The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation

Abstract

To the Editor Diabetes caused by severe mutations in beta cell genes is usually diagnosed as neonatal diabetes [1] or MODY [2]. Activating mutations in KCJN11, the gene encoding the ATP-sensitive potassium channel subunit Kir6.2, have been described in very-early-onset diabetes ( A) was found in a single patient. This child was born at 40 weeks’ gestation and weighed 2,450 g. He was diagnosed with diabetes during the third week of life based on a plasma glucose of 35–50 mmol/l, without ketoacidosis, which was measured when he presented with pneumonia and bilateral acute otitis media. The patient was treatedwith insulin, with a dose of 0.7–1.0 U/kg used initially and subsequently decreased. At 9 years, 11 months he weighed 27.5 kg and his daily insulin requirement was 7 U (0.25 U/kg) as a single morning injection of intermediate-acting insulin. Despite little modification to his diet he rarely experienced hyperglycaemia above 11 mmol/l, and had an HbA1c level of 6.6%. These observations suggested endogenous beta cell function, which was confirmed by a fasting plasma C-peptide of 443 pmol/l (glucose 6.7 mmol/l) and an increase in plasma insulin concentration of 70 pmol/l during an IVGTT (Fig. 1). As patients with Kir6.2 diabetes may respond to sulphonylureas, we assessed whether this patient could successfully transfer to sulphonylurea tablets [3, 4]. Glipizide gastrointestinal therapeutic system (GITS), a controlledrelease sulphonylurea, was introduced [5]. A dose of 5 mg was administered for 2 days, then 10 mg; insulin was simultaneously slowly withdrawn over a period of 5 days. As the patient experienced a few mild hypoglycaemic episodes during the first 2 days after the discontinuation of insulin the glipizide GITS dose was decreased to 5 mg. While on this dose, a day profile of his capillary glucose concentrations revealed that they were between 4 and 6 mmol/l; a result confirmed by a 72-h record obtained using a continuous glucose monitoring system (Medtronic, Northridge, CA, USA). The IVGTT was repeated 3 weeks after a stable glipizide dose was achieved. At this time the patient’s fasting glucose level was 5.4mmol/l, and his C-peptide level was 347 pmol/l. T. Klupa and E. L. Edghill contributed equally to this work