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.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK056268-16
Application #
8764054
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Leschek, Ellen W
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Martin, Gregory M; Rex, Emily A; Devaraneni, Prasanna et al. (2016) Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations. J Biol Chem 291:21971-21983
Stanley, Charles A (2016) Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. J Clin Endocrinol Metab 101:815-26
Bhatti, Tricia R; Ganapathy, Karthik; Huppmann, Alison R et al. (2016) Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect. J Clin Endocrinol Metab 101:914-22
Kalish, Jennifer M; Boodhansingh, Kara E; Bhatti, Tricia R et al. (2016) Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome. J Med Genet 53:53-61
Lord, Katherine; Radcliffe, Jerilynn; Gallagher, Paul R et al. (2015) High Risk of Diabetes and Neurobehavioral Deficits in Individuals With Surgically Treated Hyperinsulinism. J Clin Endocrinol Metab 100:4133-9
Stanley, Charles A; Rozance, Paul J; Thornton, Paul S et al. (2015) Re-evaluating "transitional neonatal hypoglycemia": mechanism and implications for management. J Pediatr 166:1520-5.e1
Kibbey, Richard G; Choi, Cheol Soo; Lee, Hui-Young et al. (2014) Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release. Diabetes 63:4218-29
De León, Diva D; Stanley, Charles A (2013) Determination of insulin for the diagnosis of hyperinsulinemic hypoglycemia. Best Pract Res Clin Endocrinol Metab 27:763-9
Peranteau, William H; Palladino, Andrew A; Bhatti, Tricia R et al. (2013) The surgical management of insulinomas in children. J Pediatr Surg 48:2517-24
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

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