Molecular Mechanisms of the Relationship between Thyroid Dysfunctions and Diabetes Mellitus

  • A. O. ShpakovEmail author


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.

Key words

diabetes mellitus insulin resistance hypothyroidism hyperthyroidism thyroid hormone deiodinase thyroid-stimulating hormone 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 8.
    Dittmar, M. and Kahaly, G.J., Genetics of the autoimmune polyglandular syndrome type 3 variant, Thyroid., 2010, vol. 20, pp. 737–743.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 11.
    Potenza, M., Via, M.A., and Yanagisawa, R.T., Excess thyroid hormone and carbohydrate metabolism, Endocr. Pract., 2009, vol. 15, pp. 254–262.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 17.
    Stagnaro-Green, A., Approach to the patient with postpartum thyroiditis, J. Clin. Endocrinol. Metab., 2012, vol. 97, pp. 334–342.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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. 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.CrossRefGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.PubMedPubMedCentralGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Szablewski, L., Role of immune system in type 1 diabetes mellitus pathogenesis, Int. Immunopharmacol., 2014, vol. 22, pp. 182–191.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 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.CrossRefGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 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.PubMedPubMedCentralGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefGoogle Scholar
  56. 56.
    Lenzen, S., Panten, U., and Hasselblatt, A., Thyroxine treatment and insulin secretion in the rat, Diabetologia, 1975, vol. 11, pp. 49–55.CrossRefPubMedGoogle Scholar
  57. 57.
    Williams, G.R., Cloning and characterization of two novel thyroid hormone receptor ß isoforms, Mol. Cell. Biol., 2000, vol. 20, pp. 8329–8342.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefGoogle Scholar
  61. 61.
    Silva, J.E. and Bianco, S.D., Thyroid-adrenergic interactions: physiological and clinical implications, Thyroid, 2008, vol. 18, pp. 157–165.CrossRefPubMedGoogle Scholar
  62. 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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  1. 1.Sechenov Institute of Evolutionary Physiology and BiochemistryRussian Academy of SciencesSt. PetersburgRussia

Personalised recommendations