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Molecular Mechanisms of the Relationship between Thyroid Dysfunctions and Diabetes Mellitus

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Abstract

Type 1 and type 2 diabetes mellitus (DM) are known to increase the incidence of thyroid gland (TG) dysfunctions. The review addresses the literature data and our experimental results on the molecular mechanisms that underlie thyroid disorders under DM. Most important of these mechanisms are the attenuation of thyrocyte adenylyl cyclase signaling system sensitivity to thyroid-stimulating hormone, the decrease in the number of thyroid hormone receptors in peripheral tissues, and the decline in activity as well as changes in the ratio of different deiodinase forms in these tissues. Decreased activity of D2 deiodinases, which convert thyroxine into the active form of triiodothyronine, is associated with the development of insulin resistance, while decreased activity of D3 deiodinases, which catalyze inactivation of triiodothyronine in pancreatic β cells, suppresses insulin secretion and leads to insulin deficiency. Thus, both the excess and the deficiency of thyroid hormones can entail diabetic pathology. Identification of thyroid disorders is of utmost importance for elaborating novel approaches to treat and prevent thyroid diseases associated with type 1 and type 2 DM.

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References

  1. Kordonouri, O., Hartmann, R., Deiss, D., Wilms, M., and Grüters-Kieslich, A., Natural course of autoimmune thyroiditis in type 1 diabetes: association with gender, age, diabetes duration, and puberty, Arch. Dis. Child., 2005, vol. 90, pp. 411–414.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Kadiyala, R., Peter, R., and Okosieme, O.E., Thyroid dysfunction in patients with diabetes: clinical implications and screening strategies, Int. J. Clin. Pract., 2010, vol. 64, pp. 1130–1139.

    Article  PubMed  CAS  Google Scholar 

  3. Palma, C.C., Pavesi, M., Nogueira, V.G., Clemente, E.L., Vasconcellos Mde, F., Pereira, L.C. Júnior Pacheco, F.F., Braga, T.G., Bello Lde, F., Soares, J.O., Dos Santos, S.C., Campos, V.P., and Gomes, M.B., Prevalence of thyroid dysfunction in patients with diabetes mellitus, Diabetol. Metab. Syndr., 2013, vol. 5, article 58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Benvenga, S., Pintaudi, B., Vita, R., Di Vieste, G., and Di Benedetto, A., Serum thyroid hormone autoantibodies in type 1 diabetes mellitus, J. Clin. Endocrinol. Metab., 2015, vol. 100, pp. 1870–1878.

    Article  PubMed  CAS  Google Scholar 

  5. Chen, H.S., Wu, T.E., Jap, T.S., Lu, R.A., Wang, M.L., Chen, R.L., and Lin, H.D., Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in Type 2 diabetic patients, Diabet. Med., 2007, vol. 24, pp. 1336–1344.

    Article  PubMed  CAS  Google Scholar 

  6. Díez, J.J. and Iglesias, P., An analysis of the relative risk for hypothyroidism in patients with Type 2 diabetes, Diabet. Med., 2012, vol. 29, pp. 1510–1514.

    Article  PubMed  Google Scholar 

  7. Barker, J.M., Clinical review: Type 1 diabetesassociated autoimmunity: natural history, genetic associations, and screening, J. Clin. Endocrinol. Metab., 2006, vol. 91, pp. 1210–1217.

    Article  PubMed  CAS  Google Scholar 

  8. Dittmar, M. and Kahaly, G.J., Genetics of the autoimmune polyglandular syndrome type 3 variant, Thyroid., 2010, vol. 20, pp. 737–743.

    Article  PubMed  CAS  Google Scholar 

  9. Dora, J.M., Machado, W.E., Rheinheimer, J., Crispim, D., and Maia, A.L., Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis, Eur. J. Endocrinol., 2010, vol. 163, pp. 427–434.

    Article  PubMed  CAS  Google Scholar 

  10. Duntas, L.H., Orgiazzi, J., and Brabant, G., The interface between thyroid and diabetes mellitus, Clin. Endocrinol. (Oxford), 2011, vol. 75, pp. 1–9.

    Article  CAS  Google Scholar 

  11. Potenza, M., Via, M.A., and Yanagisawa, R.T., Excess thyroid hormone and carbohydrate metabolism, Endocr. Pract., 2009, vol. 15, pp. 254–262.

    Article  PubMed  Google Scholar 

  12. Franklyn, J.A., Sheppard, M.C., and Maisonneuve, P., Thyroid function and mortality in patients treated for hyperthyroidism, JAMA, 2005, vol. 294, pp. 71–80.

    Article  PubMed  CAS  Google Scholar 

  13. Collet, T.H., Gussekloo, J., Bauer, D.C., den Elzen, W.P., Cappola, A.R., Balmer, P., Iervasi, G., Åsvold, B.O., Sgarbi, J.A., Völzke, H., Gencer, B., Maciel, R.M., Molinaro, S., Bremner, A., Luben, R.N., Maisonneuve, P., Cornuz, J., Newman, A.B., Khaw, K.T., Westendorp, R.G., Franklyn, J.A., Vittinghoff, E., Walsh, J.P., and Rodondi, N., Thyroid studies collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality, Arch. Intern. Med., 2012, vol. 172, pp. 799–809.

    Article  PubMed  CAS  Google Scholar 

  14. Mohn, A., Di Michele, S., Di Luzio, R., Tumini, S., and Chiarelli, F., The effect of subclinical hypothyroidism on metabolic control in children and adolescents with Type 1 diabetes mellitus, Diabet. Med., 2002, vol. 19, pp. 70–73.

    Article  PubMed  CAS  Google Scholar 

  15. Roos, A., Bakker, S.J., Links, T.P., Gans, R.O., and Wolffenbuttel, B.H., Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects, J. Clin. Endocrinol. Metab., 2007, vol. 92, pp. 491–496.

    Article  PubMed  CAS  Google Scholar 

  16. Garduño-Garcia Jde, J., Alvirde-Garcia, U., López-Carrasco, G., Padilla Mendoza, M.E., Mehta, R., Arellano-Campos, O., Choza, R., Sauque, L., Garay-Sevilla, M.E., Malacara, J.M., Gomez-Perez, F.J., and Aguilar-Salinas, C.A., TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects, Eur. J. Endocrinol., 2010, vol. 163, pp. 273–278.

    Article  PubMed  CAS  Google Scholar 

  17. Stagnaro-Green, A., Approach to the patient with postpartum thyroiditis, J. Clin. Endocrinol. Metab., 2012, vol. 97, pp. 334–342.

    Article  PubMed  CAS  Google Scholar 

  18. Laugwitz, K.L., Allgeier, A., Offermanns, S., Spicher, K., Van Sande, J., Dumont, J.E., and Schultz, G., The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families, Proc. Natl. Acad. Sci. USA, 1996, vol. 93, pp. 116–120.

    Article  PubMed  CAS  Google Scholar 

  19. Buch, T.R., Biebermann, H., Kalwa, H., Pinkenburg, O., Hager, D., Barth, H., Aktories, K., Breit, A., and Gudermann, T., G13-dependent activation of MAPK by thyrotropin, J. Biol. Chem., 2008, vol. 283, pp. 20 330–20 341.

    Article  CAS  Google Scholar 

  20. Chen, C.R., McLachlan, S.M., and Rapoport, B., Suppression of thyrotropin receptor constitutive activity by a monoclonal antibody with inverse agonist activity, Endocrinol., 2007, vol. 148, pp. 2375–2382.

    Article  CAS  Google Scholar 

  21. Bestetti, G.E., Reymond, M.J., Perrin, I.V., Kniel, P.C., Lemarchand-Béraud, T., and Rossi, G.L., Thyroid and pituitary secretory disorders in streptozotocin-diabetic rats are associated with severe structural changes of these glands, Virchows Arch. B. Cell. Pathol. Incl. Mol. Pathol., 1987, vol. 53, pp. 69–78.

    Article  PubMed  CAS  Google Scholar 

  22. Liu, C. and Shu, C., Morphological studies of the adrenal zona glomerulosa cells and the thyroid and pituitary glands in streptozocin-induced experimental diabetic rats, Zhonghua Bing Li Xue Za Zhi, 1996, vol. 25, pp. 358–360.

    PubMed  CAS  Google Scholar 

  23. Nascimento-Saba, C.C., Breitenbach, M.M., and Rosenthal, D., Pituitary-thyroid axis in short- and long-term experimental diabetes mellitus, Braz. J. Med. Biol. Res., 1997, vol. 30, pp. 269–274.

    Article  PubMed  CAS  Google Scholar 

  24. Derkach, K.V., Moiseyuk, I.V., and Shpakov, A.O., Influence of prolonged streptozotocin diabetes on function of the thyroid gland in rats, Dokl. Akad. Nauk, 2013, vol. 251, no. 6, pp. 691–694.

    Google Scholar 

  25. Moiseyuk, I.V., Derkach, K.V., and Shpakov, A.O., Functional activity of the thyroid gland in male rats with acute and mild streptozotocin diabetes, J. Evol. Bioch. Physiol., 2014, vol. 50, no. 4, pp. 310–320.

    Article  CAS  Google Scholar 

  26. Fahrenkrug, J. and Hannibal, J., Localisation of the neuropeptide PACAP and its receptors in the rat parathyroid and thyroid glands, Gen. Comp. Endocrinol., 2011, vol. 171, pp. 105–113.

    Article  PubMed  CAS  Google Scholar 

  27. Tanguy, Y., Falluel-Morel, A., Arthaud, S., Boukhzar, L., Manecka, D.L., Chagraoui, A., Prevost, G., Elias, S., Dorval-Coiffec, I., Lesage, J., Vieau, D., Lihrmann, I., Jégou, B., and Anouar, Y., The PACAP-regulated gene selenoprotein T is highly induced in nervous, endocrine, and metabolic tissues during ontogenetic and regenerative processes, Endocrinol., 2011, vol. 152, pp. 4322–4335.

    Article  CAS  Google Scholar 

  28. Unnikrishnan, A.G., Kumaravel, V., Nair, V., Rao, A., Jayakumar, R.V., Kumar, H., and Sanjeevi, C.B., TSH receptor antibodies in subjects with type 1 diabetes mellitus, Ann. N. Y. Acad. Sci., 2006, vol. 1079, pp. 220–225.

    Article  PubMed  CAS  Google Scholar 

  29. Bliddal, H., Bech, K., Johansen, K., and Nerup, J., Thyroid-stimulating immunoglobulins in insulindependent diabetes mellitus, Eur. J. Clin. Invest., 1984, vol. 14, pp. 474–478.

    Article  PubMed  CAS  Google Scholar 

  30. López Medina, J.A., López-Jurado Romero de la Cruz, R., Delgado García, A., Espigares Martín, R., Barrionuevo Porras, J.L., and Ortega Martos, L., Beta-cell, thyroid and celiac autoimmunity in children with type 1 diabetes, An. Pediatr. (Barc.), 2004, vol. 61, pp. 320–325.

    Article  Google Scholar 

  31. Costagliola, S., Morgenthaler, N.G., Hoermann, R., Badenhoop, K., Struck, J., Freitag, D., Poertl, S., Weglöhner, W., Hollidt, J.M., Quadbeck, B., Dumont, J.E., Schumm-Draeger, P.M., Bergmann, A., Mann, K., Vassart, G., and Usadel, K.H., Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease, J. Clin. Endocrinol. Metab., 1999, vol. 84, pp. 90–97.

    PubMed  CAS  Google Scholar 

  32. Vadivelu, N., Stephen, D.C., Kanagasabapathy, A.S., and Seshadri, M.S., Thyroid stimulating hormone receptor antibody in thyroid diseases, Indian J. Med. Res., 1990, vol. 92, pp. 220–223.

    PubMed  CAS  Google Scholar 

  33. Shpakov, A.O., Zharova, O.A., and Derkach, K.V., Autoantibodies to extracellular regions of G protein-coupled receptors and receptor tyrosine kinases as one of the causes of autoimmune diseases, J. Evol. Bioch. Physiol., 2017, vol. 53, no. 2, pp. 93–110.

    Article  CAS  Google Scholar 

  34. Krzewska, A. and Ben-Skowronek, I., Effect of associated autoimmune diseases on type 1 diabetes mellitus incidence and metabolic control in children and adolescents, Biomed. Res. Int., 2016, vol. 2016, 6219730.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Schroeder, A.C. and Privalsky, M.L., Thyroid hormones, t3 and t4, in the brain, Front. Endocrinol. (Lausanne), 2014, vol. 5, article 40.

    Google Scholar 

  36. Marsili, A., Zavacki, A.M., Harney, J.W., and Larsen, P.R., Physiological role and regulation of iodothyronine deiodinases: a 2011 update, J. Endocrinol. Invest., 2011, vol. 34, pp. 395–407.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Mentuccia, D., Proietti-Pannunzi, L., Tanner, K., Bacci, V., Pollin, T.I., Poehlman, E.T., Shuldiner, A.R., and Celi, F.S., Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor, Diabetes, 2002, vol. 51, pp. 880–883.

    Article  PubMed  CAS  Google Scholar 

  38. Canani, L.H., Capp, C., Dora, J.M., Meyer, E.L., Wagner, M.S., Harney, J.W., Larsen, P.R., Gross, J.L., Bianco, A.C., and Maia, A.L., The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus, J. Clin. Endocrinol. Metab., 2005, vol. 90, pp. 3472–3478.

    Article  PubMed  CAS  Google Scholar 

  39. Estivalet, A.A., Leiria, L.B., Dora, J.M., Rheinheimer, J., Boucas, A.P., Maia, A.L., and Crispim, D., D2 Thr92Ala and PPAR?2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients, Obesity (Silver Spring), 2010, vol. 19, pp. 825–832.

    Article  CAS  Google Scholar 

  40. Leiria, L.B., Dora, J.M., Wajner, S.M., Estivalet, A.A., Crispim, D., and Maia, A.L., The rs225017 polymorphism in the 3’UTR of the human DIO2 gene is associated with increased insulin resistance, PLoS One, 2014, vol. 9, e103960.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Yalakanti, D. and Dolia, P.B., Association of type II5’ monodeiodinase Thr92Ala single nucleotide gene polymorphism and circulating thyroid hormones among type 2 diabetes mellitus patients, Indian J. Clin. Biochem., 2016, vol. 31, pp. 152–161.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang, X., Sun, J., Han, W., Jiang, Y., Peng, S., Shan, Z., and Teng, W., The type 2 deiodinase Thr92Ala polymorphism is associated with worse glycemic control in patients with type 2 diabetes mellitus: A systematic review and meta-analysis, J. Diabetes Res., 2016, vol. 2016, article 5928726.

    PubMed  PubMed Central  Google Scholar 

  43. Weinstein, S.P., O’Boyle, E., and Haber, R.S., Thyroid hormone increases basal and insulin-stimulated glucose transport in skeletal muscle. The role of GLUT4 glucose transporter expression, Diabetes, 1994, vol. 43, pp. 1185–1189.

    Article  PubMed  CAS  Google Scholar 

  44. Torrance, C.J., Devente, J.E., Jones, J.P., and Dohm, G.L., Effects of thyroid hormone on GLUT4 glucose transporter gene expression and NIDDM in rats, Endocrinol., 1997, vol. 138, pp. 1204–1214.

    Article  CAS  Google Scholar 

  45. Kurylowicz, A., Jonas, M., Lisik, W., Jonas, M., Wicik, Z.A., Wierzbicki, Z., Chmura, A., and Puzianowska-Kuznicka, M., Obesity is associated with a decrease in expression but not with the hypermethylation of thermogenesis-related genes in adipose tissues, J. Transl. Med., 2015, vol. 13, article 31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Alrefaie, Z. and Awad, H., Effect of vitamin D3 on thyroid function and de-iodinase 2 expression in diabetic rats, Arch. Physiol. Biochem., 2015, vol. 121, pp. 206–209.

    Article  PubMed  CAS  Google Scholar 

  47. Mory, D.B., Gabbay, M.A., Rocco, E.R., Kasamatsu, T., Crispim, F., Miranda, W.L., and Dib, S.A., High frequency of vitamin D receptor gene polymorphism FokI in Brazilian Type 1 diabetes mellitus patients with clinical autoimmune thyroid disease, Diabetol. Metab. Syndr., 2016, vol. 8, article 29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Szablewski, L., Role of immune system in type 1 diabetes mellitus pathogenesis, Int. Immunopharmacol., 2014, vol. 22, pp. 182–191.

    Article  PubMed  CAS  Google Scholar 

  49. Gereben, B., Zavacki, A.M., Ribich, S., Kim, B.W., Huang, S.A., Simonides, W.S., Zeöld, A., and Bianco, A.C., Cellular and molecular basis of deiodinase- regulated thyroid hormone signaling, Endocr. Rev., 2008, vol. 29, pp. 898–938.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Medina, M.C., Molina, J., Gadea, Y., Fachado, A., Murillo, M., Simovic, G., Pileggi, A., Hernández, A., Edlund, H., and Bianco, A.C., The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion, Endocrinol., 2011, vol. 152, pp. 3717–3727.

    Article  CAS  Google Scholar 

  51. Medina, M.C., Fonesca, T.L., Molina, J., Fachado, A., Castillo, M., Dong, L., Soares, R., Hernández, A., Caicedo, A., and Bianco, A.C., Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic ß-cells and disrupts glucose homeostasis, Endocrinol., 2014, vol. 155, pp. 3160–3171.

    Article  CAS  Google Scholar 

  52. Dentice, M., Luongo, C., Huang, S., Ambrosio, R., Elefante, A., Mirebeau-Prunier, D., Zavacki, A.M., Fenzi, G., Grachtchouk, M., Hutchin, M., Dlugosz, A.A., Bianco, A.C., Missero, C., Larsen, P.R., and Salvatore, D., Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes, Proc. Natl. Acad. Sci. USA, 2007, vol. 104, pp. 14 466–14 471.

    Article  CAS  Google Scholar 

  53. Simonides, W.S., Mulcahey, M.A., Redout, E.M., Muller, A., Zuidwijk, M.J., Visser, T.J., Wassen, F.W., Crescenzi, A., da-Silva, W.S., Harney, J., Engel, F.B., Obregon, M.J., Larsen, P.R., Bianco, A.C., and Huang, S.A., Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats, J. Clin. Invest., 2008, vol. 118, pp. 975–983.

    PubMed  PubMed Central  CAS  Google Scholar 

  54. Thomas, M.K., Rastalsky, N., Lee, J.H., and Habener, J.F., Hedgehog signaling regulation of insulin production by pancreatic beta-cells, Diabetes, 2000, vol. 49, pp. 2039–2047.

    Article  PubMed  CAS  Google Scholar 

  55. Dimitriadis, G.D. and Raptis, S.A., Thyroid hormone excess and glucose intolerance, Exp. Clin. Endocrinol. Amp. Diabetes, 2001, vol. 109, pp. S225–S239.

    Article  CAS  Google Scholar 

  56. Lenzen, S., Panten, U., and Hasselblatt, A., Thyroxine treatment and insulin secretion in the rat, Diabetologia, 1975, vol. 11, pp. 49–55.

    Article  PubMed  CAS  Google Scholar 

  57. Williams, G.R., Cloning and characterization of two novel thyroid hormone receptor ß isoforms, Mol. Cell. Biol., 2000, vol. 20, pp. 8329–8342.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Cheng, S.Y., Leonard, J.L., and Davis, P.J., Molecular aspects of thyroid hormone actions, Endocr. Rev., 2010, vol. 31, pp. 139–170.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Zhang, X.K. and Kahl, M., Regulation of retinoid and thyroid hormone action through homodimeric and heterodimeric receptors, Trends Endocrinol. Metab., 1993, vol. 4, pp. 156–162.

    Article  PubMed  CAS  Google Scholar 

  60. Nannipieri, M., Cecchetti, F., Anselmino, M., Camastra, S., Niccolini, P., Lamacchia, M., Rossi, M., Iervasi, G., and Ferrannini, E., Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/ or type 2 diabetes: effects of weight loss, Int. J. Obes. (London), 2009, vol. 33, pp. 1001–1006.

    Article  CAS  Google Scholar 

  61. Silva, J.E. and Bianco, S.D., Thyroid-adrenergic interactions: physiological and clinical implications, Thyroid, 2008, vol. 18, pp. 157–165.

    Article  PubMed  CAS  Google Scholar 

  62. Lin, J.Z., Martagón, A.J., Cimini, S.L., Gonzalez, D.D., Tinkey, D.W., Biter, A., Baxter, J.D., Webb, P., Gustafsson, J.Å., Hartig, S.M., and Phillips, K.J., Pharmacological activation of thyroid hormone receptors elicits a functional conversion of white to brown fat, Cell Rep., 2015, vol. 13, pp. 1528–1537.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Original Russian Text © A.O. Shpakov, 2018, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2018, Vol. 54, No. 4, pp. 225–233.

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Shpakov, A.O. Molecular Mechanisms of the Relationship between Thyroid Dysfunctions and Diabetes Mellitus. J Evol Biochem Phys 54, 257–266 (2018). https://doi.org/10.1134/S0022093018040014

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