Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-27T03:23:43.992Z Has data issue: false hasContentIssue false
  • English
  • Français

Insulin sensitivity in male sheep born to ewes treated with testosterone during pregnancy

Published online by Cambridge University Press:  14 July 2020

Albert Carrasco Open the ORCID record for Albert Carrasco [Opens in a new window] ,
Mónica P. Recabarren ,
Pedro P. Rojas-García ,
Nelson Silva ,
Jonathan Fuenzalida ,
Teresa Sir-Petermann  and
Sergio E. Recabarren
Albert Carrasco*
Affiliation:
Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillán, Chile
Mónica P. Recabarren
Affiliation:
Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillán, Chile
Pedro P. Rojas-García
Affiliation:
Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillán, Chile
Nelson Silva
Affiliation:
Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillán, Chile
Jonathan Fuenzalida
Affiliation:
Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillán, Chile
Teresa Sir-Petermann
Affiliation:
Laboratory of Endocrinology and Metabolism, Western School of Medicine, Universidad de Chile, Santiago, Chile
Sergio E. Recabarren
Affiliation:
Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Chillán, Chile
*
Address for correspondence: Albert Carrasco, Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, Universidad de Concepción, Avenida Vicente Méndez 595, Chillán, Chile. Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

In animal models, exposure to excess testosterone during gestation induces polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in female offspring, suggesting that the hyperandrogenemic intrauterine environment may have a role in the etiology of PCOS. Additionally, few studies have also addressed metabolic and reproductive outcomes in male offspring. In the present study, the intravenous glucose tolerance test (IGTT) was used to assess the insulin–glucose homeostasis at various ages during sexual development in male sheep born to testosterone-treated ewes. To further analyze the programming effect of testosterone on insulin–glucose homeostasis, indexes of insulin sensitivity were assessed in orchidectomized post-pubertal males born to testosterone-treated ewes (Torq-males) and orchidectomized post-puberal controls (Corq-males) before and 48 h after a testosterone injection. There was no difference in insulin sensitivity indexes between males born to testosterone-treated ewes (T-males) and control males born to control ewes (C-males) at 5, 10, 20 and 30 weeks of age, representing the infantile, early and late pre-pubertal, and early post-pubertal stage of sexual development, respectively. In orchidectomized males, basal levels of insulin and glucose were not different between both groups before and after the testosterone injection; however, Torq-males released more insulin before and after T challenge during the first 20 min of the test. Despite this, plasma glucose concentrations were not different in both groups during IVGTT, resulting in an insulin sensitivity index composite similar between groups. We concluded that the effect of prenatal exposure to excess testosterone may reprogram the pancreatic β-cells insulin release in ovine males, with effects more evident in castrated males versus intact males.

Keywords

insulin sensitivityPCOSfetal programming
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 3 , June 2021 , pp. 456 - 464
Check for updates
Copyright
© The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Barker, DJ, Clark, P. Fetal undernutrition and disease in later life. Rev Reprod. 1997; 2, 105–112.CrossRefGoogle ScholarPubMed
Patel, MS, Srinivasan, M. Metabolic programming: causes and consequences. J Biol Chem. 2002; 277, 1629–1632.CrossRefGoogle ScholarPubMed
Fowden, AL, Forhead, AJ. Endocrine mechanisms of intrauterine programming. Reproduction. 2004; 127, 515–526.CrossRefGoogle ScholarPubMed
Godfrey, KM, Barker, DJ. Fetal programming and adult health. Public Health Nutr. 2001; 4, 611–624.CrossRefGoogle ScholarPubMed
Wood, RI, Foster, DL. Sexual differentiation of reproductive neuroendocrine function in sheep. Rev Reprod. 1998; 3, 130–140.CrossRefGoogle Scholar
Recabarren, SE, Padmanabhan, V, Codner, E, et al. Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone. Am J Physiol Endocrinol Metab. 2005; 289, E801–E806.CrossRefGoogle ScholarPubMed
Eisner, JR, Dumesic, DA, Kemnitz, JW, Abbott, DA. Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys. J Clin Endocrinol Metab. 2000; 85, 1206–1210.Google ScholarPubMed
Sharma, TP, Herkimer, C, West, C, et al. Fetal programming: prenatal androgen disrupts positive feedback actions of estradiol but does not affect timing of puberty in female sheep. Biol Reprod. 2002; 66, 924–933.CrossRefGoogle Scholar
Dumesic, DA, Abbott, DH, Padmanabhan, V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007; 8, 127–141.CrossRefGoogle ScholarPubMed
Rojas-García, PP, Recabarren, MP, Sarabia, L, et al. Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams. Am J Physiol Endocrinol Metab. 2010; 299, E998–E1005.CrossRefGoogle ScholarPubMed
Recabarren, SE, Recabarren, M, Rojas-Garcia, PP, Cordero, M, Reyes, C, Sir-Petermann, T. Prenatal exposure to androgen excess increases LH pulse amplitude during postnatal life in male sheep. Horm Metab Res. 2012; 44, 688–693.Google ScholarPubMed
Recabarren, MP, Rojas-García, PP, Einspanier, R, Padmanabhan, V, Sir-Petermann, T, Recabarren, SE. Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development. Reproduction. 2013; 145, 567–576.CrossRefGoogle ScholarPubMed
Recabarren, SE, Smith, R, Rios, R, et al. Metabolic profile in sons of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008; 93, 1820–1826.CrossRefGoogle ScholarPubMed
Recabarren, SE, Rojas-García, PP, Recabarren, MP, et al. Prenatal testosterone excess reduces sperm count and motility. Endocrinology. 2008; 149, 6444–6448.CrossRefGoogle ScholarPubMed
Sir-Petermann, T, Maliqueo, M, Angel, B, Lara, HE, Pérez-Bravo, F, Recabarren, SE. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod. 2002; 17, 2573–2579.CrossRefGoogle ScholarPubMed
Matsuda, M, DeFronzo, RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999; 22, 1462–1470.CrossRefGoogle ScholarPubMed
Grulet, H, Durlach, V, Hecart, AC, Gross, A, Leutenegger, M. Study of the rate of early glucose disappearance following insulin injection: insulin sensitivity index. Diabetes Res Clin Pract. 1993; 20, 201–207.CrossRefGoogle ScholarPubMed
Padmanabhan, V, Veiga-Lopez, A, Abbott, DH, Recabarren, SE, Herkimer, C. Developmental programming: impact of prenatal testosterone excess and postnatal weight gain on insulin sensitivity index and transfer of traits to offspring of overweight females. Endocrinology. 2010; 151, 595–605.CrossRefGoogle ScholarPubMed
Veiga-Lopez, A, Steckler, TL, Abbott, DH, et al. Developmental programming: impact of excess prenatal testosterone on intrauterine fetal endocrine milieu and growth in sheep. Biol Reprod. 2011; 84, 87–96.CrossRefGoogle Scholar
Holness, MJ, Langdown, ML, Sugden, MC. Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus. Biochem J. 2000; 349, 657–665.CrossRefGoogle ScholarPubMed
de Gasparo, M, Milner, GR, Norris, PD, Milner, RD. Effect of glucose and amino acids on foetal rat pancreatic growth and insulin secretion in vitro. J Endocrinol. 1978; 77, 241–248.CrossRefGoogle ScholarPubMed
Rhoten, WB. Insulin secretory dynamics during development of rat pancreas. Am J Physiol. 1980; 239, E57–E63.Google ScholarPubMed
Tuch, BE, Jones, A, Turtle, JR. Maturation of the response of human fetal pancreatic explants to glucose. Diabetologia. 1985; 28, 28–31.CrossRefGoogle ScholarPubMed
Otonkoski, T, Andersson, S, Knip, M, Simell, O. Maturation of insulin response to glucose during human fetal and neonatal development. Studies with perifusion of pancreatic islet-like cell clusters. Diabetes. 1988; 37, 286–291.CrossRefGoogle Scholar
Swenne, I. Pancreatic beta-cell growth and diabetes mellitus. Diabetologia. 1992; 35, 193–201.CrossRefGoogle ScholarPubMed
Rae, M, Grace, C, Hogg, K, et al. The pancreas is altered by in utero androgen exposure: implications for clinical conditions such as polycystic ovary syndrome (PCOS). PLoS One. 2013; 8, e56263.CrossRefGoogle ScholarPubMed
Ramaswamy, S, Grace, C, Mattei, AA, et al. Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion. Sci Rep. 2016; 6, 27408.CrossRefGoogle ScholarPubMed
Gatford, KL, De Blasio, MJ, Thavaneswaran, P, Robinson, JS, McMillen, IC, Owens, JA. Postnatal ontogeny of glucose homeostasis and insulin action in sheep. Am J Physiol Endocrinol Metab. 2004; 286, E1050–E1059.CrossRefGoogle Scholar
Muniyappa, R, Lee, S, Chen, H, Quon, MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008; 294, E15–E26.CrossRefGoogle ScholarPubMed
Lorenzo, C, Haffner, SM, Stancáková, A, Laakso, M. Relation of direct and surrogate measures of insulin resistance to cardiovascular risk factors in nondiabetic finnish offspring of type 2 diabetic individuals. J Clin Endocrinol Metab. 2010; 95, 5082–5090.CrossRefGoogle ScholarPubMed
Lorenzo, C, Haffner, SM, Stančáková, A, Kuusisto, J, Laakso, M. Fasting and OGTT-derived measures of insulin resistance as compared with the euglycemic-hyperinsulinemic clamp in nondiabetic finnish offspring of type 2 diabetic individuals. J Clin Endocrinol Metab. 2015; 100, 544–550.CrossRefGoogle ScholarPubMed
Cabello, P. Estudio de la sensibilidad a la insulina en machos ovinos de 5-10-20 y 30 semanas de edad expuestos a un exceso de testosterona in utero. Memoria de Título presentada a la Facultad de Ciencias Veterinarias para optar al título de Médico Veterinario. 2006 Universidad de Concepción, Chillán, Chile.Google Scholar
Rojas-García, PP, Recabarren, MP, Sir-Petermann, T, et al. Altered testicular development as a consequence of increase number of Sertoli cell in male lambs exposed prenatally to excess testosterone. Endocrine. 2013; 43, 705–713.CrossRefGoogle ScholarPubMed
Recabarren, SE, Recabarren, M, Rojas-Garcia, PP, Cordero, M, Reyes, C, Sir-Petermann, T. Prenatal exposure to androgen excess increases LH pulse amplitude during postnatal life in male sheep. Horm Metab Res. 2012; 44, 688–693.Google ScholarPubMed
Bruns, CM, Baum, ST, Colman, RJ, et al. Insulin resistance and impaired insulin secretion in prenatally androgenized male rhesus monkeys. J Clin Endocrinol Metab. 2004; 89, 6218–6223.CrossRefGoogle ScholarPubMed
Morimoto, S, Morales, A, Zambrano, E, Fernandez-Mejia, C. Sex steroids effects on the endocrine pancreas. J Steroid Biochem Mol Biol. 2010; 122, 107–113.CrossRefGoogle ScholarPubMed
Morimoto, S, Fernandez-Mejia, C, Romero-Navarro, G, Morales-Peza, N, Díaz-Sánchez, V. Testosterone effect on insulin content, messenger ribonucleic acid levels, promoter activity, and secretion in the rat. Endocrinology. 2001; 142, 1442–1447.CrossRefGoogle ScholarPubMed
Díaz-Sánchez, V, Morimoto, S, Morales, A, Robles-Díaz, G, Cerbón, M. Androgen receptor in the rat pancreas: genetic expression and steroid regulation. Pancreas. 1995; 11, 241–245.CrossRefGoogle ScholarPubMed
Pitteloud, N, Hardin, M, Dwyer, AA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005; 90, 2636–2641.CrossRefGoogle ScholarPubMed
Yialamas, MA, Dwyer, AA, Hanley, E, Lee, H, Pitteloud, N, Hayes, FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007; 92, 4254–4259.CrossRefGoogle ScholarPubMed
Traish, AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. 2014; 88, 106–116.CrossRefGoogle ScholarPubMed
Aversa, A, Bruzziches, R, Francomano, D, Spera, G, Lenzi, A. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest. 2010; 33, 776–783.CrossRefGoogle ScholarPubMed
More, AS, Mishra, JS, Gopalakrishnan, K, Blesson, CS, Hankins, GD, Sathishkumar, K. Prenatal testosterone exposure leads to gonadal hormone-dependent hyperinsulinemia and gonadal hormone-independent glucose intolerance in adult male rat offspring. Biol Reprod. 2016; 94, 1–11.CrossRefGoogle ScholarPubMed
Saad, F, Aversa, A, Isidori, AM, Zafalon, L, Zitzmann, M, Gooren, L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011; 165, 675–685.CrossRefGoogle ScholarPubMed
Manikkam, M, Crespi, EJ, Doop, DD, et al. Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology. 2004; 145, 790–798.CrossRefGoogle Scholar
Wolf, CJ, Hotchkiss, A, Ostby, JS, LeBlanc, GA, Gray, LE Jr. Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study. Toxicol Sci. 2002; 65, 71–86.CrossRefGoogle ScholarPubMed
Recabarren, SE, Rojas-García, PP, Recabarren, MP, Norambuena, K, Sir-Petermann, T. Impacto de la exposición prenatal a testosterona sobre parámetros biométricos y endocrinos en ovinos recién nacidos. Arch Med Vet. 2009; 41, 43–51.CrossRefGoogle Scholar
Steckler, T, Wang, J, Bartol, FF, Roy, SK, Padmanabhan, V. Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment. Endocrinology. 2005; 146, 3185–3193.CrossRefGoogle ScholarPubMed
Sir-Petermann, T, Hitchsfeld, C, Maliqueo, M, et al. Birth weight in offspring of mothers with polycystic ovarian syndrome. Hum Reprod. 2005; 20, 2122–2126.CrossRefGoogle ScholarPubMed
Recabarren, SE, Sir-Petermann, T, Rios, R, et al. Pituitary and testicular function in sons of women with polycystic ovary syndrome from infancy to adulthood. J Clin Endocrinol Metab. 2008; 93, 3318–3324.CrossRefGoogle Scholar