{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T07:21:24Z","timestamp":1763018484946,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:00:00Z","timestamp":1651795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cushing\u2019s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM\u2013) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 \u00b5g twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM\u2212 (p &lt; 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p &lt; 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms23095217","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T14:49:38Z","timestamp":1651848578000},"page":"5217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Incretin Response to Mixed Meal Challenge in Active Cushing\u2019s Disease and after Pasireotide Therapy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1081-5727","authenticated-orcid":false,"given":"Mattia","family":"Barbot","sequence":"first","affiliation":[{"name":"Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6046-5198","authenticated-orcid":false,"given":"Alessandro","family":"Mondin","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1942-7202","authenticated-orcid":false,"given":"Daniela","family":"Regazzo","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Guarnotta","sequence":"additional","affiliation":[{"name":"Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza \u201cG. D\u2019Alessandro\u201d, UOC di Malattie Endocrine, del Ricambio e della Nutrizione, Universit\u00e0 degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8745-6171","authenticated-orcid":false,"given":"Daniela","family":"Basso","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Unit, Department of Medicine DIMED, University-Hospital of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1731-9395","authenticated-orcid":false,"given":"Carla","family":"Giordano","sequence":"additional","affiliation":[{"name":"Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza \u201cG. D\u2019Alessandro\u201d, UOC di Malattie Endocrine, del Ricambio e della Nutrizione, Universit\u00e0 degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Scaroni","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Ceccato","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3389\/fendo.2018.00284","article-title":"Diabetes Mellitus Secondary to Cushing\u2019s Disease","volume":"9","author":"Barbot","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1210\/er.2016-1105","article-title":"Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management","volume":"38","author":"Scaroni","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1530\/EJE-13-0754","article-title":"Is diabetes in Cushing\u2019s syndrome only a consequence of hypercortisolism?","volume":"170","author":"Giordano","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2020). Classification and diagnosis of diabetes: Standards of medical care in diabetes. Diabetes Care, 43, S14\u2013S31.","DOI":"10.2337\/dc20-S002"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1007\/s00125-015-3522-y","article-title":"Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance","volume":"58","author":"Eriksen","year":"2015","journal-title":"Diabetologia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1007\/s00125-012-2459-7","article-title":"Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes","volume":"55","author":"Jensen","year":"2012","journal-title":"Diabetologia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1042\/CS20140719","article-title":"Glucocorticoids suppress GLP-1 secretion: Possible contribution to their diabetogenic effects","volume":"129","author":"Kappe","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.cmet.2013.04.008","article-title":"Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action","volume":"17","author":"Campbell","year":"2013","journal-title":"Cell Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.diabres.2011.09.002","article-title":"Postprandial metabolic responses to mixed versus liquid meal tests in healthy men and men with type 2 diabetes","volume":"94","author":"Brodovicz","year":"2011","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3803\/EnM.2018.33.2.139","article-title":"Recent Updates on the Diagnosis and Management of Cushing\u2019s Syndrome","volume":"33","author":"Nieman","year":"2018","journal-title":"Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1007\/s11102-015-0645-6","article-title":"Comorbidities in Cushing\u2019s disease","volume":"18","author":"Sharma","year":"2015","journal-title":"Pituitary"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/S2213-8587(21)00235-7","article-title":"Consensus on diagnosis and management of Cushing\u2019s disease: A guideline update","volume":"9","author":"Fleseriu","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1056\/NEJMoa1105743","article-title":"A 12-Month Phase 3 Study of Pasireotide in Cushing\u2019s Disease","volume":"366","author":"Colao","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.1210\/jc.2013-1771","article-title":"Hyperglycemia Associated With Pasireotide: Results from a Mechanistic Study in Healthy Volunteers","volume":"98","author":"Henry","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1007\/s11102-020-01055-x","article-title":"Is pasireotide-induced diabetes mellitus predictable? A pilot study on the effect of a single dose of pasireotide on glucose homeostasis","volume":"23","author":"Barbot","year":"2020","journal-title":"Pituitary"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1210\/jc.2008-0125","article-title":"The Diagnosis of Cushing\u2019s Syndrome: An Endocrine Society Clinical Practice Guideline","volume":"93","author":"Nieman","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1210\/endo-126-5-2635","article-title":"Immunohistochemical Localization of the Glucocorticoid Receptor in Pancreatic \u03b2-Cells of the Rat","volume":"126","author":"Fischer","year":"1990","journal-title":"Endocrinology"},{"key":"ref_18","first-page":"749","article-title":"Meal test for glucose-dependent insulinotropic peptide (GIP) in obese and type 2 diabetic patients","volume":"59","author":"Hill","year":"2010","journal-title":"Physiol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1210\/jc.2010-0119","article-title":"Reduced Glucose Tolerance and Insulin Resistance Induced by Steroid Treatment, Relative Physical Inactivity, and High-Calorie Diet Impairs the Incretin Effect in Healthy Subjects","volume":"95","author":"Hansen","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1530\/EJE-13-0610","article-title":"Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial","volume":"170","author":"Muskiet","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s00125-008-0951-x","article-title":"Impaired fasting glycaemia vs impaired glucose tolerance: Similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action","volume":"51","author":"Vaag","year":"2008","journal-title":"Diabetologia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.metabol.2005.03.024","article-title":"Impact of glucagon response on postprandial hyperglycemia in men with impaired glucose tolerance and type 2 diabetes mellitus","volume":"54","author":"Henkel","year":"2005","journal-title":"Metabolism"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1677\/JOE-07-0299","article-title":"Melanocortin crosstalk with adipose functions: ACTH directly induces insulin resistance, promotes a pro-inflammatory adipokine profile and stimulates UCP-1 in adipocytes","volume":"196","author":"Iwen","year":"2008","journal-title":"J. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2337\/diabetes.48.1.77","article-title":"Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: A quantitative double-label immunohistochemical analysis","volume":"48","author":"Kumar","year":"1999","journal-title":"Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1007\/s40618-018-0839-7","article-title":"Insulin sensitivity and secretion and adipokine profile in patients with Cushing\u2019s disease treated with pasireotide","volume":"41","author":"Guarnotta","year":"2018","journal-title":"J. Endocrinol. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1080\/19382014.2021.1889941","article-title":"Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1","volume":"13","author":"Campbell","year":"2021","journal-title":"Islets"},{"key":"ref_27","first-page":"49","article-title":"Effects of somatostatin analogs on glucose homeostasis in rats","volume":"212","author":"Brueggen","year":"2012","journal-title":"J. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s11102-021-01161-4","article-title":"Managing pasireotide-associated hyperglycemia: A randomized, open-label, Phase IV study","volume":"24","author":"Samson","year":"2021","journal-title":"Pituitary"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s11102-013-0483-3","article-title":"Managing hyperglycemia in patients with Cushing\u2019s disease treated with pasireotide: Medical expert recommendations","volume":"17","author":"Colao","year":"2014","journal-title":"Pituitary"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:07:21Z","timestamp":1760137641000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,6]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095217"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095217","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,5,6]]}}}