{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:09:29Z","timestamp":1760058569494,"version":"build-2065373602"},"reference-count":21,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We report a case of metreleptin use in a patient with SHORT syndrome, a rare congenital disorder characterized by partial lipodystrophy, distinctive dysmorphic features, and severe insulin resistance. The patient was initially misdiagnosed with type 1 diabetes in early childhood because of insulin dependence, but genetic testing later confirmed a pathogenic PIK3R1 variant consistent with SHORT syndrome. Despite high-dose insulin therapy and adjunctive agents, glycemic control remained poor. Introduction of metreleptin led to a rapid and sustained improvement in glycemic control, with a marked reduction in insulin requirements. Notably, the patient did not exhibit hepatic steatosis or hypertriglyceridemia\u2014features typically associated with metreleptin-responsive lipodystrophy\u2014suggesting a broader therapeutic potential of the drug. Treatment interruption due to weight issues resulted in swift metabolic deterioration, including a sharp rise in glycosylated hemoglobin and increased insulin needs. Upon reinitiation, metabolic parameters rapidly improved. This case highlights the potential utility of metreleptin in treating severe insulin resistance in SHORT syndrome, even in the absence of classical metabolic complications. Further studies are needed to define its role in atypical lipodystrophy syndromes with unusual metabolic phenotypes.<\/jats:p>","DOI":"10.1210\/jcemcr\/luaf218","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T11:11:13Z","timestamp":1760008273000},"source":"Crossref","is-referenced-by-count":0,"title":["Metreleptin In SHORT Syndrome With Uncontrolled Diabetes"],"prefix":"10.1210","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7813-5488","authenticated-orcid":false,"given":"Emmanouil","family":"Korakas","sequence":"first","affiliation":[{"name":"2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens , Athens 12462 ,","place":["Greece"]},{"name":"Department of Diabetes & Endocrinology, University College London Hospital NHS Foundation Trust , London NW12BU ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5829-7327","authenticated-orcid":false,"given":"Aikaterini","family":"Kountouri","sequence":"additional","affiliation":[{"name":"2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens , Athens 12462 ,","place":["Greece"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-7886","authenticated-orcid":false,"given":"Ignatios","family":"Ikonomidis","sequence":"additional","affiliation":[{"name":"2nd Department of Cardiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens , Athens 12462 ,","place":["Greece"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Georgiou","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, School of Health Sciences, University of Ioannina , Ioannina 45110 ,","place":["Greece"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baris","family":"Akinci","sequence":"additional","affiliation":[{"name":"Department of Technological Research, Izmir Biomedicine and Genome Center, Dokuz Eyl\u00fcl University, Izmir 35340, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4620-4039","authenticated-orcid":false,"given":"Vaia","family":"Lambadiari","sequence":"additional","affiliation":[{"name":"2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens , Athens 12462 ,","place":["Greece"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"2025100913161653300_luaf218-B1","volume-title":"GeneReviews","author":"Innes","year":"1993-2024"},{"issue":"4","key":"2025100913161653300_luaf218-B2","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/cge.12688","article-title":"Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management","volume":"89","author":"Avila","year":"2016","journal-title":"Clin Genet"},{"issue":"1","key":"2025100913161653300_luaf218-B3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ajhg.2013.05.019","article-title":"PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy","volume":"93","author":"Thauvin-Robinet","year":"2013","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2025100913161653300_luaf218-B4","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.ajhg.2013.05.023","article-title":"SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling","volume":"93","author":"Chudasama","year":"2013","journal-title":"Am J Hum Genet"},{"key":"2025100913161653300_luaf218-B5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.metabol.2017.04.010","article-title":"Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy","volume":"72","author":"Akinci","year":"2017","journal-title":"Metabolism"},{"issue":"11","key":"2025100913161653300_luaf218-B6","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1210\/jc.2011-1159","article-title":"Lipodystrophies: genetic and acquired body fat disorders","volume":"96","author":"Garg","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2025100913161653300_luaf218-B7","doi-asserted-by":"crossref","first-page":"1383318","DOI":"10.3389\/fendo.2024.1383318","article-title":"A rapid action plan to improve diagnosis and management of lipodystrophy syndromes","volume":"15","author":"Fourman","year":"2024","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"6","key":"2025100913161653300_luaf218-B8","doi-asserted-by":"crossref","first-page":"922","DOI":"10.4158\/EP11229.OR","article-title":"Clinical effects of long-term metreleptin treatment in patients with lipodystrophy","volume":"17","author":"Chan","year":"2011","journal-title":"Endocr Pract"},{"issue":"9","key":"2025100913161653300_luaf218-B9","doi-asserted-by":"crossref","first-page":"e1385","DOI":"10.1002\/mgg3.1385","article-title":"SHORT syndrome in two Chinese girls: a case report and review of the literature","volume":"8","author":"Zhang","year":"2020","journal-title":"Mol Genet Genomic Med"},{"issue":"1","key":"2025100913161653300_luaf218-B10","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1507\/endocrj.EJ20-0291","article-title":"Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review","volume":"68","author":"Masunaga","year":"2021","journal-title":"Endocr J"},{"issue":"10","key":"2025100913161653300_luaf218-B11","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1111\/jdi.13549","article-title":"Novel PIK3R1 mutation of SHORT syndrome: a case report with a 6-month follow-up","volume":"12","author":"Yin","year":"2021","journal-title":"J Diabetes Investig"},{"issue":"5","key":"2025100913161653300_luaf218-B12","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1111\/jdi.12825","article-title":"Treatment of a case of severe insulin resistance as a result of a PIK3R1 mutation with a sodium-glucose cotransporter 2 inhibitor","volume":"9","author":"Hamaguchi","year":"2018","journal-title":"J Diabetes Investig"},{"issue":"6","key":"2025100913161653300_luaf218-B13","doi-asserted-by":"crossref","first-page":"450","DOI":"10.7326\/L16-0372","article-title":"Sodium-glucose cotransporter 2 inhibitor improves complications of lipodystrophy: a case report","volume":"166","author":"Kawana","year":"2017","journal-title":"Ann Intern Med"},{"issue":"17","key":"2025100913161653300_luaf218-B14","doi-asserted-by":"crossref","first-page":"e88766","DOI":"10.1172\/jci.insight.88766","article-title":"Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations","volume":"1","author":"Huang-Doran","year":"2016","journal-title":"JCI Insight"},{"issue":"2","key":"2025100913161653300_luaf218-B15","first-page":"315","article-title":"Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis","volume":"119","author":"Semple","year":"2009","journal-title":"J Clin Invest"},{"issue":"8","key":"2025100913161653300_luaf218-B16","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1056\/NEJMoa012437","article-title":"Leptin-replacement therapy for lipodystrophy","volume":"346","author":"Oral","year":"2002","journal-title":"N Engl J Med"},{"issue":"10","key":"2025100913161653300_luaf218-B17","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1172\/JCI0215001","article-title":"Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy","volume":"109","author":"Petersen","year":"2002","journal-title":"J Clin Invest"},{"issue":"2","key":"2025100913161653300_luaf218-B18","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1210\/jc.2006-1546","article-title":"Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy","volume":"92","author":"Ebihara","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"2025100913161653300_luaf218-B19","doi-asserted-by":"crossref","first-page":"E1749","DOI":"10.1210\/jc.2013-2317","article-title":"Metreleptin improves blood glucose in patients with insulin receptor mutations","volume":"98","author":"Brown","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2025100913161653300_luaf218-B20","doi-asserted-by":"crossref","first-page":"e1032","DOI":"10.1210\/clinem\/dgab782","article-title":"Long-term effects of metreleptin in Rabson-Mendenhall syndrome on glycemia, growth, and kidney function","volume":"107","author":"Okawa","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2025100913161653300_luaf218-B21","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1210\/jc.2003-031952","article-title":"Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome","volume":"89","author":"Cochran","year":"2004","journal-title":"J Clin Endocrinol Metab"}],"container-title":["JCEM Case Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcemcr\/article-pdf\/3\/11\/luaf218\/64563162\/luaf218.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcemcr\/article-pdf\/3\/11\/luaf218\/64563162\/luaf218.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:16:27Z","timestamp":1760030187000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcemcr\/article\/doi\/10.1210\/jcemcr\/luaf218\/8278346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,25]]},"references-count":21,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,9,25]]}},"URL":"https:\/\/doi.org\/10.1210\/jcemcr\/luaf218","relation":{},"ISSN":["2755-1520"],"issn-type":[{"value":"2755-1520","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11]]},"published":{"date-parts":[[2025,9,25]]},"article-number":"luaf218"}}