Congenital Hyperinsulinemic Hypoglycemia and Hyperammonemia due to Pathogenic Variants in GLUD1

  • Kakali Roy
  • Amit Kumar Satapathy
  • Jayne A. L. Houhton
  • Sarah E. Flanagan
  • Venkatesan Radha
  • Viswanathan Mohan
  • Rajni Sharma
  • Vandana JainEmail author
Clinical Brief


Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disorder, characterized by dysregulated insulin secretion. Pathogenic variants in at least twelve different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, UCP2, TRMT10A HK1, and PGM1) are known to cause CHI. Pathogenic variants in the GLUD1 gene, which encodes the enzyme glutamate dehydrogenase (GDH), account for 5% of the cases of congenital hyperinsulinemic hypoglycemia. Pathogenic variants in GLUD1 typically present in late infancy, are diet and/or diazoxide-responsive and cause protein-induced hyperinsulinemic hypoglycemia as insulin secretion is triggered by allosteric activation of GDH by leucine. The authors are presenting three unrelated Indian children, who manifested with fasting as well as dietary protein induced hypoglycemia in late infancy, and were diagnosed to have hyperinsulinemic hyperammonemic hypoglycemia due to pathogenic variants in GLUD1. Although the hypoglycemia responded to diazoxide, delayed diagnosis and irregular treatment had resulted in neurological problems in two of the three children. Early identification, appropriate dietary modifications and regular treatment with diazoxide can prevent adverse neurological outcome.


Hyperinsulinism-hyperammonemia (HI/HA) syndrome Leucine sensitive hypoglycemia Neurological disabilities 



VR and VM wish to acknowledge the financial support given by Indian Council for Medical Research, New Delhi, India, through the project “Changing treatment profile in Monogenic forms of Diabetes such as Neonatal Diabetes and Maturity-Onset Diabetes of the Young (MODY) by Translational Genomics Research” awarded to VR.

Authors’ Contribution

KK and VJ prepared the manuscript. KK, AKS, RS and VJ managed the cases. SEF, JALH, VR and VM have helped in mutation studies. VJ has critically reviewed the manuscript and will act as a guarantor. All authors have given their inputs and approved the final manuscript.

Compliance with Ethical Standards

Conflict of Interest


Supplementary material

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ESM 1 (DOCX 11 kb)


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Copyright information

© Dr. K C Chaudhuri Foundation 2019

Authors and Affiliations

  1. 1.Department of PediatricsAll India Institute of Medical SciencesNew DelhiIndia
  2. 2.Department of PediatricsAll India Institute of Medical SciencesBhubaneswarIndia
  3. 3.Institute of Biomedical and Clinical ScienceUniversity of Exeter Medical SchoolExeterUK
  4. 4.Department of Molecular GeneticsMadras Diabetes Research FoundationChennaiIndia
  5. 5.Division of Pediatric Endocrinology, Department of PediatricsAll India Institute of Medical SciencesNew DelhiIndia

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