Glucose metabolism disorders in patients with adrenal gland disorders: pathophysiology and management


The aim of this review is to explore and discuss disorders of glucose metabolism that can arise in individuals with adrenal gland disorders, as well as to enumerate the available therapeutic treatments for these while considering their benefits and drawbacks. Hyperfunctioning adrenal glands, as in hypercortisolism, hyperaldosteronism, and malignancy, or hypofunctioning of adrenal glands, as in adrenal insufficiency, can lead to carbohydrate metabolism dysregulation with subsequent glucometabolic repercussions, either hyperglycemia or hypoglycemia. Glycemic disorders further affect patients’ quality of life and represent a therapeutic dilemma for physicians. Current management strategies for glycemic dysregulation in individuals with adrenal gland disorders are fighting the underlying causes, as well as utilizing antidiabetic therapies that aid in maintaining euglycemia. Further research focused on discovering drug preparations of greater accuracy and effectiveness tailored to patients with adrenal problems as well as studies investigating optimal lifestyle management models for these individuals will assist towards achieving optimal regulation of glucose metabolism.

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  1. 1.

    Mazziotti G, Gazzaruso C, Giustina A (2011) Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol Metab 22:499–506.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Fagerholm V, Haaparanta M, Scheinin M (2011) Α 2-adrenoceptor regulation of blood glucose homeostasis. Basic Clin Pharmacol Toxicol 108:365–370.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Cassuto H, Kochan K, Chakravarty K et al (2005) Glucocorticoids regulate transcription of the gene for phosphoenolpyruvate carboxykinase in the liver via an extended glucocorticoid regulatory unit. J Biol Chem 280:33873–33884.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Geer EB, Islam J, Buettner C (2014) Mechanisms of glucocorticoid-induced insulin resistance. Endocrinol Metab Clin N Am 43:75–102.

    CAS  Article  Google Scholar 

  6. 6.

    Fischer B, Rausch U, Wollny P, Westphal H, Seitz JAG (1990) Immunohistochemical localization of the glucocorticoid receptor pancreatic beta-cells of the rat. Endocrinology 126:2635–2641

    CAS  Article  Google Scholar 

  7. 7.

    Kamba A, Daimon M, Murakami H et al (2016) Association between higher serum cortisol levels and decreased insulin secretion in a general population. PLoS One 11:1–10.

    CAS  Article  Google Scholar 

  8. 8.

    Vilsbøll T, Krarup T, Madsbad S, Holst JJ (2003) Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114:115–121.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Nauck M, Stöckmann F, Ebert RCW (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46–52

    CAS  Article  Google Scholar 

  10. 10.

    Hansen KB, Vilsbøll T, Bagger JI et al (2010) Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects. J Clin Endocrinol Metab 95:3309–3317.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Mullan K, Black N, Thiraviaraj A et al (2010) Is there value in routine screening for Cushing’s syndrome in patients with diabetes? J Clin Endocrinol Metab 95:2262–2265.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Feelders RA, Pulgar SJ, Kempel A, Pereira AM (2012) The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 167:311–326.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Hofland LJ, Lamberts SWJ (2003) The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 24:28–47.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Scaroni C, Zilio M, Foti M, Boscaro M (2017) Glucose metabolism abnormalities in cushing syndrome: from molecular basis to clinical management. Endocr Rev 38:189–219.

    Article  PubMed  Google Scholar 

  15. 15.

    Colao A, Petersenn S, Newell-Price J et al (2012) A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 366:914–924.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    MacKenzie Feder J, Bourdeau I, Vallette S et al (2014) Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of phase III trial. Pituitary 17:519–529.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Boscaro M, Bertherat J, Findling J et al (2014) Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, phase II study. Pituitary 17:320–326.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Reznik Y, Bertherat J, Borson-Chazot F et al (2013) Management of hyperglycaemia in Cushing’s disease: experts’ proposals on the use of pasireotide. Diabetes Metab 39:34–41.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Inzucchi SE, Bergenstal RM, Buse JB et al (2012) Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 35:1364–1379.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Silverstein JM (2016) Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly. Pituitary 19:536–543.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Erbil Y, Ademoǧlu E, Özbey N et al (2006) Evaluation of the cardiovascular risk in patients with subclinical Cushing syndrome before and after surgery. World J Surg 30:1665–1671.

    Article  PubMed  Google Scholar 

  22. 22.

    Chiodini I, Tauchmanovà L, Torlontano M et al (2002) Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism. J Clin Endocrinol Metab 87:5491–5494.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Tauchmanovà L, Rossi R, Biondi B et al (2002) Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 87:4872–4878.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Van Raalte DH, Nofrate V, Bunck MC et al (2010) Acute and 2-week exposure to prednisolone impair different aspects of β-cell function in healthy men. Eur J Endocrinol 162:729–735.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Barzon L, Sonino N, Fallo F, Palu GBM (2003) Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 149:273–285.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Paschou SA, Kandaraki E, Dimitropoulou F et al (2016) Subclinical Cushing’s syndrome in patients with bilateral compared to unilateral adrenal incidentalomas: a systematic review and meta-analysis. Endocrine 51:225–235.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Fernandez-Real JM, Ricart EW, Simò R, Salinas IWS (1998) Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours. Clin Endocrinol 49:53–61

    CAS  Article  Google Scholar 

  28. 28.

    Altieri B, Tirabassi G, Della CS et al (2016) Adrenocortical tumors and insulin resistance: what is the first step? Int J Cancer 138:2785–2794.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Shimamoto K, Shiiki M, Ise T et al (1994) Does insulin resistance participate in an impaired glucose tolerance in primary aldosteronism? J Hypertens 8:755–759

    CAS  Google Scholar 

  30. 30.

    Luther JM (2014) Effects of aldosterone on insulin sensitivity and secretion. Steroids 91:54–60.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Watanabe D, Yatabe M, Ichihara A (2016) Evaluation of insulin sensitivity and secretion in primary aldosteronism. Clin Exp Hypertens 38:613–617.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Kumagai E, Adachi H, Jacobs DR et al (2011) Plasma aldosterone levels and development of insulin resistance. Hypertension 58:1043–1048.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Tancredi M, Johannsson G, Eliasson B et al (2017) Prevalence of primary aldosteronism among patients with type 2 diabetes. Clin Endocrinol 87:233–241.

    CAS  Article  Google Scholar 

  34. 34.

    Young WF (2007) Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol 66:607–618.

    CAS  Article  Google Scholar 

  35. 35.

    Barth E, Albuszies G, Baumgart K et al (2007) Glucose metabolism and catecholamines. Crit Care Med 35:S508–S518.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Douma S, Petidis K, Kartali N et al (2008) Pheochromocytoma presenting as diabetic ketoacidosis. J Diabetes Complicat 22:295–296.

    Article  PubMed  Google Scholar 

  37. 37.

    Beninato T, Kluijfhout WP, Drake FT et al (2017) Resection of pheochromocytoma improves diabetes mellitus in the majority of patients. Ann Surg Oncol 24:1208–1213.

    Article  PubMed  Google Scholar 

  38. 38.

    Bluher M, Windgassen MPR (2000) Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma. Diabetes Care 23:1591–1592

    CAS  Article  Google Scholar 

  39. 39.

    Mesmar B, Poola-Kella S, Malek R (2017) The physiology behind diabetes mellitus in patients with pheochromocytoma: a review of the literature. Endocr Pract 23:999–1005.

    Article  PubMed  Google Scholar 

  40. 40.

    La Batide-Alanore A, Chatellier GPP-F (2003) Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens 21:1703–1707

    Article  Google Scholar 

  41. 41.

    Abecassis M, McLoughlin MJ, Langer B, Kudlow JE (1985) Serendipitous adrenal masses: prevalence, significance, and management. Am J Surg 149:783–788

    CAS  Article  Google Scholar 

  42. 42.

    Bovio S, Cataldi A, Reimondo G et al (2006) Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Investig 29:298–302

    CAS  Article  Google Scholar 

  43. 43.

    Sydney GI, Ioakim KJ, Paschou SA (2019) Insulin resistance and adrenal incidentalomas: a bidirectional relationship. Maturitas 121:1–6.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Ivovic M, Marina LV, Vujovic S et al (2013) Nondiabetic patients with either subclinical Cushing’s or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications. Metabolism 62:786–792.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Reincke M, Fassnacht M, Väth S, Mora PAB (1997) Adrenal incidentalomas: a manifestation of the metabolic syndrome? Endocr Res 22:757–761

    Article  Google Scholar 

  46. 46.

    Muscogiuri G, Sorice GP, Prioletta A, Mezza T, Cipolla C, Salomone E, Giaccari A, Pontecorvi ADCS (2011) The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship? Clin Endocrinol 74:300–305

    CAS  Article  Google Scholar 

  47. 47.

    Wagnerova H, Dudasova DLI (2009) Hormonal and metabolic evaluation of adrenal incidentalomas. Neoplasma 56:521–525.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Ensincks J, Williams RH (1974) Disorders causing hypoglycemia. In: Williams RH (ed) Textbook of Endocrinology, 5th edn. Saunders, Philadelphia, pp 627–659

    Google Scholar 

  49. 49.

    Yoshikawa KWH (1980) Hypoglycemia by adrenocortical carcinoma with Cushing’s syndrome. Tohoku J Exp Med 132:49–60

    CAS  Article  Google Scholar 

  50. 50.

    Aszkanazy CL, Jenkins LSW (1958) Adrenal cortical carcinoma associated with hypoglycemia. Canad M A J 79:482–484

    CAS  Google Scholar 

  51. 51.

    Ueland GAHE (2018) Metabolic complications in adrenal insufficiency. Front Horm Res 49:104–113.

    Article  PubMed  Google Scholar 

  52. 52.

    Mazziotti G, Formenti AM, Frara S et al (2017) Diabetes in Cushing disease. Curr Diab Rep 17.

  53. 53.

    Paschou SA, Vryonidou A, Goulis DG (2016) Adrenal incidentalomas: a guide to assessment , treatment and follow-up. Maturitas 92:79–85.

    Article  PubMed  Google Scholar 

  54. 54.

    Munir AN-PJ (2010) Management of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1):82–85

    CAS  Article  Google Scholar 

  55. 55.

    Ferraù FKM (2015) Metabolic comorbidities in Cushing’s syndrome. Eur J Endocrinol 173:M133–M157.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Poli G, Cantini G, Armignacco R, Fucci R, Santi R, Canu L, Nesi G, Mannelli MLM (2016) Metformin as a new anti-cancer drug in adrenocortical carcinoma. Oncotarget.

  57. 57.

    Pan Z, Xie D, Choudhary V et al (2014) The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells. Mol Cell Endocrinol 394:119–128.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ambrosi B, Arosio M, Dall’Asta C, Cannavo S, Libe R, Vigo T, Chiodini I, Epaminonda P, Trimarchi FB-PP (2004) Effects of the chronic administration of the PPARγ receptor ligand, rosiglitazone, in Cushing’s disease. Eur J Endocrinol 151:173–178

    CAS  Article  Google Scholar 

  59. 59.

    Alevizaki M, Philippou G, Zapanti L, Alevizaki CC, Anastasiou E MM (2004) Significant improvement of recurrent pituitary-dependent Cushing’s syndrome after administration of a PPARγ agonist. Progr 86th Annu Meet Endocr Soc New Orleans, LA 418 (Abstract P2-453)

  60. 60.

    Cannavo S, Ambrosi B, Chiodini I, Vigo T, Russo A, Milici C, Barbetta L, Dall’Asta C, Adda GAM (2004) Baseline and CRH-stimulated ACTH and cortisol levels after administration of the peroxisome proliferator-activated receptor-γ ligand, rosiglitazone, in Cushing’s disease. J Endocrinol Investig 27:RC8–RC11

    CAS  Article  Google Scholar 

  61. 61.

    Suri D, Weiss RE (2005) Effect of pioglitazone on adrenocorticotropic hormone and cortisol secretion in Cushing’s disease. J Clin Endocrinol Metab 90:1340–1346

    CAS  Article  Google Scholar 

  62. 62.

    Clore JNT-HL (2009) Glucocorticoid-induced hyperglycemia. Endocr Pr 15:469–474

    Article  Google Scholar 

  63. 63.

    van Raalte DH et al (2011) Glucagon-like peptide-1 receptor agonist treatment prevents glucocorticoid-induced glucose intolerance and islet-cell dysfunction in humans. Diabetes Care 34:412–417

    Article  Google Scholar 

  64. 64.

    Anderson AWB (2013) 11b-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease. Drugs 73:1385–1393

    CAS  Article  Google Scholar 

  65. 65.

    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JDC, Dacquin R, Mee PJ, McKee MD, Jung DYZZ, Kim JK, Mauvais-Jarvis F, Ducy PKG (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469

    CAS  Article  Google Scholar 

  66. 66.

    Conrado DJ, Krishnaswami S, Shoji S, Kolluri SH-HJ, McCabe D, Rojo RTB (2016) Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis. J Pharmacokinet Pharmacodyn 43:325–341

    CAS  Article  Google Scholar 

  67. 67.

    Im J, Yu B, Jeon J, Kim S (2008) Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta 396:66–69

    CAS  Article  Google Scholar 

  68. 68.

    Hwang Y, Jeong I, Ahn K, Chung H (2009) The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced beta-cell function in middle-aged male subjects. Diabetes Metab Res Rev 25:768–772

    CAS  Article  Google Scholar 

  69. 69.

    Winhofer Y, Handisurya A, Tura A et al (2010) Osteocalcin is related to enhanced insulin secretion in gestational diabetes. Diabetes Care 33:139–143

    CAS  Article  Google Scholar 

  70. 70.

    Fischer E, Adolf C, Pallauf A, Then C, Bidlingmaier M, Beuschlein F, Seissler JRM (2013) Aldosterone excess impairs first phase insulin secretion in primary aldosteronism. J Clin Endocrinol Metab 98:2513–2520

  71. 71.

    Rogowicz-Frontczak A, Majchrzak A, Zozulińska-Ziółkiewicz D (2017) Insulin resistance in endocrine disorders — treatment options. Endokrynol Pol 68:334–342.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Kardalas E, Paschou SA, Anagnostis P et al (2018) Hypokalemia: a clinical update. Endocr Connect 7:R135–R146

    CAS  Article  Google Scholar 

  73. 73.

    Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi G, Novello M, Favret G, Melis ACA, Sechi LA (2006) Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab 91:3457–3463

    CAS  Article  Google Scholar 

  74. 74.

    Diamanti-Kandarakis E, Zapanti E, Peridis MH et al (2003) Insulin resistance in pheochromocytoma improves more by surgical rather than by medical treatment. Horm (Athens) 2:61–66

    Article  Google Scholar 

  75. 75.

    Pogorzelski R, Toutounchi S, Krajewska E et al (2014) The effect of surgical treatment of phaeochromocytoma on concomitant arterial hypertension and diabetes mellitus in a single-centre retrospective study. Cent Eur J Urol 67:361–365

  76. 76.

    Stenstrom G, Sjostrom LSU (1984) Diabetes mellitus in phaeochromocytoma: fasting blood glucose levels before and after surgery in 60 patients with phaeochromocytoma. Acta Endocrinol 106:511–515

  77. 77.

    Bornstein SR, Allolio B, Arlt Wet al (2015) Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 101:364–389.

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Ioakim, K.J., Sydney, G.I. & Paschou, S.A. Glucose metabolism disorders in patients with adrenal gland disorders: pathophysiology and management. Hormones 19, 135–143 (2020).

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  • Adrenal
  • Incidentalomas
  • Hypoglycemia
  • Hyperglycemia
  • Type 2 diabetes
  • Insulin resistance
  • Antidiabetic medications