A case of genetic hypoglycemia in an adult: A Molecular Approach

Context: We present a case of a young adult with GCK mutation who had neonatal hypoglycaemia, re-emerging with hypoglycaemia later in life. Mechanistic insight is gained from detailed clinical, cellular and genomic analysis. Conclusion: This case highlights the variable phenotype of GCK mutations. In depth molecular analyses in the islets has revealed possible mechanisms for nesidioblastosis and insulin hypersecretion. Overall design: We investigated a 22-year-old man with asymptomatic hypoglycaemia with a family history of maternal hypoglycaemia. Genetic testing yielded a novel GCK mutation that was subsequently found in his mother, sister and nephew. After partial pancreatectomy, immunohistochemistry revealed diffuse nesidioblastosis. Functional analysis of his islets by assessing intracellular calcium, a surrogate marker for insulin secretion, revealed normal basal but increased glucose stimulated insulin secretion. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS gene, upregulated CKB gene and downregulated DLK1 and NPY genes in beta-cells, which may explain the metabolic and histological phenotype associated with glucokinase mutation. There were more larger islets in the patient's pancreas than in control subjects but there was no difference in the proportion of beta cells in the islets. His hypoglycaemia was persistent after pancreatectomy and was refractory to diazoxide therapy. Octreotide partially improved hypoglycaemia.