Background: Very early onset diabetes mellitus (neonatal diabetes mellitus (NDM)) seems to be unrelated to autoimmunity in most instances. A number of conditions are associated with NDM, some of which have been elucidated at the molecular level. Among these, the recently elucidated mutations in the KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunit of the pancreatic KATP channel involved in regulation of insulin secretion, account for one third to half of the PNDM cases.1,2,3 Molecular analysis of chromosome 6 anomalies (found in more than 60% in transient NDM), and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 (found in around 50% of permanent NDM), provides a tool to characterized NDM in the neonatal period.
Objective and hypotheses: Proof of concept of the action leading to endogenous insulin secretion by glibenclamide has been fully established when the potassium channel display an activating mutation which impairs membrane depolarization, insulin secretion and is responsible for neonatal diabetes mellitus. It is also important to understand that this glibenclamide effect leading to insulin secretion is also present when the potassium channel is normal and the cause of neonatal diabetes mellitus unrelated to potassium channel mutation. The use of glibenclamide is therefore possible to treat neonatal diabetes mellitus, providing that there are insulin secreting cell in the endocrine pancreas.4
Results: Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available;4 however, more cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control, and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be implemented. However, obtaining a genetic diagnosis remains imperative.
Conclusion: The pros and cons of using sulfonylurea before genetic testing will be discussed.
References: 1. Pearson ER, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355 467477, 2006.
2. Babenko AP, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355 456466, 2006.
3. Busiah K, et al. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study. Lancet Diabetes Endocrinol 1 199207, 2013.
4. Carmody D, et al. Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol Metab 99 E2709E2714, 2014.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology