engleski

Very low doses of glibenclamide as successful replacement for insulin therapy in a patient with neonatal diabetes due to a mutation of KCNJ11 gene encoding Kir6.2

Introduction Permanent neonatal diabetes mellitus (PNDM) is a rare form of insulin dependent diabetes diagnosed within the first six months of life. Recently, activating mutation in the KCNJ11 gene encoding Kir6.2 subunit of the adenosin triphosphate -sensitive potassium (KATP) channel have been described as the most frequent cause of PNDM. Under physiological circumstances KATP channel closure plays a central role in glucose-stimulated insulin secretion from pancreatic beta cells. Sulphonylurea drugs stimulate insulin secretion by binding to and closing KATP channels and thus, bypassing beta cell metabolism and stimulating insulin release. Aim We describe patient with PNDM in whom insulin therapy was successfully switched to low doses of oral glibenclamide. Results Our patient is now a 5.5 year old boy diagnosed with PNDM at the age of 3 months. When diagnosed he had severe hyperglycaemia (64.8 mmol/l) and ketoacidosis (pH 6.97, serum bicarbonate 4.2 mmol/l). Autoimmune antibodies glutamic acid decarboxilase (GAD), islet cell (ICA) and thyrosine phosphatise (IA-2) antibodies were negative. Insulin therapy was started, and moderate glycaemic control was achieved (HbA1c 7.1-8.6%). C-peptide concentrations were low in two samples (0.13 nmol/l and 0.09 nmol/l ; referent range 0.2-1.3 nmol/l). At the age of 20 months the insulin requirements were reduced (required insulin dose was 0.3 IU/kg/day). At the age of 4.5 years, KCNJ11 gene was sequenced and found that the boy carries a de novo activating R201H mutation. Insulin therapy was switched to oral glibenclamide. Very low doses of glibenclamide (initially 0.175 mg/kg/day, lowered to 0.12 mg/kg/day in the next 6 months) were sufficient to attain excellent glycaemic control (HbA1c 6, 0%, 3 and 6 months after switching to glibenclamide). Oscillations in blood glucose levels were in a narrow range and an adequate rise in basal C-peptide concentration was detected (0.4 nmol/l). Conclusion The first PNDM patient in Croatia was found to have a genetic defect impairing the Kir6.2 subunit of the KATP channel. Very low doses of oral glibenclamide provided better metabolic control and undoubtedly better quality of life compared with previous insulin therapy.

neonatal diabetes; KCNJ11; Kir6.2; glibenclamide

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