Evidence map›Paper›PMID 42856426›Full record

ArticleResearch square2026

Comprehensive assessment of the genotype-phenotype spectrum and treatment for monoallelic insulin receptoropathy in a cohort of 505 people.

Rebecca J Brown, Jingxiang Xu, Jian'an Luan, Bruno Donadille, Vahid Aslanzadeh, Christine Bellanné-Chantelot, Valeria Grasso, Delphine Collin-Chavagnac, Mafalda Mucciolo, Ingrid Allix and 53 more

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Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

63 authors.

Rebecca J BrownDiabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0002-2589-7382
Jingxiang XuInstitute for Genetics and Cancer; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Jian'an LuanIMS Epidemiology, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Bruno DonadilleAssistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Endocrinology, Diabetology and Reproductive Endocrinology Department, Sorbonne University, European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France.
Vahid AslanzadehInstitute for Genetics and Cancer; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Christine Bellanné-ChantelotAssistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Medical Genetics Department, Sorbonne University, Paris, France.
Valeria GrassoDepartment of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Delphine Collin-ChavagnacHospices Civils de Lyon HCL, Biochemistry and Molecular Biology Department, CHU Lyon, Lyon, France.
Mafalda MuccioloTranslational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Ingrid AllixAngers University Hospital, Endocrinology Diabetology and Nutrition Department, Angers, France.
Anne BachelotAssistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Endocrinology and Reproductive Medicine Department, IE3M, European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France.
Sabine BaronNantes University, University Hospital, Paediatric Endocrinology Department, Nantes, France.
Danila BeneventoMonogenic Diabetes Clinic, Endocrinology and Diabetes Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Laurence BlancoBordeaux University Hospital, Endocrinology Diabetology Nutrition Department, Bordeaux, France.
Muriel BourgeonAssistance Publique-Hôpitaux de Paris, Antoine Béclère Hospital, Diabetology Unit, Internal Medicine and Immunology Department, Paris-Saclay University, Clamart, France.
Sophie Christin-MaitreAssistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, Endocrinology, Diabetology and Reproductive Endocrinology Department, European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France.
Elaine CochranDiabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Régis CoutantAngers University Hospital, Pediatric Endocrinology Department, Angers, France.
Lea DehghaniAssistance Publique-Hôpitaux de Paris, Cochin Hospital, Diabetology and Clinical Immunology Department, Paris-Cité University, Paris, France.
Annalisa DeodatiMonogenic Diabetes Clinic, Endocrinology and Diabetes Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Charlotte DjakouréLa Rochelle Hospital, Endocrinology-Diabetology Unit, La Rochelle, France.
Danièle Dubois-LaforgueAssistance Publique-Hôpitaux de Paris, Cochin Hospital, Diabetology and Clinical Immunology Department, Paris-Cité University, Paris, France.
Lise DuranteauAssistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Medical Gynecology Department, Paris-Saclay University, Le Kremlin-Bicêtre, France.
Claire-Lise GayHospices Civils de Lyon HCL, Pediatric Endocrinology Department, Bron, France.
Siri Atma W GreeleyKovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, USA.
Tulay GuranMarmara University, School of Medicine, Department of Pediatric Endocrinology and Diabetes, Istanbul, Turkey.
Balamurugan KandasamyKovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, USA.
Marie Laloi-MichelinAssistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Diabetology and Endocrinology Department, Paris, France.
Pascale MahotNantes University Hospital, Endocrinology Diabetology Nutrition Department, Nantes, France.
Dominique MaiterUniversity Hospital Saint-Luc, UC Louvain, Endocrinology and Nutrition Department, European Reference Network for Rare Endocrine Conditions, Brussels, Belgium.
Viswanathan MohanDr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care); Madras Diabetes Research Foundation, (ICMR Collaborating Centre of Excellence), Chennai, India.
Rinki MurphyDepartment of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Estelle NobécourtLa Reunion University, University Hospital, Endocrinology, Diabetes and Nutrition Department, GHSR, Saint-Pierre de La Réunion, France.
Novella RapiniDepartment of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Sylvie SalenaveAssistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Reproductive Endocrinology Department, Le Kremlin-Bicêtre, France.
Pratik ShahThe Royal London Children's Hospital, Barts Health NHS Trust; Queen Mary University of London, London, UK.
Megan StartzellDiabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Igor TauveronClermont-Ferrand University Hospital, Endocrinology Department, Clermont Auvergne University, Clermont-Ferrand, France.
Daniel TerralClermont-Ferrand University Hospital, Paediatric Department, Clermont-Ferrand, France.
A Kemal TopalogluMassachusetts General Hospital, Division of Pediatric Endocrinology, Harvard Medical School, Boston, MA, USA.
Praveen V PAmrita Institute of Medical Sciences, Cochin, India.
Marie-Christine VantyghemUniversity Hospital of Lille, Diabetes and Nutrition Department, EGID Center, University of Lille, Lille, France.
Venkatesan RadhaMadras Diabetes Research Foundation, Department of Molecular Genetics, Chennai, India.
Martin WabitschDivision of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Peter WinocourEast and North Hertfordshire NHS Trust, Queen Elizabeth II Hospital, Welwyn Garden City, UK.
Hannele Yki-JärvinenUniversity of Helsinki, Department of Medicine (HUS Inpatient and Rehabilitation).
Jacques YoungAssistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Reproductive Endocrinology Department, Le Kremlin-Bicêtre, France.
Rachel WilliamsNottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Kashyap PatelInstitute of Biomedical and Clinical Science, University of Exeter, Exeter, UK.
Loredana MarcovecchioDepartment of Paediatrics; University of Cambridge, Cambridge, UK.
Louis LebretonBordeaux University Hospital Pellegrin, Biochemistry Department, Bordeaux, France.
Camille VatierAssistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Endocrinology, Diabetology and Reproductive Endocrinology Department, Sorbonne University, European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France.
Nicholas WarehamIMS Epidemiology, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Anna StearsNational Severe Insulin Resistance Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Elise BismuthAssistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Pediatric Endocrinology and Diabetes Department, Paris, France.
David SavageMRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Isabelle JéruAssistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Medical Genetics Department, Sorbonne University, Paris, France.
Stephen O'RahillyMRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Kevin ColcloughRoyal Devon University Healthcare Foundation Trust, Exeter, UK.
Gemma V BrierleyDepartment of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Fabrizio BarbettiDepartment of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Corinne VigourouxAssistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Endocrinology, Diabetology and Reproductive Endocrinology Department, Sorbonne University, European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France.
Robert K SempleInstitute for Neuroscience and Cardiovascular Research; Institute for Genetics and Cancer, University of Edinburgh, Edinburgh, UK.ORCID 0000-0001-6539-3069

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Background: Insulin signalling is mediated by the Methods: We aggregated genetic and clinical data from 505 individuals with monoallelic rare Results: 240 probands and 265 relatives were studied. There was marked female predominance among probands (Male:Female = 1:3.4) and earlier female presentation, most often with hyperandrogenism. Presentation with diabetes, hyperinsulinaemia, or hypoglycaemia was common in both sexes. Missense variants were 14-fold enriched in the IC domain compared to gnomAD, concentrated in key functional motifs including activation and catalytic loops, whereas LoF variants were distributed in proportion to domain length. The p.M1180K variant was normally expressed but autophosphorylation-deficient. Most EC variant carriers - including genetically-ascertained individuals with EC LoF or deleterious missense variants - showed moderate to severe IR from puberty onwards. Across the whole cohort with IC or EC variants, diabetes occurred in 56% and hypoglycaemia in 55%, the latter a presenting feature in 11% of probands and common among relatives. Birthweight standard deviation score (SDS) was reduced (-1.0) and BMI SDS modestly increased (+0.7). Hyperandrogenism and/or Polyendocrine Metabolic Ovarian Syndrome affected 82% of postpubertal females, while GDM affected 20-53% of pregnancies. Lipid profiles were normal. Conclusions: The human

Indexed as

DiabetesGeneticsGrowthHyperinsulinismHypoglycaemiaINSRInsulin ReceptorInsulin ResistancePregnancyType A Insulin Resistance

Identifiers

PMID42856426
PMCPMC13648858

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