International Guidelines for the Diagnosis and Management of Hyperinsulinism

Diva D De Leon¹, Jean Baptiste Arnoux², Indraneel Banerjee³, Ignacio Bergada⁴, Tricia Bhatti⁵, Louise S Conwell⁶, Junfen Fu⁷, Sarah E Flanagan⁸, David Gillis⁹, Thomas Meissner¹⁰, Klaus Mohnike¹¹, Tai L S Pasquini¹², Pratik Shah¹³, Charles A Stanley¹, Adrian Vella¹⁴, Tohru Yorifuji¹⁵, Paul S Thornton¹⁶

Affiliations

¹ Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, AP-HP, University of Paris-Cité, Paris, France.
³ Paediatric Endocrinology, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK.
⁴ Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CONICET - FEI), Division de Endrocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
⁵ Department of Clinical Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶ Australia and Children's Health Queensland Clinical Unit, Department of Endocrinology and Diabetes, Queensland Children's Hospital, Children's Health Queensland, Greater Brisbane Clinical School, Medical School, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
⁷ National Clinical Research Center for Child Health, Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China.
⁸ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
⁹ Hadassah Medical Center, Department of Pediatrics, Ein-Kerem, Jerusalem and Faculty of Medicine, Hebrew-University, Jerusalem, Israel.
¹⁰ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
¹¹ Department of General Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
¹² Research and Policy Director, Congenital Hyperinsulinism International, Glen Ridge, New Jersey, USA.
¹³ Pediatric Endocrinology, The Royal London Children's Hospital, Queen Mary University of London, London, UK.
¹⁴ Division of Diabetes, Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.
¹⁶ Congenital Hyperinsulinism Center, Cook Children's Medical Center and Texas Christian University Burnett School of Medicine, Fort Worth, Texas, USA.

PMID: 37454648
PMCID: PMC11124746
DOI: 10.1159/000531766

Practice Guideline

International Guidelines for the Diagnosis and Management of Hyperinsulinism

Diva D De Leon et al. Horm Res Paediatr. 2024.

. 2024;97(3):279-298.

doi: 10.1159/000531766. Epub 2023 Jul 14.

Authors

Affiliations

¹ Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, AP-HP, University of Paris-Cité, Paris, France.
³ Paediatric Endocrinology, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK.
⁴ Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CONICET - FEI), Division de Endrocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
⁵ Department of Clinical Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶ Australia and Children's Health Queensland Clinical Unit, Department of Endocrinology and Diabetes, Queensland Children's Hospital, Children's Health Queensland, Greater Brisbane Clinical School, Medical School, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
⁷ National Clinical Research Center for Child Health, Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China.
⁸ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
⁹ Hadassah Medical Center, Department of Pediatrics, Ein-Kerem, Jerusalem and Faculty of Medicine, Hebrew-University, Jerusalem, Israel.
¹⁰ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
¹¹ Department of General Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
¹² Research and Policy Director, Congenital Hyperinsulinism International, Glen Ridge, New Jersey, USA.
¹³ Pediatric Endocrinology, The Royal London Children's Hospital, Queen Mary University of London, London, UK.
¹⁴ Division of Diabetes, Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.
¹⁶ Congenital Hyperinsulinism Center, Cook Children's Medical Center and Texas Christian University Burnett School of Medicine, Fort Worth, Texas, USA.

PMID: 37454648
PMCID: PMC11124746
DOI: 10.1159/000531766

Abstract

Background: Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide.

Summary: Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in "developed" countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use.

Key messages: This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

Keywords: Guidelines; Hyperinsulinism; Hypoglycemia; Insulin.

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Conflict of interest statement

D.D.L. has received research funding from Zealand Pharma, Tiburio Therapeutics, Twist Bioscience, and Crinetics Pharmaceuticals and consulting fees from Zealand Pharma, Crinetics Pharmaceuticals, Hanmi Pharmaceutical, and Eiger Biopharmaceuticals and is named inventor inventor in patents # USA Patent Number 9,616,108, 2017, USA Patent Number 9,821,031, 2017, Europe Patent Number EP 2120994, 2018, Europe Patent Number EP2818181, 2019. J.B.A. has received consulting fees from Alexion, Immedica, Zealand Pharma, Sobi, Pierre Fabre, and BioMari and speaker honorarium from Sanofi, Genzyme, Recordati, Pierre Fabre, and Vitaflo. I.B. has received funding support from Merck, Crinetics, Zealand, and Diurnal. He is also the Chair of the ESPE Communications Committee and BSPED-NIHR Clinical Studies Group. He is a co-opted member of NICE guidelines. L.S.C. is an advisory Board member and consultant to Zealand Pharma. T.M. received research payments from Zealand Pharma. T.L.S.P. is an employee of Congenital Hyperinsulinism International. A.V. received an investigator-initiated grant from Novo Nordisk and has consulted for vTv Therapeutics, Zeeland Pharmaceuticals, Crinetics, and Rezolute. P.S.T. has received research payments from Ascendis, Novo Nordisk, OPKO, Rezolute, and Zealand and was a member of the Board of the PES at the time of writing. The following report to have no COI: I.B., T.B., J.F.F., S.E.F., D.G., K.M., P.S., C.A.S., and T.Y.

Figures

**Fig. 1.**
Schematic beta-cell with pathways involved in insulin secretion. Pathways of glucose and amino acid stimulation of beta-cell insulin secretion showing sites of the more common genetic forms of hyperinsulinism, such as the ATP-sensitive (K_ATP) potassium channel, comprised of SUR1 and Kir6.2 subunits encoded by the *ABCC8* and *KCNJ11* genes. Most genetic forms of hyperinsulinism affect steps by which increased ATP generation closes K_ATP channels to depolarize the plasma membrane and activate an influx of calcium to “trigger” release of insulin from storage granules into the circulation. Additional factors, such as stimulation by the gut incretin, GLP1, can act downstream of the triggering pathway to “amplify” insulin release. Drugs such as diazoxide and glyburide bind to the KATP channel to inhibit or activate insulin release, respectively. GK, glucokinase; HK1, hexokinase 1; GDH, glutamate dehydrogenase; SCHAD, short-chain acyl-CoA dehydrogenase; MCT1, mono-carboxylate transporter 1; ATP, adenosine triphosphate; HNF1A & HNF4A, hepatic nuclear factors 1 alpha and 4 alpha; SUR1, sulfonylurea receptor 1; Kir6.2, potassium channel subunit; K_ATP channel, ATP-sensitive potassium channel; K⁺, potassium ion; Ca⁺⁺, calcium ion; Ins, insulin; GLP1, glucagon-like peptide 1. Dotted line with dash indicates inhibit, Solid line with + indicates stimulates.

See this image and copyright information in PMC

References

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International Guidelines for the Diagnosis and Management of Hyperinsulinism

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International Guidelines for the Diagnosis and Management of Hyperinsulinism

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Conflict of interest statement

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