Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management

Nature Reviews Endocrinology (2024)Cite this article

Subjects

Abstract

Acromegaly is a rare endocrine disease caused by hypersecretion of growth hormone, most commonly arising due to a pituitary adenoma. Diabetes mellitus is a common complication of acromegaly, occurring in approximately one-third of patients. The risk of diabetes mellitus in acromegaly is driven by increased exposure to growth hormone, which directly attenuates insulin signalling and stimulates lipolysis, leading to decreased glucose uptake in peripheral tissues. Acromegaly is a unique human model, where insulin resistance occurs independently of obesity and is paradoxically associated with a lean phenotype and reduced body adipose tissue mass. Diabetes mellitus in patients with acromegaly is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, preventive measures and optimized treatment of diabetes mellitus are essential in these patients. However, specific recommendations for the management of diabetes mellitus secondary to acromegaly are lacking due to limited research on this subject. This Review explores the underlying mechanisms for diabetes mellitus in acromegaly and its effect on morbidity and mortality. We also discuss treatment modalities for diabetes mellitus that are suited for patients with acromegaly. Improved understanding of these issues will lead to better management of acromegaly and its associated metabolic complications.

Key points

  • Diabetes mellitus is a common complication of acromegaly, occurring in approximately 30% of patients.

  • Diabetes mellitus has an important effect on outcomes in acromegaly; patients with acromegaly and associated diabetes mellitus have 60% higher overall mortality and a twofold higher cardiovascular mortality than those without diabetes mellitus.

  • Measures aimed at preventing diabetes mellitus and optimizing its treatment are of crucial importance for reducing cardiovascular risks and possibly improving long-term outcomes in patients with acromegaly.

  • In managing patients with acromegaly and associated diabetes mellitus, a multimodal personalized approach is needed to achieve biochemical, tumour, symptom and metabolic control, ultimately preventing comorbidities.

  • Data on management of acromegaly-related diabetes mellitus are limited; treatment options with a favourable effect on acromegaly-related complications are preferred.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Signalling pathways affected by GH in human adipocytes and muscle cells.
Fig. 2: Mortality in patients with acromegaly with and without associated diabetes mellitus.
Fig. 3: A holistic person-centred approach to management of acromegaly-related diabetes mellitus.

Similar content being viewed by others

References

  1. Fleseriu, M., Langlois, F., Lim, D. S. T., Varlamov, E. V. & Melmed, S. Acromegaly: pathogenesis, diagnosis, and management. Lancet Diabetes Endocrinol. 10, 804–826 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Colao, A. et al. Acromegaly. Nat. Rev. Dis. Prim. 5, 20 (2019).

    Article  PubMed  Google Scholar 

  3. Gadelha, M. R., Kasuki, L., Lim, D. S. T. & Fleseriu, M. Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocr. Rev. 40, 268–332 (2019).

    Article  PubMed  Google Scholar 

  4. Pivonello, R. et al. Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities. Pituitary 20, 46–62 (2017).

    Article  PubMed  Google Scholar 

  5. Esposito, D. et al. Effect of diabetes on morbidity and mortality in patients with acromegaly. J. Clin. Endocrinol. Metab. 107, 2483–2492 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Moller, N. & Jorgensen, J. O. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr. Rev. 30, 152–177 (2009).

    Article  PubMed  Google Scholar 

  7. Freda, P. U. et al. Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly. J. Clin. Endocrinol. Metab. 93, 2334–2343 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Moller, N. et al. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J. Clin. Endocrinol. Metab. 74, 1012–1019 (1992).

    CAS  PubMed  Google Scholar 

  9. Nielsen, S., Moller, N., Christiansen, J. S. & Jorgensen, J. O. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes 50, 2301–2308 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Hjelholt, A. J. et al. Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle: a 2 x 2 factorial, randomised, crossover study in human individuals. Diabetologia 63, 2641–2653 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Zierler, K. L. & Rabinowitz, D. Roles of insulin and growth hormone, based on studies of forearm metabolism in man. Medicine 42, 385–402 (1963).

    Article  CAS  PubMed  Google Scholar 

  12. Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859–2865 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963).

    Article  CAS  PubMed  Google Scholar 

  14. Nellemann, B. et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol. 210, 392–402 (2014).

    Article  CAS  Google Scholar 

  15. del Rincon, J. P. et al. Growth hormone regulation of p85α expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes 56, 1638–1646 (2007).

    Article  PubMed  Google Scholar 

  16. Barbour, L. A. et al. Increased P85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess. J. Biol. Chem. 280, 37489–37494 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Nielsen, C. et al. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J. Clin. Endocrinol. Metab. 93, 2842–2850 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Jessen, N. et al. Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. Am. J. Physiol. Endocrinol. Metab. 288, E194–199 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Arlien-Soborg, M. C. et al. Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly. EBioMedicine 75, 103763 (2022).

    Article  PubMed  Google Scholar 

  20. Chen, J. W. et al. A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. Am. J. Physiol. Endocrinol. Metab. 284, E1149–1155 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Vila, G., Jorgensen, J. O. L., Luger, A. & Stalla, G. K. Insulin resistance in patients with acromegaly. Front. Endocrinol. 10, 509 (2019).

    Article  Google Scholar 

  22. Alexopoulou, O. et al. Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. Pituitary 17, 81–89 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Dal, J. et al. Acromegaly incidence, prevalence, complications and long-term prognosis: a nationwide cohort study. Eur. J. Endocrinol. 175, 181–190 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Petrossians, P. et al. Acromegaly at diagnosis in 3173 patients from the Liege Acromegaly Survey (LAS) Database. Endocr. Relat. Cancer 24, 505–518 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Slagboom, T. N. A., van Bunderen, C. C., De Vries, R., Bisschop, P. H. & Drent, M. L. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary 26, 319–332 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  26. González, B., Vargas, G., de Los Monteros, A. L. E., Mendoza, V. & Mercado, M. Persistence of diabetes and hypertension after multimodal treatment of acromegaly. J. Clin. Endocrinol. Metab. 103, 2369–2375 (2018).

    Article  PubMed  Google Scholar 

  27. Esposito, D., Ragnarsson, O., Johannsson, G. & Olsson, D. S. Prolonged diagnostic delay in acromegaly is associated with increased morbidity and mortality. Eur. J. Endocrinol. 182, 523–531 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Lenders, N. F., McCormack, A. I. & Ho, K. K. Y. Management of endocrine disease: does gender matter in the management of acromegaly? Eur. J. Endocrinol. 182, R67–R82 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Holdaway, I. M., Bolland, M. J. & Gamble, G. D. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur. J. Endocrinol. 159, 89–95 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Esposito, D. et al. Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study. Eur. J. Endocrinol. 178, 459–469 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Arnardottir, S. et al. Long-term outcomes of patients with acromegaly: a report from the Swedish Pituitary Register. Eur. J. Endocrinol. 186, 329–339 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Bolfi, F., Neves, A. F., Boguszewski, C. L. & Nunes-Nogueira, V. S. Mortality in acromegaly decreased in the last decade: a systematic review and meta-analysis. Eur. J. Endocrinol. 179, 59–71 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Katznelson, L. et al. Acromegaly: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 3933–3951 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Fleseriu, M. et al. A pituitary society update to acromegaly management guidelines. Pituitary 24, 1–13 (2021).

    Article  PubMed  Google Scholar 

  35. Cozzolino, A. et al. Metabolic complications in acromegaly after neurosurgery: a meta-analysis. Eur. J. Endocrinol. 183, 597–606 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Biagetti, B., Aulinas, A., Casteras, A., Perez-Hoyos, S. & Simo, R. HOMA-IR in acromegaly: a systematic review and meta-analysis. Pituitary 24, 146–158 (2021).

    Article  PubMed  Google Scholar 

  37. Kinoshita, Y. et al. Impaired glucose metabolism in Japanese patients with acromegaly is restored after successful pituitary surgery if pancreatic β-cell function is preserved. Eur. J. Endocrinol. 164, 467–473 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Frara, S., Maffezzoni, F., Mazziotti, G. & Giustina, A. Current and emerging aspects of diabetes mellitus in acromegaly. Trends Endocrinol. Metab. 27, 470–483 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Hannon, A. M., Thompson, C. J. & Sherlock, M. Diabetes in patients with acromegaly. Curr. Diab Rep. 17, 8 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. He, W. et al. Surgical outcomes and predictors of glucose metabolism alterations for growth hormone-secreting pituitary adenomas: a hospital-based study of 151 cases. Endocrine 63, 27–35 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Gatto, F. et al. Biological and biochemical basis of the differential efficacy of first and second generation somatostatin receptor ligands in neuroendocrine neoplasms. Int. J. Mol. Sci. 20, 3940 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kumar, U. et al. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes 48, 77–85 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Jorgensen, N. T. et al. Glucose metabolism, gut-brain hormones, and acromegaly treatment: an explorative single centre descriptive analysis. Pituitary 26, 152–163 (2023).

    Article  PubMed  Google Scholar 

  44. Colao, A. et al. Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-month study. J. Clin. Endocrinol. Metab. 94, 2907–2914 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Colao, A. et al. Impact of somatostatin analogs versus surgery on glucose metabolism in acromegaly: results of a 5-year observational, open, prospective study. J. Clin. Endocrinol. Metab. 94, 528–537 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Colao, A., Auriemma, R. S., Galdiero, M., Lombardi, G. & Pivonello, R. Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: a prospective study. J. Clin. Endocrinol. Metab. 94, 3746–3756 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Cambuli, V. M. et al. Glycometabolic control in acromegalic patients with diabetes: a study of the effects of different treatments for growth hormone excess and for hyperglycemia. J. Endocrinol. Invest. 35, 154–159 (2012).

    CAS  PubMed  Google Scholar 

  48. Mazziotti, G. et al. Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies. J. Clin. Endocrinol. Metab. 94, 1500–1508 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Caron, P. J. et al. Glucose and lipid levels with lanreotide autogel 120 mg in treatment-naive patients with acromegaly: data from the PRIMARYS study. Clin. Endocrinol. 86, 541–551 (2017).

    Article  CAS  Google Scholar 

  50. Cozzolino, A. et al. Somatostatin analogs and glucose metabolism in acromegaly: a meta-analysis of prospective interventional studies. J. Clin. Endocrinol. Metab. https://doi.org/10.1210/jc.2017-02566 (2018).

    Article  PubMed  Google Scholar 

  51. Gatto, F. et al. Cell specific interaction of pasireotide: review of preclinical studies in somatotroph and corticotroph pituitary cells. Pituitary 22, 89–99 (2019).

    Article  CAS  PubMed  Google Scholar 

  52. Colao, A. et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J. Clin. Endocrinol. Metab. 99, 791–799 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gadelha, M. R. et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2, 875–884 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Henry, R. R. et al. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J. Clin. Endocrinol. Metab. 98, 3446–3453 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Moustaki, M. et al. Secondary diabetes mellitus in acromegaly. Endocrine 81, 1–15 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shimon, I. et al. Efficacy and safety of long-acting pasireotide in patients with somatostatin-resistant acromegaly: a multicenter study. Endocrine 62, 448–455 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Lasolle, H. et al. Pasireotide-LAR in acromegaly patients treated with a combination therapy: a real-life study. Endocr. Connect. 8, 1383–1394 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stelmachowska-Banas, M., Czajka-Oraniec, I., Tomasik, A. & Zgliczynski, W. Real-world experience with pasireotide-LAR in resistant acromegaly: a single center 1-year observation. Pituitary 25, 180–190 (2022).

    Article  CAS  PubMed  Google Scholar 

  59. Akirov, A. et al. Long-term safety and efficacy of long-acting pasireotide in acromegaly. Endocrine 74, 396–403 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Witek, P. et al. The effect of 6 months’ treatment with pasireotide lar on glucose metabolism in patients with resistant acromegaly in real-world clinical settings. Front. Endocrinol. 12, 633944 (2021).

    Article  Google Scholar 

  61. Gadelha, M. et al. Long-term efficacy and safety of pasireotide in patients with acromegaly: 14 years of single-center real-world experience. J. Clin. Endocrinol. Metab. 108, e1571–e1579 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Gadelha, M. R. et al. Risk factors and management of pasireotide-associated hyperglycemia in acromegaly. Endocr. Connect. 9, 1178–1190 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wolf, P. et al. Impairment in insulin secretion without changes in insulin resistance explains hyperglycemia in patients with acromegaly treated with pasireotide LAR. Endocr. Connect. 11, e220296 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Melmed, S. et al. A consensus statement on acromegaly therapeutic outcomes. Nat. Rev. Endocrinol. 14, 552–561 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Wass, J. A. et al. Long-term treatment of acromegaly with bromocriptine. Br. Med. J. 1, 875–878 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wass, J. A., Cudworth, A. G., Bottazzo, G. F., Woodrow, J. C. & Besser, G. M. An assessment of glucose intolerance in acromegaly and its response to medical treatment. Clin. Endocrinol. 12, 53–59 (1980).

    Article  CAS  Google Scholar 

  67. Feek, C. M., Bevan, J. S., Taylor, S., Brown, N. S. & Baird, J. D. The effect of bromocriptine on insulin secretion and glucose tolerance in patients with acromegaly. Clin. Endocrinol. 15, 473–478 (1981).

    Article  CAS  Google Scholar 

  68. Chiba, T. et al. Effect of long term bromocriptine treatment on glucose intolerance in acromegaly. Horm. Metab. Res. 14, 57–61 (1982).

    Article  CAS  PubMed  Google Scholar 

  69. Rau, H., Althoff, P. H., Schmidt, K., Badenhoop, K. & Usadel, K. H. Bromocriptine treatment over 12 years in acromegaly: effect on glucose tolerance and insulin secretion. Clin. Investig. 71, 372–378 (1993).

    Article  CAS  PubMed  Google Scholar 

  70. Roemmler, J. et al. The acute effect of a single application of cabergoline on endogenous GH levels in patients with acromegaly on pegvisomant treatment. Growth Horm. IGF Res. 20, 338–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Cincotta, A. H. & Meier, A. H. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care 19, 667–670 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Andersen, I. B., Andreassen, M. & Krogh, J. The effect of dopamine agonists on metabolic variables in adults with type 2 diabetes: a systematic review with meta analysis and trial sequential analysis of randomized clinical trials. Diabetes Obes. Metab. 23, 58–67 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Kamath, V. et al. Effects of a quick-release form of bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women. Diabetes Care 20, 1697–1701 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Drake, W. M. et al. Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant. Eur. J. Endocrinol. 149, 521–527 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Marazuela, M. et al. Long-term treatment of acromegalic patients resistant to somatostatin analogues with the GH receptor antagonist pegvisomant: its efficacy in relation to gender and previous radiotherapy. Eur. J. Endocrinol. 160, 535–542 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Lindberg-Larsen, R. et al. The impact of pegvisomant treatment on substrate metabolism and insulin sensitivity in patients with acromegaly. J. Clin. Endocrinol. Metab. 92, 1724–1728 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Ghigo, E. et al. Comparison of pegvisomant and long-acting octreotide in patients with acromegaly naive to radiation and medical therapy. J. Endocrinol. Invest. 32, 924–933 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Hodish, I. & Barkan, A. Long-term effects of pegvisomant in patients with acromegaly. Nat. Clin. Pract. Endocrinol. Metab. 4, 324–332 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Berg, C. et al. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J. Clin. Endocrinol. Metab. 95, 3648–3656 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Higham, C. E., Rowles, S., Russell-Jones, D., Umpleby, A. M. & Trainer, P. J. Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly. J. Clin. Endocrinol. Metab. 94, 2459–2463 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Urbani, C. et al. Effects of medical therapies for acromegaly on glucose metabolism. Eur. J. Endocrinol. 169, 99–108 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Colao, A. et al. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur. J. Endocrinol. 154, 467–477 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Feola, T. et al. Pegvisomant improves glucose metabolism in acromegaly: a meta-analysis of prospective interventional studies. J. Clin. Endocrinol. Metab. 104, 2892–2902 (2019).

    Article  PubMed  Google Scholar 

  84. Fleseriu, M. et al. More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY. Eur. J. Endocrinol. 185, 525–538 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ma, L. et al. Combined therapy of somatostatin analogues with pegvisomant for the treatment of acromegaly: a meta-analysis of prospective studies. BMC Endocr. Disord. 20, 126 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Muhammad, A. et al. Efficacy and safety of switching to pasireotide in patients with acromegaly controlled with pegvisomant and first-generation somatostatin analogues (PAPE study). J. Clin. Endocrinol. Metab. 103, 586–595 (2018).

    Article  PubMed  Google Scholar 

  87. Ronchi, C. L. et al. Long-term effects of radiotherapy on cardiovascular risk factors in acromegaly. Eur. J. Endocrinol. 164, 675–684 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Colao, A., Grasso, L. F. S., Di Somma, C. & Pivonello, R. Acromegaly and heart failure. Heart Fail. Clin. 15, 399–408 (2019).

    Article  PubMed  Google Scholar 

  89. Colao, A., Ferone, D., Marzullo, P. & Lombardi, G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr. Rev. 25, 102–152 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Colao, A. et al. Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy. J. Clin. Endocrinol. Metab. 85, 193–199 (2000).

    CAS  PubMed  Google Scholar 

  91. Lopez-Velasco, R. et al. Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic hypertension? J. Clin. Endocrinol. Metab. 82, 1047–1053 (1997).

    CAS  PubMed  Google Scholar 

  92. Vila, G. et al. Hypertension in acromegaly in relationship to biochemical control and mortality: global ACROSTUDY outcomes. Front. Endocrinol. 11, 577173 (2020).

    Article  Google Scholar 

  93. Ahmad, E., Lim, S., Lamptey, R., Webb, D. R. & Davies, M. J. Type 2 diabetes. Lancet 400, 1803–1820 (2022).

    Article  PubMed  Google Scholar 

  94. Poulsen, J. E. Recovery from retinopathy in a case of diabetes Simmonds’ disease. Diabetes 2, 7–12 (1953).

    Article  CAS  PubMed  Google Scholar 

  95. Wright, A. D. et al. Serum growth hormone levels and the response of diabetic retinopathy to pituitary ablation. Br. Med. J. 2, 346–348 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ray, B. S., Pazianos, A. G., Greenberg, E., Peretz, W. L. & McLean, J. M. Pituitary ablation for diabetic retinopathy. I. Results of hypophysectomy. (A ten-year evaluation). JAMA 203, 79–84 (1968).

    Article  CAS  PubMed  Google Scholar 

  97. Alzaid, A. A., Dinneen, S. F., Melton, L. J. III & Rizza, R. A. The role of growth hormone in the development of diabetic retinopathy. Diabetes Care 17, 531–534 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Yuno, A. et al. Advanced proliferative diabetic retinopathy and macular edema in acromegaly: a case report and literature review. Diabetol. Int. 13, 575–579 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Azzoug, S. & Chentli, F. Diabetic retinopathy in acromegaly. Indian J. Endocrinol. Metab. 18, 407–409 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Wu, T. E. & Chen, H. S. The role of growth hormone and IGF-1 in retinopathy: a prospective study of retinopathy in patients with acromegaly and impaired fasting glucose. Diabetol. Metab. Syndr. 14, 38 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Fuchtbauer, L. et al. Increased number of retinal vessels in acromegaly. Eur. J. Endocrinol. 182, 293–302 (2020).

    Article  CAS  PubMed  Google Scholar 

  102. Kamenicky, P., Mazziotti, G., Lombes, M., Giustina, A. & Chanson, P. Growth hormone, insulin-like growth factor-1, and the kidney: pathophysiological and clinical implications. Endocr. Rev. 35, 234–281 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Mukhi, D., Nishad, R., Menon, R. K. & Pasupulati, A. K. Novel actions of growth hormone in podocytes: implications for diabetic nephropathy. Front. Med. 4, 102 (2017).

    Article  Google Scholar 

  104. Bellush, L. L. et al. Protection against diabetes-induced nephropathy in growth hormone receptor/binding protein gene-disrupted mice. Endocrinology 141, 163–168 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Baldelli, R. et al. Microalbuminuria in insulin sensitivity in patients with growth hormone-secreting pituitary tumor. J. Clin. Endocrinol. Metab. 93, 710–714 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Vouzouneraki, K. et al. Carpal tunnel syndrome in acromegaly: a nationwide study. Eur. J. Endocrinol. 184, 209–216 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Lewis, P. D. Neuromuscular involvement in pituitary gigantism. Br. Med. J. 2, 499–500 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Low, P. A., McLeod, J. G., Turtle, J. R., Donnelly, P. & Wright, R. G. Peripheral neuropathy in acromegaly. Brain 97, 139–152 (1974).

    Article  CAS  PubMed  Google Scholar 

  109. Jamal, G. A., Kerr, D. J., McLellan, A. R., Weir, A. I. & Davies, D. L. Generalised peripheral nerve dysfunction in acromegaly: a study by conventional and novel neurophysiological techniques. J. Neurol. Neurosurg. Psychiatry 50, 886–894 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hicks, C. W. & Selvin, E. Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr. Diab Rep. 19, 86 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Esposito, D., Ragnarsson, O., Johannsson, G. & Olsson, D. S. Incidence of benign and malignant tumors in patients with acromegaly is increased: a nationwide population-based study. J. Clin. Endocrinol. Metab. 106, 3487–3496 (2021).

    PubMed  Google Scholar 

  112. Dal, J. et al. Cancer incidence in patients with acromegaly: a cohort study and meta-analysis of the literature. J. Clin. Endocrinol. Metab. 103, 2182–2188 (2018).

    Article  PubMed  Google Scholar 

  113. Tomic, D., Shaw, J. E. & Magliano, D. J. The burden and risks of emerging complications of diabetes mellitus. Nat. Rev. Endocrinol. 18, 525–539 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Bonagiri, P. R. & Shubrook, J. H. Review of associations between type 2 diabetes and cancer. Clin. Diabetes 38, 256–265 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Colao, A. et al. The association of fasting insulin concentrations and colonic neoplasms in acromegaly: a colonoscopy-based study in 210 patients. J. Clin. Endocrinol. Metab. 92, 3854–3860 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Cheng, S., Gomez, K., Serri, O., Chik, C. & Ezzat, S. The role of diabetes in acromegaly associated neoplasia. PLoS One 10, e0127276 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Xiao, Z. H. et al. Cancer risk and its association with diabetes mellitus in patients with acromegaly: a two center-based study. Endocr. Pract. 29, 699–704 (2023).

    Article  PubMed  Google Scholar 

  118. Davies, M. J. et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the american diabetes association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 45, 2753–2786 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Reyes-Vidal, C. M. et al. Adipose tissue redistribution and ectopic lipid deposition in active acromegaly and effects of surgical treatment. J. Clin. Endocrinol. Metab. 100, 2946–2955 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kahn, S. E., Cooper, M. E. & Del Prato, S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383, 1068–1083 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Yau, H., Rivera, K., Lomonaco, R. & Cusi, K. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr. Diab Rep. 13, 329–341 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Samson, S. L. et al. Managing pasireotide-associated hyperglycemia: a randomized, open-label, phase IV study. Pituitary 24, 887–903 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lupsa, B. C. & Inzucchi, S. E. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia 61, 2118–2125 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Yoshida, N. et al. Ketoacidosis as the initial clinical condition in nine patients with acromegaly: a review of 860 cases at a single institute. Eur. J. Endocrinol. 169, 127–132 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Quarella, M., Walser, D., Brandle, M., Fournier, J. Y. & Bilz, S. Rapid onset of diabetic ketoacidosis after SGLT2 inhibition in a patient with unrecognized acromegaly. J. Clin. Endocrinol. Metab. 102, 1451–1453 (2017).

    Article  PubMed  Google Scholar 

  126. Weiss, J. et al. Diabetic ketoacidosis in acromegaly; a rare complication precipitated by corticosteroid use. Diabetes Res. Clin. Pract. 134, 29–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  127. Zaina, A. et al. Sodium glucose cotransporter 2 inhibitors treatment in acromegalic patients with diabetes-a case series and literature review. Endocrine 73, 65–70 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors express their gratitude to Eva Hessman and Helen Sjöblom (Biomedical Library, Gothenburg University Library, University of Gothenburg, Gothenburg, Sweden) for developing the search strings and conducting the study search for this Review. The authors are grateful to Daniele Micciché (medical student at Università del Piemonte Orientale, Novara, Italy) for his contribution to the development of Table 1. The authors acknowledge Peter Todd (Tajut Ltd., Kaiapoi, New Zealand) for third-party editorial assistance with language editing and the formatting of the table and reference list, for which he received financial compensation from ALF funding. The authors acknowledge the support of the Swedish government under the ALF agreement. ALF is the Swedish acronym for an agreement between the central government and the Swedish regions with the aim of promoting clinical research and education. The funding source did not have any involvement in the project design or any other phase of the project.

Author information

Authors and Affiliations

  1. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Daniela Esposito, Oskar Ragnarsson & Gudmundur Johannsson

  2. Department of Medicine (Division of Endocrinology, Diabetes and Clinical Nutrition), Sahlgrenska University Hospital, Gothenburg, Sweden

    Daniela Esposito, Oskar Ragnarsson & Gudmundur Johannsson

  3. Department of Internal Medicine, Endocrine Division (SEMPR), University Hospital, Federal University of Parana, Curitiba, Brazil

    Cesar Luiz Boguszewski

  4. Endocrinlogy Unit, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy

    Annamaria Colao

  5. UNESCO Chair for Health Education and Sustainable Development, Federico II University, Naples, Italy

    Annamaria Colao

  6. Pituitary Center, Department of Medicine and Neurological Surgery, Oregon Health and Science University, Portland, OR, USA

    Maria Fleseriu

  7. Endocrinology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Federico Gatto & Diego Ferone

  8. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

    Jens Otto Lunde Jørgensen

  9. Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

    Oskar Ragnarsson

  10. Endocrinology, Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy

    Diego Ferone

Authors
  1. Daniela Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cesar Luiz Boguszewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annamaria Colao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Fleseriu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Federico Gatto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jens Otto Lunde Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oskar Ragnarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Diego Ferone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gudmundur Johannsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Daniela Esposito.

Ethics declarations

Competing interests

D.E. has received lecture fees from Ipsen and Pfizer AB. C.L.B. has received lecture fees from Ipsen, Recordati and Novo Nordisk, has been Principal Investigator of Research Studies for Novartis and Recordati, and served as consultant for Ipsen, Recordati, Crinetics, and Novo Nordisk. A.C. has been Principal Investigator of Research Studies for Novartis, Ipsen, Pfizer, Lilly, Merck and Novo Nordisk, a consultant for Novartis, Ipsen, and Pfizer, and received honoraria from Novartis, Ipsen and Pfizer. M.F. has received grants to their institution from Amryt, Crinetics, Ionis, and Recordati and has received occasional consulting fees or has served as occasional Advisory Board Member for Amryt, Camurus, Ipsen, Pfizer, and Recordati. F.G. has received lecture/manuscript writing fees from Recordati Rare Diseases, Camurus, Ipsen and Pfizer. J.O.L.J. has served as Advisory Board Member for Novo Nordisk. D.F. has received lecture, advisory board and steering committee fees as well as a research grant from Recordati Rare Diseases, Camurus, Novartis-Advanced Accelerator Applications, Ipsen, and Bristol Myers Squibb. G.J. has served as a consultant for Novo Nordisk, Shire, and Astra Zeneca and has received lecture fees from Eli Lilly, Ipsen, Novartis, Novo Nordisk, Merck Serono, Otsuka, and Pfizer AB. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Marek Bolanowski, Leandro Kasuki, Jochen Schopohl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

We searched PubMed for full-text articles published in English from the inception of the data base until June 20, 2023, using the terms “acromegaly”, “somatotropin hypersecretion syndrome”, “inappropriate GH secretion syndrome” in combination with the terms “diabetes mellitus” and “insulin resistance”. Articles were screened using the Rayyan web application. Some articles were not included in the Review due to word length limitation, irrelevance or lack of importance.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Esposito, D., Boguszewski, C.L., Colao, A. et al. Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00993-x

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41574-024-00993-x

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing