Permanent Neonatal Diabetes (pndm) In Patients With Atp-sensitive Potassium Channel Gene Mutations

Objective:Permanent neonatal diabetes mellitus (PNDM) is a rare and particular form of diabetes, often diagnosed within the first 6 months of life. Recently, mutations in KCNJ11 gene and ABCC8 gene encoding Kir6.2 subunit and SUR1 subunit of the ATP sensitive K+ channel of the pancreaticβcell have been described to be the major cause of PNDM. It is reported that insulin injection can be successfully transferred to oral sulfonylurea therapy in most of those PNDM patients. The purpose of this study is to investigate mutations in KCNJ11 gene and ABCC8 gene in Chinese PNDM patients to identify the major pathogenic genotype and genotype-phenotype relationships of Chinese PNDM patients, and to make an observation of the oral sulfonylurea therapy transition in those patients with KCNJ11/ABCC8 gene mutation.Methods:1. Detailed clinical data were collected from 9 PNDM patients and their parents. After getting informed consent from them, peripheral venous blood were drawn for genome DNA extraction. All 40 exons of KCNJ11 and ABCC8 gene were amplified by polymerase chain reaction for direct sequencing. The results were verified by PCR cloning.2. According to the results of gene sequence, glybenclamide was given to the patients with gene mutation from a dose of 0.15mg/kg/day under a strict glucose level monitoring. Insulin dose were gradually decreased in accordance with the glucose level until insulin was totally discontinued. Simple C peptide releasing test was done before and after therapy transition to contrast the secreting function of pancreaticβcell of the patients. A 72-hour continuous glucose monitoring was performed after transition. Drug adverse reactions were also observed. Results:1. A heterozygous mutation, a G to A mutant at nucleotide 602, which resulted in an argine-to-histidine substitution at position 210 of the KCNJ11 gene was identified in a PNDM patient with iDEND syndrome. After the identification of gene diagnosis, a transition from insulin injection to oral glybenclamide therapy was successfully performed. The patient made a sensitive response to glybenclamide and an ultimate dose of 0.20mg/kg/day was used. After transition to glybenclamide therapy, the basal and postprandial serum C-peptide level of the patient were both obviously increased. Continuous glucose monitoring system showed a steady glucose level during 24 hours without hyper- or hypoglycemia.2. KCNJ11 and ABCC8 gene mutation were not found in all 8 other PNDM patients, but E23K SNP (rs5219) were found in 5 patients, I337V SNP (rs5215) were found in 6 patients and rs5213 SNP were found in 7 patients of them. The 3 SNPs above were simultaneously carried by 5 patients of them.Conclusions:Mutations in KCNJ11 gene encoding Kir6.2 can cause PNDM in Chinese children, and oral sulfonylurea therapy may be a more appropriate therapeutic measure than insulin injection for those patients. However, the frequency of pathogenic genotype distribution and the genotype-phenotype relationships in Chinese PNDM patients may be different from the reports of other countries. In addition to mutations in KCNJ11 and ABCC8 gene, some SNPs with closely association with diabetes may participate in the pathogenesis of PNDM.