Abstract
Effects of hypothyroidism on the glucose and insulin levels are controversial, and its impact on the Langerhans islet morphology of adult subjects has been poorly addressed. In spite of hypothyroidism and diabetes mellitus are more frequent in females than in males, most studies using animal models have been done in males. The effect of hypothyroidism on the immunolabeling of thyroid hormone receptors (TRs) and thyrotropin receptor (TSHR) of islet cells is unknown. The aim of this study was to determine the effect of hypothyroidism on the glucose and insulin concentrations, morphometry of islets, and immunostaining of TRs α1–2 and β1 and TSHR of islet cells in female rabbits. Control and hypothyroid (0.02 % of methimazole for 30 days) animals were used to quantify blood levels of glucose and insulin, density of islets, cross-sectional area (CSA) of islets, number of cells per islet, cell proliferation, and the immunolabeling of TRs α1–2, TRβ1, and TSHR. Student’s t or Mann–Whitney-U tests, two-way ANOVAs, and Fischer’s tests were applied. Concentrations of glucose and insulin, as well as the insulin resistance were similar between groups. Hypothyroidism did not affect the density or the CSA of islets. The analysis of islets by size showed that hypothyroidism reduced the cell number in large and medium islets, but not in small ones. In small islets, cell proliferation was increased. The immunoreactivity of TRα1–2, TRβ1, and TSHR was increased by hypothyroidism in all islet sizes. Our results show that hypothyroidism affects differentially the islet cells depending on the size of islets.
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P. Marchetti, F. Dotta, D. Lauro, F. Purrello, An overview of pancreatic beta-cell defects in human type 2 diabetes: implications for treatment. Regul. Pept. 146, 4–11 (2008)
T. Mezza, G. Muscogiuri, G.P. Sorice, G. Clemente, J. Hu, A. Pontecorvi, J.J. Holst, A. Giaccari, R.N. Kulkarni, Insulin resistance alters islet morphology in nondiabetic humans. Diabetes 63(3), 994–1007 (2014)
O.M. Ahmed, M.A. Gabar, T.M. Ali, Impacts of the coexistence of diabetes and hypothyroidism on body weight gain, leptin and various metabolic aspects in albino rats. J. Diabetes Complications 26(6), 491–500 (2012)
K. Gulle, N.G. Ceri, M. Akpolat, M. Arasli, B. Demirci, The effects of dexpanthenol in streptozotocin-induced diabetic rats: histological, histochemical and immunological evidences. Histol. Histopathol. (2014) (Epub ahead of print)
G. Brenta, S. Danzi, I. Klein, Potential therapeutic applications of thyroid hormone analogs. Nat. Clin. Pract. Endocrinol. Metab. 3(9), 632–640 (2007)
E. Ortega, J. Koska, N. Pannacciulli, J.C. Bunt, J. Krakoff, Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals. Eur. J. Endocrinol. 158, 217–221 (2008)
A. Roos, S.J. Bakker, T.P. Links, R.O. Gans, B.H. Wolffenbuttel, Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J. Clin. Endocrinol. Metab. 92(2), 491–496 (2007)
G.B. Diaz, A.A. Paladini, M.E. Garcia, J.J. Gagliardino, Changes induced by hypothyroidism in insulin secretion and in the properties of islet plasma membranes. Arch. Int. Physiol. Biochim. Biophys. 101(5), 263–269 (1993)
M. Mazaki-Tovi, Y. Feuermann, G. Segev, E. Klement, E. Yas-Natan, A. Farkas, A. Kol, A. Shamay, Increased serum leptin and insulin concentrations in canine hypothyroidism. Vet. J. 183, 109–114 (2010)
N. Dariyerli, G. Andican, A.B. Catakoğlu, H. Hatemi, G. Burçak, Hyperuricemia in hypothyroidism: is it associated with post-insulin infusion glycemic response? Tohoku J. Exp. Med. 199(2), 58–59 (2003)
P. Fragner, J. Quette, S. Aratan-Spire, Thyroid status and the regulation of thyrotropin-releasing hormone synthesis in rat pancreatic islets: comparison with insulin regulation. Biochem Biophys Res Commun. 247(3), 564–568 (1998)
T. Szkudelski, W. Michalski, K. Szkudelska, The effect of thyroid hormones on blood insulin level and metabolic parameters in diabetic rats. J. Physiol. Biochem. 59(2), 71–76 (2003)
Y. Lin, Z. Sun, Thyroid hormone potentiates insulin signaling and attenuates hyperglycemia and insulin resistance in a mouse model of type 2 diabetes. Br. J. Pharmacol. 162(3), 597–610 (2011)
C. Verga-Falzacappa, C. Mangialardo, L. Madaro, D. Ranieri, L. Lupoi, A. Stigliano, M.R. Torrisi, M. Bouchè, V. Toscano, S. Misiti, Thyroid hormone T3 counteracts STZ induced diabetes in mouse. PLoS One 6(5), e19839 (2011)
I.K. Hwang, I.Y. Kim, Y.N. Kim, S.S. Yi, Y.H. Lee, E.J. Ju, I.S. Lee, I.S. Park, M.H. Won, Y.S. Yoon, J.K. Seong, Effects of methimazole on the onset of type 2 diabetes in leptin receptor-deficient rats. J. Vet. Med. Sci. 71(3), 275–280 (2009)
S. Morimoto, M.A. Cerbón, A. Alvarez-Alvarez, G. Romero-Navarro, V. Díaz-Sánchez, Insulin gene expression pattern in rat pancreas during the estrous cycle. Life Sci. 68(26), 2979–2985 (2001)
S. Morimoto, A. Morales, E. Zambrano, C. Fernandez-Mejia, Sex steroids effects on the endocrine pancreas. J. Steroid Biochem. Mol. Biol. 122(4), 107–113 (2010)
A. Zinke, D. Schmoll, M. Zachmann, J. Schmoll, H. Junker, R. Grempler, G. Kirsch, R. Walther, Expression of thyroid hormone receptor isoform α1 in pancreatic islets. Exp. Clin. Endocrinol. Diabetes 111(4), 198–202 (2003)
C. Verga-Falzacappa, V. Patriarca, B. Bucci, C. Mangialardo, S. Michienzi, G. Moriggi, A. Stigliano, E. Brunetti, V. Toscano, S. Misiti, The TRbeta1 is essential in mediating T3 action on Akt pathway in human pancreatic insulinoma cells. J. Cell. Biochem. 106, 835–848 (2009)
T. Tsiligianni, A. Saratsi, U. Besenfelder, A. Anastasiadis, E. Vainas, P. Saratsis, G. Brem, The use of cytological examination of vaginal smears (CEVS) in the selection of rabbits for superovulation. Theriogenology 61, 989–995 (2004)
E. Cuevas, E. Ausó, M. Telefont, G. Morreale de Escobar, C. Sotelo, P. Berbel, Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence-derived neurons. Eur J Neurosci. 22(3), 541–551 (2005)
A. Chamson-Reig, S.M. Thyssen, E. Arany, D.J. Hill, Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. J. Endocrinol. 191(1), 83–92 (2006)
K. Kou, Y. Saisho, S. Sato, T. Yamada, H. Itoh, Islet number rather than islet size is a major determinant of β- and α-cell mass in humans. J. Clin. Endocrinol. Metab. 99(5), 1733–1740 (2014)
S.B. Geutskens, F. Homo-Delarche, J.M. Pleau, S. Durant, H.A. Drexhage, W. Savino, Extracellular matrix distribution and islet morphology in the early postnatal pancreas: anomalies in the non-obese diabetic mouse. Cell Tissue Res. 318(3), 579–589 (2004)
M.M. Smits, E.J. van Geenen, The clinical significance of pancreatic steatosis. Nat. Rev. Gastroenterol. Hepatol. 8(3), 169–177 (2011)
A. Matsuda, N. Makino, T. Tozawa, N. Shirahata, T. Honda, Y. Ikeda, H. Sato, M. Ito, Y. Kakizaki, M. Akamatsu, Y. Ueno, S. Kawata, Pancreatic fat accumulation, fibrosis, and acinar cell injury in the Zucker diabetic fatty rat fed a chronic high-fat diet. Pancreas 43(5), 735–743 (2014)
A. Jörns, M. Tiedge, S. Lenzen, Thyroxine induces pancreatic beta-cell apoptosis in rats. Diabetologia 45(6), 851–855 (2002)
B. Farhat, A. Almelkar, K. Ramachandran, S.J. Williams, H.H. Huang, D. Zamierowski, L. Novikova, L. Stenho-Bittel, Small human islets comprised of more β-cells with higher insulin content than large islets. Islets 5(2), 87–94 (2013)
V. Aïello, A. Moreno-Asso, J.M. Servitja, M. Martin, Thyroid hormones promote endocrine differentiation at expenses of exocrine tissue. Exp. Cell Res. 322(2), 236–248 (2014)
M.A. Kowalik, A. Perra, M. Pibiri, M.T. Cocco, J. Samarut, M. Plateroti, G.M. Ledda-Columbano, A. Columbano, TRβ is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells. J. Hepatol. 53, 686–692 (2010)
L. Tian, J. Ni, T. Guo, J. Liu, Y. Dang, Q. Guo, L. Zhang, TSH stimulates the proliferation of vascular smooth muscle cells. Endocrine 46(3), 651–658 (2014)
A. Van-Keymeulen, J.E. Dumont, P.P. Roger, TSH induces insulin receptors that mediate insulin costimulation of growth in normal human thyroid cells. Biochem. Biophys. Res. Commun. 279(1), 202–203 (2000)
A.L. De Paul, J.H. Mukdsi, C.G. Pellizas, M. Montesinos, S. Gutiérrez, S. Susperreguy, A. Del Río, C.A. Maldonado, A.I. Torres, Thyroid hormone receptor alpha 1-beta 1 expression in epididymal epithelium from euthyroid and hypothyroid rats. Histochem. Cell Biol. 129(5), 631–642 (2008)
B. Zandieh-Doulabi, M. Platvoet-ter Schiphorst, A. Kalsbeek, W.M. Wiersinga, O. Bakker, Hyper and hypothyroidism change the expression and diurnal variation of thyroid hormone receptor isoforms in rat liver without major changes in their zonal distribution. Mol. Cell. Endocrinol. 219(1–2), 69–75 (2004)
Acknowledgments
This study was done in the Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala (UATx), México. It was granted for the Programa de Mejoramiento del Profesorado (PROMEP-SEP; UATLX-PTC-085 to EC), and partially supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT; 106226 to EC and 225126 Apoyo de Infraestructura al Cuerpo Académico Fisiología del Comportamiento, UATx). Authors also thank to CONACyT for giving a research fellowship to R–C J (487362).
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Rodríguez-Castelán, J., Nicolás, L., Morimoto, S. et al. The Langerhans islet cells of female rabbits are differentially affected by hypothyroidism depending on the islet size. Endocrine 48, 811–817 (2015). https://doi.org/10.1007/s12020-014-0418-4
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DOI: https://doi.org/10.1007/s12020-014-0418-4