{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:10:02Z","timestamp":1788952202906,"version":"build-2803163510"},"reference-count":21,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016646","name":"HCA Healthcare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Proinsulin-secreting neuroendocrine tumors (NETs) are a rare cause of severe hypoglycemia, characterized by normal or low insulin levels and disproportionate elevations of proinsulin. Clinical features and optimal management of unresectable cases remain poorly defined, in part due to such few cases described in the literature. We describe a 47-year-old female with metastatic large-cell neuroendocrine carcinoma who presented with obstructive jaundice and was incidentally found to have profound, asymptomatic fasting hypoglycemia. Initial insulin and C-peptide levels were within reference ranges, but proinsulin concentrations were markedly elevated. The patient developed recurrent, refractory hypoglycemia requiring high-dose corticosteroids, glucagon, diazoxide, octreotide, and ultimately central-line infusion of 70% concentrated dextrose via total parenteral nutrition. Glycemic control could not be achieved despite maximal medical therapy, and the patient experienced rapid clinical deterioration leading to comfort-focused hospice management. This case highlights the diagnostic challenges of proinsulin-driven hypoglycemia and underscores the need for earlier recognition and improved treatment pathways for patients with proinsulin-secreting NETs.<\/jats:p>","DOI":"10.1210\/jcemcr\/luag217","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:55:02Z","timestamp":1784807702000},"source":"Crossref","is-referenced-by-count":0,"title":["Metastatic proinsulin-secreting tumor: a rare cause of persistent hypoglycemia"],"prefix":"10.1210","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9772-4163","authenticated-orcid":false,"given":"Robert J","family":"Heins","sequence":"first","affiliation":[{"name":"Kansas City University College of Osteopathic Medicine , Kansas City, MO 64106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Yazji","sequence":"additional","affiliation":[{"name":"Kansas City University College of Osteopathic Medicine , Kansas City, MO 64106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9244-6147","authenticated-orcid":false,"given":"Philip","family":"Eber","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, JFK Medical Center: HCA Florida JFK Hospital , Atlantis, FL 33462, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Furlan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, JFK Medical Center: HCA Florida JFK Hospital , Atlantis, FL 33462, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"1","key":"2026090903485951500_luag217-B1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/MPA.0000000000001196","article-title":"Proinsulin-expressing neuroendocrine tumors of the pancreas: an underrecognized entity","volume":"48","author":"Celli","year":"2019","journal-title":"Pancreas"},{"issue":"5","key":"2026090903485951500_luag217-B2","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/0026-0495(77)90099-3","article-title":"Proinsulin and C-peptide: a review","volume":"26","author":"Kitabchi","year":"1977","journal-title":"Metabolism"},{"issue":"3","key":"2026090903485951500_luag217-B3","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvac196","article-title":"A novel somatic mutation implicates ATP6V0D1 in proinsulin processing","volume":"7","author":"Avari","year":"2023","journal-title":"J Endocr Soc"},{"issue":"8","key":"2026090903485951500_luag217-B4","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1007\/s11605-017-3428-8","article-title":"A systematic review of proinsulin-secreting pancreatic neuroendocrine tumors","volume":"21","author":"Murtha","year":"2017","journal-title":"J Gastrointest Surg"},{"issue":"3-4","key":"2026090903485951500_luag217-B5","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1159\/000501455","article-title":"Proinsulin-secreting neuroendocrine tumors of the pancreas: a single-centre experience","volume":"6","author":"Kriger","year":"2019","journal-title":"Gastrointest Tumors"},{"key":"2026090903485951500_luag217-B6","first-page":"18-0049","article-title":"Refractory spontaneous hypoglycaemia: a diagnostic conundrum","volume":"2018","author":"Cheah","year":"2018","journal-title":"Endocrinol Diabetes Metab Case Rep"},{"issue":"3","key":"2026090903485951500_luag217-B7","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1210\/jc.2008-1410","article-title":"Evaluation and management of adult hypoglycemic disorders: an endocrine society clinical practice guideline","volume":"94","author":"Cryer","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026090903485951500_luag217-B8","first-page":"e339","article-title":"Proinsulin-predominant pancreatic neuroendocrine tumor\u2013induced hypoglycemia after Roux-en-Y gastric bypass surgery","volume":"5","author":"Edwards","year":"2019","journal-title":"AACE Clin Case Rep"},{"key":"2026090903485951500_luag217-B9","article-title":"Neuroendocrine tumor secreting proinsulin: an overlooked entity. Presented at the 26th European congress of endocrinology; 2024","volume":"99","author":"Augusto","year":"2024","journal-title":"Endocr Abstr"},{"issue":"7","key":"2026090903485951500_luag217-B10","doi-asserted-by":"crossref","first-page":"785","DOI":"10.2169\/internalmedicine.54.3772","article-title":"Transformation of a nonfunctioning islet cell tumor of the pancreas into a proinsulinoma with lung metastasis","volume":"54","author":"Yoshioka","year":"2015","journal-title":"Intern Med"},{"issue":"8","key":"2026090903485951500_luag217-B11","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1007\/BF03347360","article-title":"Proinsulin-secreting neuroendocrine tumor of the pancreas","volume":"26","author":"Piovesan","year":"2003","journal-title":"J Endocrinol Invest"},{"issue":"5","key":"2026090903485951500_luag217-B12","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1172\/JCI107845","article-title":"Interactions of proinsulin with insulin receptors on the plasma membrane of the liver","volume":"54","author":"Freychet","year":"1974","journal-title":"J Clin Invest"},{"issue":"9","key":"2026090903485951500_luag217-B13","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/0026-0495(91)90072-5","article-title":"Effects of human proinsulin on glucose turnover and intermediary metabolism","volume":"40","author":"Davis","year":"1991","journal-title":"Metabolism"},{"issue":"5","key":"2026090903485951500_luag217-B14","first-page":"1282","article-title":"The effects of human proinsulin on glucose turnover and intermediary metabolism in insulin-dependent diabetes mellitus","volume":"75","author":"Davis","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026090903485951500_luag217-B15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/nyas.13435","article-title":"Insulin regulation of gluconeogenesis","volume":"1411","author":"Hatting","year":"2018","journal-title":"Ann N Y Acad Sci"},{"issue":"6","key":"2026090903485951500_luag217-B16","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1172\/JCI108047","article-title":"Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood","volume":"55","author":"Horwitz","year":"1975","journal-title":"J Clin Invest"},{"issue":"2","key":"2026090903485951500_luag217-B17","doi-asserted-by":"crossref","first-page":"86","DOI":"10.4274\/jcrpe.1891","article-title":"Diagnosis and management of hyperinsulinaemic hypoglycaemia","volume":"7","author":"Ro\u017eenkov\u00e1","year":"2015","journal-title":"J Clin Res Pediatr Endocrinol"},{"issue":"4","key":"2026090903485951500_luag217-B18","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/modpathol.2016.217","article-title":"Somatostatin receptor expression related to TP53 and RB1 alterations in neuroendocrine neoplasms with a Ki-67 index above 20","volume":"30","author":"Konukiewitz","year":"2017","journal-title":"Mod Pathol"},{"issue":"1","key":"2026090903485951500_luag217-B19","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1365-2265.1995.tb01901.x","article-title":"Octreotide exacerbated fasting hypoglycaemia in a patient with a proinsulinoma","volume":"43","author":"Gama","year":"1995","journal-title":"Clin Endocrinol"},{"issue":"8","key":"2026090903485951500_luag217-B20","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1002\/(SICI)1097-0142(19980415)82:8<1585::AID-CNCR22>3.0.CO;2-#","article-title":"The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia","volume":"82","author":"Hoff","year":"1998","journal-title":"Cancer"},{"issue":"2","key":"2026090903485951500_luag217-B21","article-title":"Successful treatment of hypoglycemia with alpelisib in pediatric patients with PIK3CA-related overgrowth Spectrum","volume":"1","author":"Nasomyont","year":"2023","journal-title":"JCEM Case Rep"}],"container-title":["JCEM Case Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcemcr\/article-pdf\/4\/10\/luag217\/71004386\/luag217.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcemcr\/article-pdf\/4\/10\/luag217\/71004386\/luag217.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:15:58Z","timestamp":1788948958000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcemcr\/article\/doi\/10.1210\/jcemcr\/luag217\/8788642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":21,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,9,3]]}},"URL":"https:\/\/doi.org\/10.1210\/jcemcr\/luag217","relation":{},"ISSN":["2755-1520"],"issn-type":[{"value":"2755-1520","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10]]},"published":{"date-parts":[[2026,9,3]]},"article-number":"luag217"}}