The Journal of clinical endocrinology and metabolism · 2026
Functional evaluation of pancreatic islets from patients with Beckwith-Wiedemann syndrome and congenital hyperinsulinism.
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Juliana Christine A, Li Changhong, Chai Jinghua, Boodhansingh Kara E, Mitteer Lauren M, Kalish Jennifer M, Bhatti Tricia R, Adzick Nick Scott, De Leon Diva D
Аннотация
CONTEXT: Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by various genetic or epigenetic abnormalities in a cluster of imprinted genes on chromosome 11p15. Congenital hyperinsulinism (HI) is one of the cardinal features of BWS, but the pathophysiology of HI in BWS has not been clearly defined.
OBJECTIVE: We describe the islet phenotype of a series of infants with severe HI and comorbid BWS who required pancreatectomy for intractable hypoglycemia.
METHODS: The cases are a subset of HI patients who required pancreatectomy and had Beckwith-Wiedemann Syndrome. Molecular testing for BWS was performed by SNP array and chromosome 11p15 methylation analysis. Functional analysis of insulin secretion in pancreatic islets isolated from pancreatectomy samples was completed with perifusion experiments and cytosolic Ca2+ measurements.
RESULTS: Similar to what we had previously described in islets isolated from the pancreas of infants with HI due to inactivating mutations in the KATP channel, BWS-HI islets have elevated concentrations of cytosolic calcium and secrete insulin in response to stimulation with a physiologic mixture of amino acids. However, unlike KATPHI islets, most BWS-HI islets retain responsiveness to stimulation with glucose and the KATP channel inhibitor glyburide. Through RNAseq analysis, we observed that expression of KCNQ1, encoding the pore-forming subunit of a voltage-gated K + channel (Kv7.1), is reduced in BWS-HI islets compared to normal human islets (3-fold; P = 4.5 × 10-7).
CONCLUSION: Our expression analysis and functional evaluation of islets isolated from BWS-HI patients reveal the spectrum of insulin secretion responses found across BWS etiologies and suggest a potential role for loss of KCNQ1 expression in the complex pathophysiology responsible for the hyperinsulinism in BWS.
OBJECTIVE: We describe the islet phenotype of a series of infants with severe HI and comorbid BWS who required pancreatectomy for intractable hypoglycemia.
METHODS: The cases are a subset of HI patients who required pancreatectomy and had Beckwith-Wiedemann Syndrome. Molecular testing for BWS was performed by SNP array and chromosome 11p15 methylation analysis. Functional analysis of insulin secretion in pancreatic islets isolated from pancreatectomy samples was completed with perifusion experiments and cytosolic Ca2+ measurements.
RESULTS: Similar to what we had previously described in islets isolated from the pancreas of infants with HI due to inactivating mutations in the KATP channel, BWS-HI islets have elevated concentrations of cytosolic calcium and secrete insulin in response to stimulation with a physiologic mixture of amino acids. However, unlike KATPHI islets, most BWS-HI islets retain responsiveness to stimulation with glucose and the KATP channel inhibitor glyburide. Through RNAseq analysis, we observed that expression of KCNQ1, encoding the pore-forming subunit of a voltage-gated K + channel (Kv7.1), is reduced in BWS-HI islets compared to normal human islets (3-fold; P = 4.5 × 10-7).
CONCLUSION: Our expression analysis and functional evaluation of islets isolated from BWS-HI patients reveal the spectrum of insulin secretion responses found across BWS etiologies and suggest a potential role for loss of KCNQ1 expression in the complex pathophysiology responsible for the hyperinsulinism in BWS.