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Gragnoli C. Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome. Appl Clin Genet. 2014;7:43-53doi: 10.2147/TACG.S39993.
Gragnoli, C. (2014). Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome. The application of clinical genetics, 743-53. https://doi.org/10.2147/TACG.S39993
Gragnoli, Claudia. "Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome." The application of clinical genetics vol. 7 (2014): 43-53. doi: https://doi.org/10.2147/TACG.S39993
Gragnoli C. Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome. Appl Clin Genet. 2014 Apr 01;7:43-53. doi: 10.2147/TACG.S39993. eCollection 2014. PMID: 24817815; PMCID: PMC4012344.
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Appl Clin Genet. 2014 Apr 01;7:43-53. doi: 10.2147/TACG.S39993. eCollection 2014.

Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome.

The application of clinical genetics

Claudia Gragnoli

Affiliations

  1. Center for Biotechnology and Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA ; Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, Rome, Italy.

PMID: 24817815 PMCID: PMC4012344 DOI: 10.2147/TACG.S39993

Abstract

Depression, type 2 diabetes (T2D), and metabolic syndrome (MetS) are often comorbid. Depression per se increases the risk for T2D by 60%. This risk is not accounted for by the use of antidepressant therapy. Stress causes hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, by triggering the hypothalamic corticotropin-releasing hormone (CRH) secretion, which stimulates the anterior pituitary to release the adrenocorticotropin hormone (ACTH), which causes the adrenal secretion of cortisol. Depression is associated with an increased level of cortisol, and CRH and ACTH at inappropriately "normal" levels, that is too high compared to their expected lower levels due to cortisol negative feedback. T2D and MetS are also associated with hypercortisolism. High levels of cortisol can impair mood as well as cause hyperglycemia and insulin resistance and other traits typical of T2D and MetS. We hypothesize that HPA axis hyperactivation may be due to variants in the genes of the CRH receptors (CRHR1, CRHR2), corticotropin receptors (or melanocortin receptors, MC1R-MC5R), glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), and of the FK506 binding protein 51 (FKBP5), and that these variants may be partially responsible for the clinical association of depression, T2D and MetS. In this review, we will focus on the correlation of stress, HPA axis hyperactivation, and the possible genetic role of the CRHR1, CRHR2, MCR1-5, NR3C1, and NR3C2 receptors and FKBP5 in the susceptibility to the comorbidity of depression, T2D, and MetS. New studies are needed to confirm the hypothesized role of these genes in the clinical association of depression, T2D, and MetS.

Keywords: ACTH; CRH; cortisol; depression; metabolic syndrome; type 2 diabetes

References

  1. Diabetes. 2004 Sep;53(9):2487-91 - PubMed
  2. Hypertension. 2007 Sep;50(3):557-64 - PubMed
  3. Am J Hum Genet. 2002 Feb;70(2):425-34 - PubMed
  4. Metabolism. 2005 Jul;54(7):848-55 - PubMed
  5. Am J Med Genet. 2002 Mar 8;114(2):222-6 - PubMed
  6. Pharmacogenomics J. 2009 Aug;9(4):225-33 - PubMed
  7. Minerva Med. 2006 Oct;97(5):373-8 - PubMed
  8. S Afr Med J. 2011 May 25;101(6):417-20 - PubMed
  9. J Clin Endocrinol Metab. 2001 Jul;86(7):3448 - PubMed
  10. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):325-30 - PubMed
  11. Adv Biochem Psychopharmacol. 1987;43:183-200 - PubMed
  12. Psychoneuroendocrinology. 2011 Oct;36(9):1276-86 - PubMed
  13. Nat Genet. 2002 Aug;31(4):429-34 - PubMed
  14. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5604-9 - PubMed
  15. Eur Arch Psychiatry Clin Neurosci. 2010 Dec;260(8):583-600 - PubMed
  16. Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):836-43 - PubMed
  17. Bipolar Disord. 2009 Sep;11(6):610-20 - PubMed
  18. JAMA. 2003 Jan 1;289(1):76-9 - PubMed
  19. Mol Psychiatry. 1999 Jan;4(1):76-84 - PubMed
  20. J Am Soc Nephrol. 2004 Oct;15(10):2719-27 - PubMed
  21. Neuroendocrinology. 2010;92 Suppl 1:77-81 - PubMed
  22. Psychoneuroendocrinology. 2011 May;36(4):484-94 - PubMed
  23. Obesity (Silver Spring). 2010 Jan;18(1):146-52 - PubMed
  24. J Clin Endocrinol Metab. 2007 Jul;92(7):2439-45 - PubMed
  25. Endocrinology. 2000 Sep;141(9):3518-21 - PubMed
  26. Ann Hum Genet. 1999 Nov;63(Pt 6):483-7 - PubMed
  27. Am J Hum Genet. 2003 Jul;73(1):49-62 - PubMed
  28. Eur J Pharmacol. 2008 May 13;585(2-3):492-501 - PubMed
  29. BMC Proc. 2009 Dec 15;3 Suppl 7:S115 - PubMed
  30. Cardiovasc Diabetol. 2012 Oct 29;11:133 - PubMed
  31. BMC Genet. 2003 Dec 31;4 Suppl 1:S8 - PubMed
  32. Am J Med Genet B Neuropsychiatr Genet. 2011 Mar;156(2):168-76 - PubMed
  33. Eur J Clin Invest. 2003 Dec;33(12):1070-4 - PubMed
  34. Novartis Found Symp. 2002;242:46-58; discussion 58-65 - PubMed
  35. Genes Brain Behav. 2006 Feb;5(1):85-95 - PubMed
  36. Am J Hum Genet. 2001 Sep;69(3):553-69 - PubMed
  37. Front Behav Neurosci. 2009 Nov 06;3:41 - PubMed
  38. JAMA. 2002 Jan 16;287(3):356-9 - PubMed
  39. Diabetes. 2005 Sep;54(9):2663-7 - PubMed
  40. PLoS One. 2010 Feb 10;5(2):e9153 - PubMed
  41. J Psychiatr Res. 2011 Jul;45(7):902-9 - PubMed
  42. Nat Genet. 2000 Apr;24(4):415-9 - PubMed
  43. Ann Hum Genet. 2006 Nov;70(Pt 6):738-48 - PubMed
  44. J Clin Endocrinol Metab. 2001 Jun;86(6):2895-8 - PubMed
  45. Genes Brain Behav. 2009 Feb;8(1):72-9 - PubMed
  46. J Affect Disord. 2011 Nov;134(1-3):138-44 - PubMed
  47. CNS Neurol Disord Drug Targets. 2013 Dec;12(8):1157-62 - PubMed
  48. Neurosci Biobehav Rev. 2008 Aug;32(6):1174-84 - PubMed
  49. Neurosci Lett. 2006 Sep 1;404(3):358-62 - PubMed
  50. BMC Psychiatry. 2013 Aug 15;13:213 - PubMed
  51. Diabetes. 2006 Jul;55(7):1985-94 - PubMed
  52. J Psychiatr Res. 2011 Sep;45(9):1160-4 - PubMed
  53. Eur J Pharmacol. 2008 Apr 7;583(2-3):303-11 - PubMed
  54. Nat Genet. 2000 Apr;24(4):410-4 - PubMed
  55. Mol Med. 1997 Oct;3(10):663-73 - PubMed
  56. Hum Hered. 2010;70(4):255-68 - PubMed
  57. Diabetes Care. 2010 Apr;33(4):792-7 - PubMed
  58. Brain Res. 2007 Dec 12;1184:160-7 - PubMed
  59. Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):476-82 - PubMed
  60. Hum Mol Genet. 2008 Nov 15;17(22):3502-8 - PubMed
  61. Mol Psychiatry. 2002;7(4):342-58 - PubMed
  62. Obesity (Silver Spring). 2008 Sep;16(9):2113-9 - PubMed
  63. Transl Psychiatry. 2011 Dec 13;1:e62 - PubMed
  64. Diabetes. 2001 Mar;50(3):675-80 - PubMed
  65. AIDS. 2007 Jan 2;21(1):65-9 - PubMed
  66. Am J Med Genet B Neuropsychiatr Genet. 2009 Mar 5;150B(2):191-201 - PubMed
  67. MMWR Morb Mortal Wkly Rep. 2010 Oct 1;59(38):1229-35 - PubMed
  68. Ciba Found Symp. 1996;201:68-80; discussion 80-9, 188-93 - PubMed
  69. Am J Med Genet B Neuropsychiatr Genet. 2005 May 5;135B(1):85-93 - PubMed
  70. J Clin Endocrinol Metab. 2008 Apr;93(4):1372-8 - PubMed
  71. J Neurosci. 2010 Feb 17;30(7):2571-81 - PubMed
  72. Diabetes Care. 2008 Dec;31(12):2383-90 - PubMed
  73. Eur J Hum Genet. 2008 May;16(5):581-6 - PubMed
  74. Hypertension. 2005 Oct;46(4):751-7 - PubMed
  75. Am J Kidney Dis. 2007 Mar;49(3):394-400 - PubMed
  76. Pharmacogenet Genomics. 2008 Jun;18(6):507-14 - PubMed
  77. Am J Hum Genet. 2005 Dec;77(6):1102-11 - PubMed
  78. Psychoneuroendocrinology. 2007 Feb;32(2):151-9 - PubMed
  79. Curr Opin Pharmacol. 2011 Aug;11(4):326-31 - PubMed
  80. Dialogues Clin Neurosci. 2011;13(1):25-39 - PubMed
  81. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):554-560 - PubMed
  82. Klin Padiatr. 2005 Jul-Aug;217(4):244-9 - PubMed
  83. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):912-7 - PubMed
  84. Obes Res. 1996 Jan;4(1):81-90 - PubMed
  85. Diabet Med. 1999 May;16(5):373-83 - PubMed
  86. Pharmacogenet Genomics. 2010 Feb;20(2):71-6 - PubMed
  87. Am J Geriatr Psychiatry. 2009 Aug;17(8):716-21 - PubMed
  88. Nat Genet. 2011 May;43(5):451-4 - PubMed
  89. Genomics. 2008 Oct;92(4):226-34 - PubMed
  90. J Clin Endocrinol Metab. 2006 May;91(5):1761-9 - PubMed
  91. Hum Mol Genet. 1997 Sep;6(9):1401-8 - PubMed
  92. Vitam Horm. 2010;82:339-65 - PubMed
  93. Tijdschr Psychiatr. 2011;53(9):613-20 - PubMed
  94. BMC Genet. 2010 Feb 24;11:14 - PubMed
  95. Nat Genet. 2000 Apr;24(4):403-9 - PubMed
  96. Mol Psychiatry. 2003 Mar;8(3):333-42 - PubMed
  97. Am J Hum Genet. 1995 Apr;56(4):926-37 - PubMed
  98. Mol Cell Neurosci. 2011 Jan;46(1):55-66 - PubMed
  99. J Hum Genet. 2012 May;57(5):320-5 - PubMed
  100. Endocr Dev. 2011;20:137-148 - PubMed
  101. Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):607-19 - PubMed
  102. Diabetes. 2000 Dec;49(12):2212-6 - PubMed
  103. Physiol Genomics. 2013 Feb 15;45(4):138-50 - PubMed
  104. BMC Med Genet. 2008 Nov 27;9:103 - PubMed
  105. Clin Endocrinol (Oxf). 2008 Jun;68(6):879-84 - PubMed
  106. BMC Med Genet. 2010 Feb 08;11:22 - PubMed
  107. PLoS One. 2011 Jan 20;6(1):e16390 - PubMed
  108. Nat Clin Pract Endocrinol Metab. 2006 May;2(5):282-90 - PubMed
  109. Brain Res. 2002 Feb 8;927(1):97-103 - PubMed
  110. Peptides. 2005 Oct;26(10):1952-64 - PubMed
  111. Psychiatr Genet. 2011 Feb;21(1):14-8 - PubMed
  112. Neuron. 1998 Jun;20(6):1093-102 - PubMed
  113. Hum Mol Genet. 2006 Nov 1;15(21):3146-53 - PubMed
  114. Neuropsychopharmacology. 2010 Feb;35(3):727-40 - PubMed
  115. Am J Med Genet B Neuropsychiatr Genet. 2010 Apr 5;153B(3):812-24 - PubMed
  116. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):722-9 - PubMed
  117. PLoS Biol. 2010 Jan 26;8(1):e1000294 - PubMed
  118. Med Hypotheses. 2007;68(6):1200-7 - PubMed
  119. Neuropeptides. 2002 Apr-Jun;36(2-3):77-84 - PubMed
  120. PLoS One. 2012;7(2):e31489 - PubMed
  121. J Affect Disord. 2012 Dec 1;141(1):72-8 - PubMed
  122. J Am Acad Child Adolesc Psychiatry. 2010 Apr;49(4):378-87 - PubMed
  123. Lancet. 1993 Feb 20;341(8843):461-2 - PubMed
  124. Amino Acids. 2006 Oct;31(3):241-50 - PubMed
  125. Psychiatr Danub. 2009 Sep;21 Suppl 1:102-5 - PubMed
  126. Arch Intern Med. 2010 Nov 22;170(21):1884-91 - PubMed
  127. J Endocrinol Invest. 2003 Jul;26(7):616-9 - PubMed
  128. J Psychiatr Res. 2011 Apr;45(4):452-9 - PubMed
  129. Neurosci Lett. 2007 Mar 6;414(2):155-8 - PubMed
  130. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3502-9 - PubMed
  131. Mol Psychiatry. 2006 Mar;11(3):252-60 - PubMed
  132. Mol Psychiatry. 2004 Dec;9(12):1075-82 - PubMed
  133. Nat Genet. 1998 Jun;19(2):162-6 - PubMed

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