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Insulin sensitivity and secretion and adipokine profile in patients with Cushing’s disease treated with pasireotide

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Abstract

Purpose

To evaluate the effect of pasireotide on β-cell and adipose function in patients with Cushing’s disease (CD).

Methods

Clinical and hormonal parameters, insulin secretion evaluated by HOMA-β and by the area under the curve (AUC2h) of C-peptide during a mixed meal tolerance test and insulin sensitivity, evaluated by the euglycaemic hyperinsulinaemic clamp, were evaluated in 12 patients with active CD, before and after 6 and 12 months of pasireotide. In addition, a panel of adipokines including leptin (Ob), leptin/leptin receptor ratio (Ob/Ob-R ratio), adiponectin, resistin, visfatin, adipocyte fatty acid binding protein (AFABP) and non-esterified fatty acids (NEFAs) was evaluated at baseline and after 12 months of pasireotide.

Results

During 12 months of pasireotide treatment, a significant decrease in weight (p = 0.004), BMI (p = 0.008), waist circumference (p = 0.009), urinary free cortisol (p = 0.007), fasting insulinaemia (p = 0.007), HOMA-β (p = 0.015) and AUC2h c-peptide (p = 0.017), concomitance with an increase in fasting glycaemia (p = 0.015) and HbA1c (p = 0.030), was found. With regard to adipokines, a significant decrease in Ob (p = 0.039), Ob/Ob-R ratio (p = 0.017) and AFABP (p = 0.036) was observed concomitant with a significant increase in Ob-R (p = 0.028) after 12 months of pasireotide.

Conclusions

12 months of treatment with pasireotide in CD is associated with an impairment of insulin secretion and an improvement of adipose function without any interference in insulin sensitivity.

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References

  1. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jørgensen JO (2002) Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med 23:278–282

    Article  Google Scholar 

  2. Patil CG, Prevedello DM, Lad SP, Vance ML, Thorner MO, Katznelson L et al (2008) Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab 93:358–362

    Article  CAS  PubMed  Google Scholar 

  3. Vance ML (2009) Cushing’s disease: radiation therapy. Pituitary 12:11–14

    Article  PubMed  Google Scholar 

  4. Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J et al (2013) Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 98:3939–3948

    Article  CAS  PubMed  Google Scholar 

  5. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Endocrine Society et al (2015) Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100:2807–2831

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G et al (2009) The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 94:223–230

    Article  CAS  PubMed  Google Scholar 

  7. Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M et al (2009) Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 94:115–122

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Schopohl J, Gu F, Rubens R, Van Gaal L, Bertherat J, Ligueros-Saylan M et al (2015) Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial. Pituitary 18:604–612

    Article  CAS  PubMed  Google Scholar 

  10. Guarnotta V, Ciresi A, Pitrone M, Pizzolanti G, Giordano C (2017) Pasireotide versus pituitary surgery: a retrospective analysis of 12 months of treatment in patients with Cushing’s disease. Endocrine. https://doi.org/10.1007/s12020-017-1276-7

    Article  PubMed  Google Scholar 

  11. Trementino L, Michetti G, Angeletti A, Marcelli G, Concettoni C, Cardinaletti C et al (2016) Single-center 10-year experience with pasireotide in Cushing’s disease: patients’ characteristics and outcome. Horm Metab Res 48:290–298

    Article  CAS  PubMed  Google Scholar 

  12. Webb SM, Ware JE, Forsythe A, Yang M, Badia X, Nelson LM, Signorovitch JE, McLeod L, Maldonado M, Zgliczynski W, de Block C, Portocarrero-Ortiz L, Gadelha M (2014) Treatment effectiveness of pasireotide on health-related quality of life in patients with Cushing’s disease. Eur J Endocrinol 171:89–98

    Article  CAS  PubMed  Google Scholar 

  13. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S (2013) Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab 98:3446–3453

    Article  CAS  PubMed  Google Scholar 

  14. Giordano C, Guarnotta V, Pivonello R, Amato MC, Simeoli C, Ciresi A et al (2013) Is diabetes in Cushing’s syndrome only a consequence of hypercortisolism? Eur J Endocrinol 170:311–319

    Article  PubMed  Google Scholar 

  15. Guarnotta V, Amato MC, Pivonello R, Arnaldi G, Ciresi A, Trementino L et al (2017) The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome. Endocrine 55:564–572

    Article  CAS  PubMed  Google Scholar 

  16. Yamashita S, Nakamura T, Shimomura I, Nishida M, Yoshida S, Kotani K et al (1996) Insulin resistance and body fat distribution. Diabetes Care 19:287–291

    Article  CAS  PubMed  Google Scholar 

  17. Amato MC, Guarnotta V, Giordano C (2013) Body composition assessment for the definition of cardiometabolic risk. J Endocrinol Invest 36:537–543

    CAS  PubMed  Google Scholar 

  18. Virtue S, Vidal-Puig A (2008) It’s not how fat you are, it’s what you do with it that counts. PLoS Biol 23:e237

    Article  Google Scholar 

  19. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM et al (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312

    Article  CAS  PubMed  Google Scholar 

  20. Valassi E, Biller BM, Klibanski A, Misra M (2012) Adipokines and cardiovascular risk in Cushing’s syndrome. Neuroendocrinology 95:187–206

    Article  CAS  PubMed  Google Scholar 

  21. Despres JP (2006) Is visceral obesity the cause of the metabolic syndrome? Ann Med 38:52–63

    Article  CAS  PubMed  Google Scholar 

  22. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM et al (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP et al (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 88:5593–5602

    Article  CAS  PubMed  Google Scholar 

  24. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF (2014) Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary 17:180–186

    Article  CAS  PubMed  Google Scholar 

  25. Liu X, Men P, Wang Y, Zhai S, Liu G (2016) Impact of dipeptidyl peptidase-4 inhibitors on serum adiponectin: a meta-analysis. Lipids Health Dis 15:204

    Article  PubMed Central  PubMed  Google Scholar 

  26. Röhrborn D, Brückner J, Sell H, Eckel J (2016) Reduced DPP4 activity improves insulin signaling in primary human adipocytes. Biochem Biophys Res Commun 471:348–354

    Article  PubMed  Google Scholar 

  27. Grigoropoulou P, Eleftheriadou I, Zoupas C, Diamanti-Kandarakis E, Tentolouris N (2013) Incretin-based therapies for type 2 diabetes mellitus: effects on insulin resistance. Curr Diabetes Rev 9:412–417

    Article  CAS  PubMed  Google Scholar 

  28. El Bekay R, Coín-Aragüez L, Fernández-García D, Oliva-Olivera W, Bernal-López R, Clemente-Postigo M et al (2016) Effects of glucagon-like peptide-1 on the differentiation and metabolism of human adipocytes. Br J Pharmacol 173:1820–1834

    Article  PubMed Central  PubMed  Google Scholar 

  29. Matthews D, Hosker J, Rudenski A, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 28:412–419

    Article  CAS  PubMed  Google Scholar 

  30. DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E222

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Trujillo ME, Scherer PE (2006) Adipose tissue-derived factors: impact on health and disease. Endocr Rev 27:762–778

    Article  CAS  PubMed  Google Scholar 

  33. Masuzaki H, Ogawa Y, Hosoda K, Miyawaki T, Hanaoka I, Hiraoka J et al (1997) Glucocorticoid regulation of leptin synthesis and secretion in humans: elevated plasma leptin levels in Cushing’s syndrome. J Clin Endocrinol Metab 82:2542–2547

    CAS  PubMed  Google Scholar 

  34. Weise M, Abad V, Considine RV, Nieman L, Rother KI (1999) Leptin secretion in Cushing’s syndrome: preservation of diurnal rhythm and absent response to corticotrophin-releasing hormone. J Clin Endocrinol Metab 84:2075–2079

    CAS  PubMed  Google Scholar 

  35. Gavrila A, Peng CK, Chan L, Mietus JE, Goldberger AL, Mantzoros CS (2003) Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab 88:2838–2843

    Article  CAS  PubMed  Google Scholar 

  36. Libè R, Morpugo PS, Cappiello V, Maffini A, Bondioni S, Locatelli M et al (2005) Ghrelin and adiponectin in patients with Cushing’s disease before and after successful transsphenoidal surgery. Clin Endocrinol 62:30–36

    Article  Google Scholar 

  37. Wagenmakers M, Roerink S, Gil L, Plantinga T, Smit J, Netea-Maier R et al (2015) Persistent centripetal fat distribution and metabolic abnormalities in patients in long-term remission of Cushing’s syndrome. Clin Endocrinol 82:180–187

    Article  CAS  Google Scholar 

  38. Barahona MJ, Sucunza N, Resmini E, Fernández-Real JM, Ricart W, Moreno-Navarrete JM et al (2009) Persistent body fat mass and inflammatory marker increases after long-term cure of Cushing’s syndrome. J Clin Endocrinol Metab 94:3365–3371

    Article  CAS  PubMed  Google Scholar 

  39. Durovcová V, Marek J, Hána V, Matoulek M, Zikán V, Haluzíková D et al (2010) Plasma concentrations of adipocyte fatty acid binding protein in patients with Cushing’s syndrome. Physiol Res 59:963–971

    PubMed  Google Scholar 

  40. Rubenstein AH, Block MB, Starr J, Melani F, Steiner DF (1992) Proinsulin and C-peptide in blood. Diabetes 21:661–672

    Article  Google Scholar 

  41. Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H et al (2004) C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes 53:250–264

    Article  CAS  PubMed  Google Scholar 

  42. Hendriksen C, Faber OK, Drejer J, Binder C (1997) Prevalence of residual B-cell function in insulin-treated diabetics evaluated by the plasma C-peptide response to intravenous glucagon. Diabetologia 13:615–619

    Article  Google Scholar 

  43. Ida S, Murata K, Kaneko R (2017) Effects of metformin treatment on blood leptin and ghrelin levels in patients with type 2 diabetes mellitus. J Diabetes 9:526–535

    Article  CAS  PubMed  Google Scholar 

  44. Ou HY, Cheng JT, Yu EH, Wu TJ (2006) Metformin increases insulin sensitivity and plasma beta-endorphin in human subjects. Horm Metab Res 38:106–111

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Dr. Marco Calogero Amato, who died before the submission of the paper, for his contribution in the performance of the clamp procedure.

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Author notes

  1. V. Guarnotta and G. Pizzolanti contributed equally to this work.

Authors and Affiliations

  1. Biomedical Department of Internal and Specialist Medicine (DIBIMIS), Section of Diabetes, Endocrinology and Metabolism, University of Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy

    V. Guarnotta, G. Pizzolanti, A. Ciresi & C. Giordano

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  1. V. Guarnotta
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Correspondence to C. Giordano.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Guarnotta, V., Pizzolanti, G., Ciresi, A. et al. Insulin sensitivity and secretion and adipokine profile in patients with Cushing’s disease treated with pasireotide. J Endocrinol Invest 41, 1137–1147 (2018). https://doi.org/10.1007/s40618-018-0839-7

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  • DOI: https://doi.org/10.1007/s40618-018-0839-7

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