . Global report on diabetes. Geneva: 2016
• 2 Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care 2007; 30: S141-S146
• 3 Ilegems E, van Krieken PP, Edlund PK, Dicker A, Alanentalo T, Eriksson M, Mandic S, Ahlgren U, Berggren PO. Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion. Sci Rep 2015; 1: 10740
• 4 Caicedo A. Paracrine and autocrine interactions in the human islet: more than meets the eye. Semin Cell Dev Biol 2013; 24: 11-21
• 5 Moutelik M. Fisiologia do pâncreas endócrino. In: Bandeira F, et al. (ed.) Endocrinologia e Diabetes, Medsi. 2003: 794-799
• 6 Eriksson UJ. Congenital anomalies in diabetic pregnancy. Seminars in Fetal & Neonatal Medicine 2008; 1-9
• 7 Edvell A, Lindström P. Development of insulin secretory function in young obese hyperglycemic mice (Umea ob/ob). Metabolism 1995; 44: 906-913
• 8 Fowden AL, Hill DJ. Intrauterine programming of the endocrine pancreas. Br Med Bull 2001; 60: 123-142
• 9 Holemans K, Aerts L, Van Assche FA. Lifetime consequences of abnormal fetal pancreatic development. J Physiol 2003; 547: 11-20
• 10 Sinzato YK, Damasceno DC, Laufer-Amorim R, Rodrigues MMP, Oshiiwa M, Taylor KN, Rudge MV. Plasma concentrations and placental immunostaining of interleukin-10 and tumor necrosis factor-α as predictors of alterations in the embryofetal organism and the placental development of diabetic rats. Braz J Med Biol Res 2011; 44: 206-211
• 11 de Campos KE, Sinzato YK, Pimenta WP, Rudge MV, Damasceno DC. Effect of maternal obesity on diabetes development in adult rat offspring. Life Sci 2007; 81: 1473-1478
• 12 Dallaqua B, Saito FH, Rodrigues T, Calderon IM, Rudge MV, Herrera E, Damasceno DC. Treatment with Azadirachta indica in diabetic pregnant rats: negative effects on maternal outcome. J Ethnopharmacol 2012; 143: 805-811
• 13 Tai MM. A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes Care 1994; 17: 152-154
• 14 de Souza MSS, Lima PHO, Sinzato YK, Rudge MVC, Pereira OCM, Damasceno DC. Effects of cigarette smoke expose on pregnancy outcome of diabetic rats and on their offspring. Reproductive Bio Medicine Online 2009; 18: 562-567
• 15 Lenzen S, Tiedge M, Jörns A, Munday R. Alloxan derivatives as a tool for the elucidation of the mechanism of the diabetogenic action of alloxan. In: Shafrir E. (ed.) Lessons from animal diabetes. Boston: 1996: 113-122
• 16 Arison RN, Ciaccio EI, Glitzer MS, Cassaro JA, Pruss MP. Light and electron microscopy of lesions in rats rendered diabetic with streptozotocin. Diabetes 1967; 16: 51-56
• 17 Rerup CC. Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 1970; 22: 485-518
• 18 Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 2008; 51: 216-226
• 19 Wei M, Ong L, Smith MT, Ross FB, Schmid K, Hoey AJ, Burstow D, Brown L. The streptozotocin-diabetic rat as a model of the chronic complications of human diabetes. Heart Lung Circ 2003; 12: 44-50
• 20 Karunanyake EH, Hearse DJ, Mellows G. The synthesis of C14Streptozotocin and its distribution and excretion in the rat. Biochem J 1974; 142: 673-683
• 21 Stoffers DA. The Development of Beta-cell Mass: Recent Progress and Potential Role of GLP-1. Horm Metab Res 2004; 35: 811-821
• 22 Portha B, Blondel O, Serradas P, McEvoy R, Giroix MH, Kergoat M, Bailbe D. The rat models of non-insulin dependent diabetes induced by neonatal streptozotocin. Diabete Metab 1989; 15: 61-75
• 23 Junod A, Lambert AE, Stauffacher W, Renold AE. Diabetogenic action of streptozotocin: relationship of dose to metabolic response. J Clin Invest 1969; 48: 2129-2139
• 24 Liang XD, Guo YY, Sun M, Ding Y, Wang N, Yuan L, De W. Streptozotocin-induced expression of Ngn3 and Pax4 in neonatal rat pancreatic α-cells. World J Gastroenterol 2011; 17: 2812-2820
• 25 Georgia S, Bhushan A. β-cell replication is the primary mechanism for maintaining postnatal b-cell mass. J Clin Investig 2004; 114: 963-968
• 26 Bonner-Weir S, Trent DF, Honey RN, Weir GC. Responses of neonatal rat islets to streptozotocin: limited Bcell regeneration and hyperglycemia. Diabetes 1981; 30: 64-69
• 27 Sinzato YK, Lima PH, Campos KE, Kiss AC, Rudge MV, Damasceno DC. Neonatally-induced diabetes: lipid profile outcomes and oxidative stress status in adult rats. Rev Assoc Med Bras 2009; 55: 384-388
• 28 Sinzato YK, Volpato GT, Iessi IL, Bueno A, Calderon IM, Rudge MVC, Damasceno DC. Neonatally induced mild diabetes in rats and its effect on maternal, placental, and fetal parameters. Exp Diabetes Res 2012; 108163
• 29 Damasceno DC, Sinzato YK, Lima PH, de Souza MS, Campos KE, Dallaqua B, Calderon IM, Rudge MV, Volpato GT. Effects of exposure to cigarette smoke prior to pregnancy in diabetic rats. Diabetol Metab Syndr 2011; 18: 3-20
• 30 Eriksson UJ, Borg LA, Cederberg J, Nordstrand H, Siman CM, Wentzel C, Wentzel P. Pathogenesis of diabetes-induced congenital malformations. Ups J Med Sci 2000; 105: 53-84
• 31 Eriksson UJ, Cederberg J, Wentzel P. Congenital malformations in offspring of diabetic mothers-animal and human studies. Rev Endocr Metab Disord 2003; 4: 79-93
• 32 Jawerbaum A, Higa R, White V, Capobianco E, Pustovrh C, Sinner D, Martínez N, González E. Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis. Reproduction 2005; 130: 695-703
• 33 Giroix MH, Portha B, Kergoat M, Picon L. Glucagon secretion in rats with non-insulin-dependent diabetes: an in vivo and in vitro study. Diabete Metab 1984; 10: 12-17
• 34 Weir GC, Clore ET, Zmachinski CJ, Bonner-Weir S. Islet secretion in a new experimental model for non-insulin-dependent diabetes. Diabetes 1981; 30: 590-595
• 35 Mendoza RG, Perego C, Finzi G, La Rosa S, Capella C, Jimenez-Ceja LM, Velloso LA, Saad MJ, Sessa F, Bertuzzi F, Moretti S, Dick Jr EJ, Davalli AM, Folli F. Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas). Diabetologia 2015; 58: 1814-1826
• 36 Orci L, Baetens D, Rufener C, Amherdt M, Ravazzola M, Studer P, Malaisse-Lagae F, Unger RH. Hypertrophy and hyperplasia of somatostatin-containing D-cells in diabetes. Proc Natl Acad Sci U S A 1976; 73: 1338-1342
• 37 Iki K, Pour PM. Distribution of pancreatic endocrine cells including IAPP-expressing cells in non-diabetic and type 2 diabetic cases. J Histochem Cytochem 2007; 55: 111-118
• 38 Soejima K, Landing BH. Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies. Pediatr Pathol 1986; 6: 25-46
• 39 Aerts L, Vercruysse L, Van Assche FA. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats. Diabetes Res Clin Pract 1997; 38: 9-19
• 40 Wu CS, Nohr EA, Bech BH, Vestergaard M, Olsen J. Long-term health outcomes in children born to mothers with diabetes: a population-based cohort study. PLoS One 2012; 7: e36727
• 41 Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol 1954; 16: 342-347
• 42 Holemans K, Aerts L, Van Assche FA. Fetal growth restriction and consequences for the offspring in animal models. J SocGynecol Invest 2003; 10: 392-399
• 43 Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 1997; 138: 1736-1741
• 44 Gittes GK. Developmental biology of the pancreas: a comprehensive review. Dev Biol 2009; 326: 4-35
• 45 Corvino SB, Volpato GT, Rudge MV, Damasceno DC. Intrauterine Growth Restricted Rats Exercised before and during Pregnancy: Maternal and Perinatal Repercussions. Evid Based Complement Alternat Med 2015; 2015: 294850
• 46 Boloker J, Gertz SJ, Simmons RA. Gestational diabetes leads to the development of diabetes in adulthood in the rat. Diabetes 2002; 51: 1499-1506
• 47 Van Assche FA, Aerts L, Holemans K. The effects of maternal diabetes on the offspring. Baillieres Clin Obstet Gynaecol 1991; 5: 485-492
• 48 Bousquet C, Guillermet J, Vernejoul F, Lahlou H, Buscail L, Susini C. Somatostatin receptors and regulation of cell proliferation. Dig Liver Dis 2004; 36: S2-S7