Successful sulfonylurea treatment of an insulin-naïve neonate with diabetes mellitus due to a KCNJ11 mutation

Abstract

Activating mutations in the K(ATP)-channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K(ATP) mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6-yr-old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75-fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K(ATP)-induced NDM, unless glycemia is well controlled, thus, a dramatically lower glyburide requirement in the infant may reflect preserved insulin content because of early sulfonylurea intervention. Safe and effective initiation of glyburide in an insulin-naïve neonatal patient with K(ATP)-dependent PNDM argues for early detection and sulfonylurea intervention.

Fig. 1

(A) Pedigree of family with Kir6.2 (KCNJ11) mutation. Arrow indicates the R201H proband; half-filled and empty symbols indicate clinically and genetically affected and unaffected individuals, respectively. The current ages of the family members and the glyburide dosing regimen (given in parentheses) are indicated. NT, not tested. (B) Glycemic control and sulfonylurea dosing in R201H proband. Blood glucose values (solid circles) and glyburide dose (open circles), vs. day of life. For days 1–8, multiple glucose readings (mean ± SEM) were measured in the hospital. Subsequent days are self-reported, random glucose measures (three times daily; mean ± SEM) from the patient’s mother. (C) Sulfonylurea dosing of the R201H proband (open circle) and the affected mother and sister (closed circles) relative to 44 NDM patients who successfully switched from insulin to sulfonylurea therapy (Box and Whisker plot adapted from Pearson et al. (5); bars represent the dosing range, box represents the lower and upper quartiles, and solid line represents median). For comparison, the maximal recommended glyburide dose to treat type 2 diabetes is shown (based on a 75 kg individual).