{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:23:01Z","timestamp":1791559381066,"version":"4.3.4"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Rabson\u2013Mendenhall syndrome (RMS) is an extremely rare autosomal recessive disorder caused by variants in the INSR gene, which encodes the insulin receptor. The condition is characterized by profound insulin resistance, resulting in diabetes that is exceptionally difficult to control and carrying a poor prognosis, typically in the second to third decade of life. Death most commonly occurs due to ketoacidosis and severe infections. There is no established consensus on optimal treatment; initial therapy usually includes metformin and pioglitazone, often combined with SGLT2 inhibitors, followed by maintenance with high doses of insulin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>Two patients with genetically confirmed RMS were treated with subcutaneous tirzepatide for 3 months (2.5\u20133.3 mg weekly), followed by a 3-month washout period. Clinical, biochemical, and body composition parameters were assessed at baseline, after treatment, and after withdrawal. After 3 months of treatment, HbA1c decreased from 8.9% to 6.3% in one patient and from 10.3% to 8.1% in the other. Insulin resistance improved in one case, whereas insulinemia decreased markedly in the other. Glycemic control deteriorated after treatment withdrawal. Tirzepatide was generally well tolerated, although both patients experienced a reduction in fat mass, and one developed proliferative retinopathy, probably related to the rapid fall in HbA1c.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Low-dose tirzepatide improved glycemic control in RMS and may represent a potential adjunctive therapy, warranting careful monitoring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1945251","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T11:44:47Z","timestamp":1787917487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Tirzepatide improves glycemic control in Rabson\u2013Mendenhall syndrome"],"prefix":"10.3389","volume":"17","author":[{"given":"David","family":"Ara\u00fajo-Vilar","sequence":"first","affiliation":[{"name":"UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela","place":["Santiago de Compostela, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Vela","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, EHU","place":["Barakaldo, Spain"]},{"name":"Division of Pediatric Endocrinology, Hospital Universitario Cruces, Barakaldo, Vizcaya, Spain CIDERER, CIBERDEM, Biobizkaia","place":["Barakaldo, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana I.","family":"Castro","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y la Nutrici\u00f3n (CIBERobn)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00eda","family":"Fern\u00e1ndez-Pombo","sequence":"additional","affiliation":[{"name":"UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela","place":["Santiago de Compostela, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Prado-Mora\u00f1a","sequence":"additional","affiliation":[{"name":"UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"Division of Endocrinology and Nutrition, University Clinical Hospital of Ourense","place":["Ourense, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Everardo J.","family":"D\u00edaz-L\u00f3pez","sequence":"additional","affiliation":[{"name":"UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela","place":["Santiago de Compostela, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Antonio","family":"S\u00e1nchez-Aparicio","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country","place":["Barakaldo, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Endocrinology and Diabetes Research Group, Biobizkaia Health Research Institute","place":["Barakaldo, Vizcaya, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Endocrinology and Diabetes Research Group, Biobizkaia Health Research Institute","place":["Barakaldo, Vizcaya, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sof\u00eda","family":"S\u00e1nchez-Iglesias","sequence":"additional","affiliation":[{"name":"UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela","place":["Santiago de Compostela, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2025.101404","article-title":"Insulin receptor variants: Extending the traditional Mendelian spectrum","volume":"27","author":"Collin-Chavagnac","year":"2025","journal-title":"Genet Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.47.8.1362","article-title":"Multiple molecular mechanisms of insulin receptor dysfunction in a patient with Donohue syndrome","volume":"47","author":"Whitehead","year":"1998","journal-title":"Diabetes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s004310050594","article-title":"Leprechaunism\/Donohue syndrome\/insulin receptor gene mutations: a syndrome delineation story from clinicopathological description to molecular understanding","volume":"156","author":"Kosztol\u00e1nyi","year":"1997","journal-title":"Eur J Pediatr"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000133625.73570.54","article-title":"Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective","volume":"83","author":"Musso","year":"2004","journal-title":"Med (Baltimore)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/diab.43.2.247","article-title":"Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance","volume":"43","author":"Moller","year":"1994","journal-title":"Diabetes"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.galenos.2020.2019.0213","article-title":"Homozygous mutation in the insulin receptor gene associated with mild type A insulin resistance syndrome: A case report","volume":"13","author":"Hac\u0131hamdio\u011flu","year":"2020","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0301","article-title":"Structural basis and genotype-phenotype correlations of INSR mutations causing severe insulin resistance","volume":"66","author":"Hosoe","year":"2017","journal-title":"Diabetes"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.80.12.8530617","article-title":"Insulin resistance associated with substitution of histidine for arginine 252 in the alpha-subunit of the human insulin receptor: trial of insulin-like growth factor I injection therapy to enhance insulin sensitivity","volume":"80","author":"Nakashima","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvae123","article-title":"Rabson-Mendenhall syndrome: Analysis of the clinical characteristics and gene mutations in 42 patients","volume":"8","author":"Gong","year":"2024","journal-title":"J Endocr Soc"},{"key":"B10","doi-asserted-by":"publisher","first-page":"97","DOI":"10.2337\/diaclin.34.2.97","article-title":"Treatment approach to patients with severe insulin resistance","volume":"34","author":"Church","year":"2016","journal-title":"Clin Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/0897190016645036","article-title":"Treatment of diabetic ketoacidosis with intravenous U-500 insulin in a patient with Rabson-Mendenhall syndrome: A case report","volume":"30","author":"Moore","year":"2017","journal-title":"J Pharm Pract"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2021-055671","article-title":"SGLT2i improves glycemic control in patients with congenital severe insulin resistance","volume":"150","author":"Galderisi","year":"2022","journal-title":"Pediatrics"},{"key":"B13","doi-asserted-by":"publisher","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"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2413871","article-title":"Tirzepatide for congenital generalized lipodystrophy","volume":"392","author":"Ten","year":"2025","journal-title":"N Engl J Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2337\/dc24-2408","article-title":"Metabolic improvements with tirzepatide in lipodystrophy: A novel option","volume":"48","author":"Meral","year":"2025","journal-title":"Diabetes Care"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/dom.16159","article-title":"Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis","volume":"27","author":"Mather","year":"2025","journal-title":"Diabetes Obes Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.12.1465","article-title":"Genotype-phenotype correlation in inherited severe insulin resistance","volume":"12","author":"Longo","year":"2002","journal-title":"Hum Mol Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1410177","article-title":"Response of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) and IGFBP-3 to IGF-I treatment in severe insulin resistance","volume":"1","author":"Quin","year":"1994","journal-title":"J Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.diabet.2017.10.014","article-title":"Early worsening of diabetic retinopathy after rapid improvement of blood glucose control in patients with diabetes","volume":"1","author":"Feldman-Billard","year":"2017","journal-title":"Diabetes Metab"},{"key":"B20","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13098-023-01195-7","article-title":"Efficacy and tolerability of the subcutaneous semaglutide for type 2 diabetes patients: an updated systematic review and meta-analysis","volume":"15","author":"Hu","year":"2023","journal-title":"Diabetol Metab Syndrome"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1945251\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T11:44:48Z","timestamp":1787917488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1945251\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":20,"alternative-id":["10.3389\/fendo.2026.1945251"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1945251","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]},"article-number":"1945251"}}