{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T14:05:19Z","timestamp":1789826719684,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"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>Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.<\/jats:p>","DOI":"10.3390\/ijms24065153","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T02:30:23Z","timestamp":1678242623000},"page":"5153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma"],"prefix":"10.3390","volume":"24","author":[{"given":"Chiara","family":"Lopez","sequence":"first","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Bima","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Bollati","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7550-7023","authenticated-orcid":false,"given":"Fabio","family":"Bioletto","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Procopio","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Arata","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele Giuseppe","family":"Candela","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3163-2361","authenticated-orcid":false,"given":"Guglielmo","family":"Beccuti","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2809-8105","authenticated-orcid":false,"given":"Ezio","family":"Ghigo","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Maccario","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6930-7073","authenticated-orcid":false,"given":"Mirko","family":"Parasiliti-Caprino","sequence":"additional","affiliation":[{"name":"Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1210\/jcem-7-10-716","article-title":"Pheochromocytoma with diabetes","volume":"7","author":"Goldner","year":"1947","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1097\/00004872-200309000-00020","article-title":"Diabetes as a marker of pheochromocytoma in hypertensive patients","volume":"21","author":"Chatellier","year":"2003","journal-title":"J. Hypertens."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s11739-015-1217-5","article-title":"Pheochromocytoma presenting as hyperglycemic hyperosmolar syndrome and unusual fever","volume":"10","author":"Lee","year":"2015","journal-title":"Intern. Emerg. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1245\/s10434-016-5701-6","article-title":"Resection of Pheochromocytoma Improves Diabetes Mellitus in the Majority of Patients","volume":"24","author":"Beninato","year":"2016","journal-title":"Ann. Surg. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ando.2020.01.001","article-title":"Prevalence and progression of carbohydrate disorders in patients with pheochromocytoma\/paraganglioma: Retrospective single-center study","volume":"81","author":"Elenkova","year":"2020","journal-title":"Ann. Endocrinol."},{"key":"ref_6","first-page":"361","article-title":"The effect of surgical treatment of phaeochromocytoma on concomitant arterial hypertension and diabetes mellitus in a single\u2013centre retrospective study","volume":"67","author":"Pogorzelski","year":"2014","journal-title":"Central Eur. J. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3632","DOI":"10.1210\/jc.2003-030000","article-title":"Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma","volume":"88","author":"Wiesner","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1016\/j.surg.2014.08.020","article-title":"Hypoglycemia after resection of pheochromocytoma","volume":"156","author":"Chen","year":"2014","journal-title":"Surgery"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s002689900454","article-title":"Pheochromocytoma, a Rare Cause of Hypertension: Long-term Follow-up of 55 Surgically Treated Patients","volume":"22","author":"Favia","year":"1998","journal-title":"World J. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/BF01658514","article-title":"Hypoglycemia Induced by Excessive Rebound Secretion of Insulin after Removal of Pheochromocytoma","volume":"14","author":"Akiba","year":"1990","journal-title":"World J. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/iju.13864","article-title":"Incidence and predictive factors of hypoglycemia after pheochromocytoma resection","volume":"26","author":"Araki","year":"2018","journal-title":"Int. J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"251","DOI":"10.7326\/0003-4819-71-2-251","article-title":"Inhibition of insulin secretion by catecholamines in pheochromocytoma","volume":"71","author":"Colwell","year":"1969","journal-title":"Ann. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0140-6736(66)92986-2","article-title":"Inhibition of insulin secretion by a phaeochromocytoma","volume":"2","author":"Wilber","year":"1966","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1677\/jme.1.01764","article-title":"Proteomic exploration of pancreatic islets in mice null for the \u03b12A adrenergic receptor","volume":"35","author":"Hu","year":"2005","journal-title":"J. Mol. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ejphar.2004.10.023","article-title":"Altered glucose homeostasis in \u03b12A-adrenoceptor knockout mice","volume":"505","author":"Fagerholm","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00210-003-0858-5","article-title":"Involvement of \u03b11 and \u03b2-adrenoceptors in adrenaline stimulation of the glucagon-secreting mouse \u03b1-cell","volume":"369","author":"Vieira","year":"2004","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/oby.2002.75","article-title":"In vivo response to \u03b11-adrenoreceptor stimulation in human white adipose tissue","volume":"10","author":"Boschmann","year":"2002","journal-title":"Obes. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15141","DOI":"10.1038\/s41598-017-15548-6","article-title":"Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle \u03b22-adrenergic receptor but not by AMPK","volume":"7","author":"Shiuchi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1080\/10799893.2016.1193522","article-title":"The role of \u03b11-adrenergic receptors in regulating metabolism: Increased glucose tolerance, leptin secretion and lipid oxidation","volume":"37","author":"Shi","year":"2017","journal-title":"J. Recept. Signal Transduct."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.1210\/jc.2017-00357","article-title":"Insulin secretion and insulin sensitivity before and after surgical treatment of pheochromocytoma or paraganglioma","volume":"102","author":"Komada","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1210\/clinem\/dgaa154","article-title":"Pheochromocytoma with adrenergic biochemical phenotype shows decreased GLP-1 secretion and impaired glucose tolerance","volume":"105","author":"Waldauf","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.14310\/horm.2002.1184","article-title":"Insulin resistance in pheochromocytoma improves more by surgical rather than by medical treatment","volume":"2","author":"Zapanti","year":"2003","journal-title":"Hormones"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cyto.2010.03.011","article-title":"Adiponectin\u2014A possible factor in the pathogenesis of carbohydrate metabolism disturbances in patients with pheochromocytoma","volume":"50","author":"Elenkova","year":"2010","journal-title":"Cytokine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1507\/endocrj.EJ18-0407","article-title":"Differences in the actions of adrenaline and noradrenaline with regard to glucose intolerance in patients with pheochromocytoma","volume":"66","author":"Abe","year":"2019","journal-title":"Endocr. J."},{"key":"ref_25","first-page":"E939","article-title":"Neural regulation of glucagon-like peptide-1 secretion in pigs","volume":"287","author":"Hansen","year":"2004","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.bbrc.2015.03.151","article-title":"Integrative function of adrenaline receptors for glucagon-like peptide-1 exocytosis in enteroendocrine L cell line GLUTag","volume":"460","author":"Harada","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1097\/HJH.0000000000002438","article-title":"Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: A position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension","volume":"38","author":"Lenders","year":"2020","journal-title":"J. Hypertens."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1210\/jc.2014-1498","article-title":"Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline","volume":"99","author":"Lenders","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1016\/j.dsx.2020.10.030","article-title":"Diabetes mellitus in pheochromocytoma and paraganglioma: Prevalence, dynamics of insulin secretion\/sensitivity and predictors of remission","volume":"14","author":"Khatiwada","year":"2020","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e4028","DOI":"10.1210\/clinem\/dgab401","article-title":"Correlation between plasma catecholamines, weight, and diabetes in pheochromocytoma and paraganglioma","volume":"106","author":"Krumeich","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.asjsur.2019.01.012","article-title":"Will the resection of pheochromocytoma improve preoperative diabetes mellitus?","volume":"42","author":"Liu","year":"2019","journal-title":"Asian J. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"999","DOI":"10.4158\/EP171914.RA","article-title":"The physiology behind diabetes mellitus in patients with pheochromocytoma: A review of the literature","volume":"23","author":"Mesmar","year":"2017","journal-title":"Endocr. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1097\/00003246-198805000-00018","article-title":"Hypoglycaemia following bilateral adrenalectomy for pheochromocytoma","volume":"16","author":"Costello","year":"1988","journal-title":"Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/S0022-5347(17)55479-8","article-title":"Possible mechanism of hypoglycemia following removal of pheochromocytoma","volume":"124","author":"Sagalowsky","year":"1980","journal-title":"J. Urol."},{"key":"ref_35","unstructured":"Cattaneo, C., and Jackowsky, C. (2004). Forensic Science International, University of Bern."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mamilla, D., Araque, K.A., Brofferio, A., Gonzales, M.K., Sullivan, J.N., Nilubol, N., and Pacak, K. (2019). Postoperative management in patients with Pheochromocytoma and Paraganglioma. Cancers, 11.","DOI":"10.3390\/cancers11070936"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s12020-009-9300-1","article-title":"Fatal hypoglycemia in malignant pheochromocytoma: Direct glucose consumption as suggested by 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography\/computed tomography imaging","volume":"37","author":"Habra","year":"2010","journal-title":"Endocrine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1002\/ccr3.3161","article-title":"Persistent hypoglycemia due to an IGF-II-secreting malignant pheochromocytoma: A case report and literature review","volume":"8","year":"2020","journal-title":"Clin. Case Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1159\/000099291","article-title":"Hypoglycemia due to ectopic release of insulin from a paraganglioma","volume":"67","author":"Uysal","year":"2007","journal-title":"Horm. Res. Paediatr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.14310\/horm.2002.1224","article-title":"Phaeochromocytoma crisis presenting with profound hypoglycaemia and subsequent hypertension","volume":"8","author":"Frankton","year":"2009","journal-title":"Hormones"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s40618-016-0536-3","article-title":"The treatment of hyperinsulinemic hypoglycaemia in adults: An update","volume":"40","author":"Pia","year":"2017","journal-title":"J. Endocrinol. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1136\/pgmj.73.864.640","article-title":"Diazoxide treatment for insulinoma: A national UK survey","volume":"73","author":"Gill","year":"1997","journal-title":"Postgrad. Med. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:50:25Z","timestamp":1760122225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,8]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065153"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065153","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,8]]}}}