Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Children with HI are at high risk of seizures and permanent brain damage and treatment of their hypoglycemia is extremely difficult. Recent work has shown that HI is associated with genetic defects in the pathways regulating beta-cell insulin secretion. Although 9 such loci have been found, many children with HI have no identifiable mutation of these genes. This includes one-third of diffuse HI cases that require pancreatectomy and half of cases that are responsive to medical treatment with diazoxide. Our hypothesis is that hyperinsulinism in these groups of children involves both novel molecular defects of known loci, as well as, previously unrecognized new genetic loci. The long-term goals of the research are to identify genotype- phenotype correlations in these disorders to guide diagnosis and treatment and to uncover new forms of congenital hyperinsulinism. A i m i will extend and expand studies of the novel genetic locus for hyperinsulinism in the historically-important dominant HI family reported by McQuarrie in 1954. Clinical phenotyping, linkage analysis, and next-gen sequencing methods have identified HK1 as a likely candidate gene. This will be confirmed by recruitment of additional pedigrees and by functional assays.
Aim 2 will extend the search for defects in novel candidate genes in our large series of children with diazoxide responsive hyperinsulinism that have no identifiable mutation. We will seek to identify either post-zygotic mutations of known loci or novel additional loci using targeted next-gen sequencing methods.
Aim 3 will continue our efforts to define the mechanisms of molecular defects in children who fail to respond to diazoxide and require pancreatectomy. We will search for novel cryptic or mosaic mutations of the two adjacent genes on l i p that are responsible for most cases of this form of HI: ABCC8/SUR1 and KCNJ11/Kir6.2. This will include functional testing of insulin release and molecular analysis of cultured islets from patients undergoing surgery to identify post-zygotic, mosaic mutations;mutations in non-coding regions, and microRNA sites;or epigenetic methylation defects.

Public Health Relevance

This translational research project seeks to define the molecular causes of congenital hyperinsulinemic hypoglycemia (HI). Novel candidate genes will be sought using next-gen DNA sequencing and advanced micro-methods to study pancreatic islets from children requiring pancreatectomy. The results will improve the treatment of children with HI and provide new insight into regulation of insulin secretion in normal humans.

National Institute of Health (NIH)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Leschek, Ellen W
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Children's Hospital of Philadelphia
United States
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Blomberg, Bjorn A; Moghbel, Mateen C; Saboury, Babak et al. (2013) The value of radiologic interventions and (18)F-DOPA PET in diagnosing and localizing focal congenital hyperinsulinism: systematic review and meta-analysis. Mol Imaging Biol 15:97-105
Faletra, Flavio; Snider, Kara; Shyng, Show-Ling et al. (2013) Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations. Gene 516:122-5
Huang, TingTing; Kelly, Andrea; Becker, Susan A et al. (2013) Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 98:F351-4
Laje, Pablo; States, Lisa J; Zhuang, Hongming et al. (2013) Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism. J Pediatr Surg 48:388-93
Snider, K E; Becker, S; Boyajian, L et al. (2013) Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab 98:E355-63
Pinney, Sara E; Ganapathy, Karthik; Bradfield, Jonathan et al. (2013) Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr 80:18-27
Li, Changhong; Liu, Chengyang; Nissim, Itzhak et al. (2013) Regulation of glucagon secretion in normal and diabetic human islets by ýý-hydroxybutyrate and glycine. J Biol Chem 288:3938-51
Macmullen, Courtney M; Zhou, Qing; Snider, Kara E et al. (2011) Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the ýý-cell sulfonylurea receptor SUR1. Diabetes 60:1797-804