Background/Aims: Activating mutations in the ABCC8 gene encoding the KATP channel subunit SUR1 cause β-cell dysfunction with non-autoimmune diabetes mellitus in neonates or infants. We investigated whether activating ABCC8 mutations affect endocrine pancreas development. Methods: We studied a male infant with compound heterozygous ABCC8 mutations (p.Arg826Trp/p.Ile93Thr) causing neonatal diabetes mellitus. He died of ketoacidosis. Postmortem pancreas specimens were evaluated by fluorescent microscopy after immunostaining for insulin, glucagon, somatostatin, and PCNA, and Hoechst 33342 nuclear staining. We compared the findings to those in 5 age-matched controls. Results: The number of islets was decreased and the number of single or small clusters of insulin cells increased in the patient compared to the age-matched controls. The islets in the patient had an insulin-cell core surrounded by intermingled glucagon and somatostatin cells. The insulin/Hoechst surface ratio was decreased and the glucagon/Hoechst surface ratio increased in the patient (4.3 and 8.8%, respectively) versus the controls (8.2 and 3.1%, respectively). Somatostatin surface staining was similar in the patient and controls (4 vs. 4.7%). PCNA staining was increased 3- to 3.5-fold, indicating increased insulin-cell proliferation compared to controls. Conclusion: Activating ABCC8 mutations impaired the balance between β and α cells in the patient, suggesting an effect on β-cell mass development.

Keywords:
Neonatal diabetes mellitus, ABCC8, Endocrine pancreas development, β cells, Humans, Newborn
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2014
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