Human Pancreas Endocrine Cell Populations and Activating <b><i>ABCC8</i></b> Mutations

Abstract

Background/Aims: Activating mutations in the ABCC8 gene encoding the K_ATP 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.

Neonatal Diabetes and the K ATP Channel: From Mutation to Therapy

“…The ability of most patients with ND to transfer to sulfonylurea therapy implies they retain significant numbers of beta cells, often despite many years of diabetes. This is consistent with post-mortem EM studies of the pancreas from patients with ND 35 , 36 . However, islets were smaller and reduced in number, and the percentage of cells staining for insulin was decreased.…”

Long-term Metabolic and Socioeducational Outcomes of Transient Neonatal Diabetes: A Longitudinal and Cross-sectional Study

“…In addition, the impact of glucotoxicity on b-cell mass cannot be excluded (23,24). Conceivably, individuals with current diabetes (TNDM participants and genetic abnormalities-carrying relatives) may have an abnormally small b-cell mass (25,26). Precise measurement of the b-cell mass remains challenging in humans.…”

Islet formation in mice and men: lessons for the generation of functional insulin-producing β-cells from human pluripotent stem cells

“…Notably, deletion of MafA in mice significantly disturbed islet morphology and impaired GSIS by affecting genes involved in glucose metabolism, insulin granule docking and insulin synthesis[56]. On a similar note, mutations in SUR1, a K + ATP channel subunit that confers β-cell function and is required for the induction of membrane depolarization, results in disrupted islet architecture[57] and causes NDM in humans[58]. Thus, it appears that factors involved in β-cell function also are necessary for islet structure.…”