Molecular Genetics And Clinical Studies Of Neonatal Diabetes Mellitus (NDM)

Objective:Neonatal diabetes mellitus (NDM) is a rare and particular form of diabetes, often diagnosed within the first6months of life. It can be classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. Recent molecular analysis of NDM identified12genetic abnormalities, mutations in KCNJ11gene and ABCC8gene encoding Kir6.2subunit and SUR1subunit of the ATP sensitive K+channel of the pancreatic β cell 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 to evaluate the contribution of the responsible gene and delineate their clinical characteristics of Chinese NDM patients, and to make an observation of the oral sulfonylurea therapy transition in those patients with KCNJ11/ABCC8gene mutation.Methods:Detailed clinical data were collected from11PNDM patients and their parents. After getting informed consent from them, peripheral venous blood were drawn for genome DNA extraction. All exons of KCNJ11、ABCC8、INS、GCK、 HNF1A、HNF4A genes were amplified by polymerase chain reaction for direct sequencing.According to the results of gene sequence, glybenclamide was given to the patients with KCNJ11/ABCC8gene mutation from a dose of0.15mg/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 pancreatic β cell of the patients. A72-hour continuous glucose monitoring was performed after transition. Drug adverse reactions were also observed. Results:A molecular basis for NDM was found in7patients:KCNJ11in one, ABCC8in four, GCK in one and HNF1A in one. Six mutations were novel:four (p.1585F, p.R275Q, p.Q211R and IVS19+17G>C) in ABCC8, one (p.R191W/A379E) in GCK, one (p.1618M) in HNF1A.After the identification of gene diagnosis, a transition from insulin injection to oral glybenclamide therapy was performed in four patients with KCNJ11or ABCC8mutations. One patients with the KCNJ11mutation (R201H) and one patients with the ABCC8mutation (Q211R) were successfully switched from insulin to SU. Both of the patients made a sensitive response to glybenclamide and an ultimate dose of0.20and0.35mg/kg/day was used respectively. 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 during24hours without hyper-or hypoglycemia.Conclusions:The majority of cases of neonatal diabetes in China can be explained by known genetic abnormalities, and oral sulfonylurea therapy may be a more appropriate therapeutic measure than insulin injection for those patients with KCNJ11or ABCC8mutations. However, the frequency of pathogenic genotype distribution and the genotype-phenotype relationships in Chinese NDM patients may be different from the reports of other countries.