Clinical characteristics and genetic analysis of 6 cases of neonatal diabetes mellitus / 中国新生儿科杂志

Objective:To study the clinical features, genetic characteristics and prognosis of neonatal diabetes mellitus (NDM).Methods:From January 2015 to January 2022, neonates with NDM admitted to the Department of Neonatology of our hospital were retrospectively reviewed.Their clinical manifestations, biochemical data, genetic tests, treatments and outcomes were analyzed.Results:A total of 6 cases with NDM were included, with 3 males and 3 females. All 6 cases were full-term infants, 5 were low birth weight infants and 1 had family history of diabetes. High blood glucose were found on 1~11 d (average 4 d) after birth. 3 cases were diagnosed during blood glucose screening for low birth weight and 3 cases were diagnosed due to infection and/or diabetic ketoacidosis. Blood C-peptide levels were below normal range in all 6 cases. Blood insulin levels were decreased in 5 cases and remained at the lower limit of normal range in 1 case. All infants received genetic tests and 4 showed abnormal results, including 2 cases of ABCC8 gene mutation [c.2060C>T (p.T687M), not reported; c.674T>C (p.L225P), reported], 1 case of KCNJ11 gene mutation [c.602G>A (p.Arg201His), not reported] and 1 case of paternal uniparental disomy (UPD)6q24 (reported). All 6 cases were treated with insulin. Glibenclamide was experimented to replace insulin in 3 cases and 1 case was successful. During follow-up (at the age 4 months~5 years old), 4 cases were diagnosed with transient NDM, 1 case with permanent NDM and 1 case died at the age of 4 months without classification. 1 case showed psychomotor and language delay and the others had otherwise normal development.Conclusions:Most NDM infants are low birth weight infants with reduced blood insulin and C-peptide.Transient NDM are common. Proactive genetic testing may help treatment.

Research progress on gene mutation of neonatal diabetes mellitus / 国际儿科学杂志

The pathogenesis of neonatal diabetes mellitus (NDM) is mostly associated with mutations in genes related to the function or the number of islet β cells and pancreatic development and differentiation.Some of them are aberrant gene mutations related to chromosome methylation.With the amplification of pathogenic gene spectrum, new characteristics of clinical phenotypes have been discovered.In addition to insulin therapy, safe and effective sulfonylurea drugs can improve the neurodevelopmental disorders of some children with K-ATP channel related gene mutations by shutting down the K-ATP channel and releasing insulin.The review describes the recent research on the mechanism of NDM gene mutations and summarizes its clinical features to provide new ideas for treatment.

Research progress on gene mutation of neonatal diabetes mellitus / 国际儿科学杂志

The pathogenesis of neonatal diabetes mellitus (NDM) is mostly associated with mutations in genes related to the function or the number of islet β cells and pancreatic development and differentiation.Some of them are aberrant gene mutations related to chromosome methylation.With the amplification of pathogenic gene spectrum,new characteristics of clinical phenotypes have been discovered.In addition to insulin therapy,safe and effective sulfonylurea drugs can improve the neurodevelopmental disorders of some children with K-ATP channel related gene mutations by shutting down the K-ATP channel and releasing insulin.The review describes the recent research on the mechanism of NDM gene mutations and summarizes its clinical features to provide new ideas for treatment.

Childhood diabetes in India

This review describes the epidemiology of childhood diabetes in India. It focuses on the incidence and prevalence of type 1 diabetes and its complications and comorbid conditions. The review also covers data related to type 2 diabetes, glucose intolerance, and monogenic diabetes from India. A brief discussion regarding unique contributions from India to the world literature is included. The topics discussed include use of camel milk as adjuvant therapy in type 1 diabetes, relevance of the A1/A2 hypothesis, and comprehensive clinico-etiopathological classification of type 1 diabetes.

Clinical features of two patients with neonatal diabetes mellitus caused by KCNJ11 gene V59A/V59M mutations / 中华内分泌代谢杂志

Two patients with neonatal diabetes tested as V59A and V59M mutations were chosen for the study. Clinical data were analyzed retrospectively. The results showed that the patient with V59A mutation was characteristic of spasm and hyperglycemia at the age of three month, and treated with insulin for a long time as unresponsive to the glibenclamide at the beginning. Myasthenia and delay of development were observed during the follow-up. At the age of two years, glibenclamide was tried for the second time with a high dose and fairly-controlled glucose level. The patient with V59M mutation was diagnosed with diarrhea, hyperglycemia, and ketosis at the age of two month, and was responsive to glibenclamide at a relatively low dose with well-controlled glucose level. These results suggest that KCNJ11 V59M mutation would show some milder clinical manifestations and better glibenclamide efficacy as compared with V59A mutation.

DEND Syndrome with Heterozygous KCNJ11 Mutation Successfully Treated with Sulfonylurea

Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (K(ATP) channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.

Scanning and analysis of the KATP channel mutations in 12 cases of infancy onset type 1 diabetes mellitus / 中华实用儿科临床杂志

Objective To screen the mutation of KATP channel mutations in Chinese pedigrees with infantile onset type 1 diabetes mellitus (T1DM) and neonatal diabetes mellitus.Methods A cohort of 12 children of infant onset T1DM and neonatal diabetes mellitus admitted into Beijing Children's Hospital between March 2004 and June 2013 were selected.PCR amplification and direct sequencing were used to analyze the 39 exons of ABCC8 gene and one exon of KCNJ11.And the mutational sites of the parents of the probands was sequenced in order to identify the inheritance.Results Analysis revealed ABCC8 mutation in 25％ (3/12 cases) of the patients,a case of transient neonatal diabetes (TNDM),a case of permanent neonatal diabetes mellitus (PNDM) and a case of infant onset T1DM.All positive patients showed a known heterozygosis mutation in the ABCC8 gene(R1182Q,c.3545G ＞ A,D209E,c.627C ＞ G,E208K c.622G ＞ A).The residue R1182Q,which was located at a position involved in joining transmembrane domain 2 to nucleotide binding domain 2,the mutations E208K and D209E were located in the intracellular region that links the transmembrane domain with the gatekeeper module.All the three mutations were located throughout the cytoplasm part of SUR1 protein.The TNDM successfully transferred from insulin to oral sulfonylureas therapy.Conclusions There is a complex genetic pathogenesis in neonatal and infant-onset diabetes.The KATP channel activating mutations is one of the main causes of neonatal diabetes mellitus and may cause T1DM in infants in China.Oral Glibenclamide therapy seems highly effective for some patients with the KATP channel activating mutations.

Approach to the patients with transient neonatal diabetes mellitus / 中华内分泌代谢杂志

[Summary]_ Transient neonatal diabetes mellitus is a kind of rare special types of diabetes. It should be distinguished from type 1 diabetes. Genetic analysis can be used to define the subtype of neonatal diabetes mellitus, which helps us to select the most appropriate treatment and to predict the disease recurrence. Sulfonylureas is able to improve insulin secretion in most patients with transient neonatal diabetes mellitus and provide effective glycemic control. A case of transient neonatal diabetes mellitus is reported in order to call attention to the diagnosis and treatment of this disease.

The updates in molecular genetic mechanisms of neonatal diabetes mellitus / 中华实用儿科临床杂志

Neonatal diabetes mellitus(NDM)occurs within the first 6 months of life. Depending on clinical outcomes,it is classified into transient neonatal diabetes mellitus(TNDM)and permanent neonatal diabetes mellitus (PNDM). TNDM,which accounts for 50% of NDM goes into remission after treatment for an average period of 12 weeks,but relapse in puberty and early adulthood. PNDM,on the other hand,is a lifelong disease without remission. The clinical features of TNDM and PNDM overlap,and the typing is based on clinical remission on follow - up. More than 20 pathogenic genes have been identified in PNDM,of which the most common are KCNJII and ABCC8 encoding the Kir6. 2 and SUR1 subunits of KATP channel accounting for 50% . TNDM is caused by defects associated with overexpres-sion of paternally expressed genes in the imprinted region of chromosome 6q24 in 70% cases. About 26% of the defects contain mutations in KCNJII,ABCC8,INS or HNFIB. In vitro and clinical studies suggest that treatment with oral sul-fonylurea can close KATP channel and improve glycemic control and neuropsychological development. However,10% of patients with KCNJII and 15% ABCC8 mutations fail to achieve glycemic control when insulin therapy is switched to o-ral sulfonylureas. Therefore,molecular diagnosis is vital not only in accurate typing but also for better prognostication.

Successful sulfonylurea treatment in a patient with permanent neonatal diabetes mellitus with a novel KCNJ11 mutation / 소아과

Permanent neonatal diabetes mellitus refers to diabetes that occurs before the age of 6 months and persists through life. It is a rare disorder affecting one in 0.2-0.5 million live births. Mutations in the gene KCNJ11, encoding the subunit Kir6.2, and ABCC8, encoding SUR1 of the ATP-sensitive potassium (K(ATP)) channel, are the most common causes of permanent neonatal diabetes mellitus. Sulfonylureas close the K(ATP) channel and increase insulin secretion. KCNJ11 and ABCC8 mutations have important therapeutic implications because sulfonylurea therapy can be effective in treating patients with mutations in the potassium channel subunits. The mutation type, the presence of neurological features, and the duration of diabetes are known to be the major factors affecting the treatment outcome after switching to sulfonylurea therapy. More than 30 mutations in the KCNJ11 gene have been identified. Here, we present our experience with a patient carrying a novel p.H186D heterozygous mutation in the KCNJ11 gene who was successfully treated with oral sulfonylurea.

Diabetes mellitus neonatal en Costa Rica / Neonatal diabetes mellitus in Costa Rica

La diabetes mellitus neonatal es un raro desorden metabólico usualmente desarrollado en las primeas 6 semanas de vida, secundario a un grupo de mutaciones y defectos del desarrollo pancreático que puede desembocar en una catástrofe clínica si no se identifica tempranamente; se divide en una variante transitoria y una permanente, siendo la primera la más frecuente, con cerca de un 60 por ciento de los casos. El manejo inicial de ambas variantes es la insulinoterapia intensiva, que en la variante transitoria puede suspenderse usualmente en los primeros meses de vida...

Study of Mechanism of Proinsulin Gene Mutations in Diabetes Mellitus / 天津医药

Objective To construct several human proinsulin mutants plasmid related to diabetes and to express in INS-1 (Insulin secreting beta cell derived line) cell. Methods Human mild proinsulin gene was used as template , and site-directed mutagenesis PCR was employed to generate four human proinsulin plasmid mutants. Each mutant plasmid was sequenced then transfected with empty plasmid and mild plasmid into INS-1 cell by liposome 2000. Insulin value in each cell solution was determined by radioimmunoassay. Results Proinsulin mutants plasmid were confirmed by sequencing. In-sulin values in culture solution of H-C(B19)G、H-L(B11)P、H-R(S6)C mutants are less than those in wild type and H-F (B25)L(P＜0.05). Comparison of insulin values between H-C(B19)G、H-L(B11)P、H-R(S6)C groups were not statistically significant(P>0.05), and all these three groups showed no significant differences with empty plasmid group statistically (P>0.05).Insulin value of H-F(B25)L was of no significant differences statistically with empty plasmid(P>0.05). Conclu-sion Four human proinsulin mutants plasmid were constructed and expressed successfully in INS-1 cell, and different mu-tants plasmid result in diabetes through different mechanism.

Clinical Profile and Outcome of Infantile Onset Diabetes Mellitus in Southern India.

Objective: To study the etiology, clinical presentation and outcome of infantile onset diabetes mellitus (IODM). Design: Descriptive cohort study. Retrospective study from 1999- 2007 and prospective from 2008-2012. Setting: The diabetic clinic at a Pediatric tertiary care referral institute in Chennai. Methods: All infants diagnosed to have diabetes at less than one year of age were studied. Study variables were age at onset, gender, mode of presentation, birth weight, initial blood glucose, serum HbA1c, serum c–peptide levels, outcome at initial presentation, insulin requirement, associated co-morbid conditions, genetic analysis and outcome at the end of the study or until they were followed up. Results: 40 infants with infantile onset diabetes were studied, constituting 8% of all children with onset of DM at less than 12 years of age. 67.5% of these children presented with diabetic keto acidosis (DKA), only 30% had a provisional diagnosis of DM or DKA at first physician contact. 63% of IODM with onset less than 6 months and 30% with onset more than 6 months were of low birth weight. Nearly 85% of the study group had low C-peptide levels. 84.5% of IODM with onset less than 6 months and 55% of those with onset more than 6 months were monogenic. Wolcott Rallison syndrome was the commonest type encountered. Genetic diagnosis aided switching over from insulin to oral sulphonylurea in 5 children with KCNJ11 and ABCC8 mutations. Missed diagnosis, recurrent admissions for metabolic instability and developmental delay were common problems in IODM. Mortality at 12.5 year follow up was 32.5%. Conclusions: IODM with onset at less than 6 months is predominantly monogenic and low birth weight is more common. 55% of IODM were misdiagnosed at onset. Developmental delay is the common co morbid condition in IODM. Genetic diagnosis aids change of therapy to oral sulphonylurea.

Four cases of transient neonatal diabetes mellitus / 中华实用儿科临床杂志

Objective To reveal the clinical features of children with transient neonatal diabetes mellitus (TNDM) in order to provide a basis for the TNDM treatment strategy formulation.Methods Four patients diagnosed as TNDM hospitalized in Beijing Children's Hospital Affiliated to Capital Medical University from Dec.2008 to Dec.2010 were chosen as research subjects.Their clinical data were analyzed retrospectively.Results The 4 patients diagnosed as TNDM started insulin therapy.Two cases of the 4 patients transferred from insulin to oral Sulfonylureas for 2-3 weeks after their conditions became steady.One patient was treated with Sulfonylureas successfully and the other one was partially effective with this therapy.After 2 to 3 years follow-up,3 cases remitted in 1 month after birth with no other severe complications,one case lost.Conclusions Infants with TNDM had unique clinical features.The patients develop diabetes in the first few weeks of life but go into remission in a few months.So the follow-up for those TNDM patient is very essential for clinical classification.Oral glibenclamide therapy seems highly effective and safe for some TNDM patients.

Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic beta-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.

Permanent Neonatal Diabetes Caused by a Novel Mutation.

Most cases of permanent form of neonatal diabetes mellitus (PNDM) are due to dominant heterozygous gain of function (activating) mutations in either KCNJ11 or ABCC8 genes, that code for Kir 6.2 and SUR1 subunits, respectively of the pancreatic β-cell KATP channel. We describe the interesting case of an infant with PNDM, in whom a compound heterozygous activating/ inactivating mutation was found with clinically unaffected parents, each carrying a heterozygous mutation in ABCC8, one predicting gain of function (neonatal diabetes) and the other a loss of function (hyperinsulinemia).

Genetic analysis of neonatal diabetes mellitus and its influence on treatment outcome / 中华内分泌代谢杂志

Fourteen neonatal diabetes mellitus(NDM)patients were recruited. 9 patients were treated with glyburide and the other 5 with insulin. ABCC8, KCNJ11, and INS genes were sequenced in 6 of them. Gene mutations were found in 2, 1, and 1 cases in these genes, respectively. One case with 6q24 hypomethylation and another without known mutation were also found. 8 out of 9 patients treated with glyburide reached euglycemia(88.9%). The other 5 patients with insulin therapy either died or lost contact. The results suggest that glyburide therapy is effective in neonatal diabetes mellitus, while insulin therapy may contribute to poor compliance.

Progress of neonatal diabetes mellitus / 国际儿科学杂志

Neonatal diabetes mellitus ( NDM ),which was often misdiagnosed as type 1 diabetes in the past,is a heterogenous single-gene genetic disease.Permanent neonatal diabetes( PNDM )is mainly associated with mutation in KCNJ11,ABCC8,and insulin associated gene instead of immunity.The most common manifestation includes diabetic ketoacidosis,intrauterine growth retardation and dehydration.Gene examination contributes to the classification of NDM and corresponding targeted therapy.Oral sulfonylurea may be used in treating patients with gene mutation of ATP-sensitive K+ channel.

Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene / Resposta a longo prazo com sulfonilureia em um paciente com diabetes associado à mutação no gene KCNJ11

OBJECTIVE: To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene. SUBJECT AND METHOD: A 29-year-old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea. RESULTS: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6 percent) and the glibenclamide dose could be reduced. CONCLUSION: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control.

OBJETIVO: Reportar o efeito a longo prazo (30 meses) da substituição de insulina por sulfonilureia em um paciente com a mutação p.G53D (c.158G>A) no gene KCNJ11. SUJEITO E MÉTODO: Paciente do sexo masculino, atualmente com 29 anos de idade, foi diagnosticado com diabetes melito no terceiro mês de vida e, após identificação da mutação p.G53D (c.158G>A) em heterozigose no gene KCNJ11, a terapia foi substituída de insulina para sulfonilureia. RESULTADOS: Seguimento a longo prazo (30 meses) mostrou que o bom controle metabólico foi mantido (HbA1c: 6,6 por cento) e a dose de glibenclamida pode ser reduzida. CONCLUSÃO: A terapia com sulfonilureia a longo prazo em pacientes com diabetes neonatal decorrente de mutações no gene KCNJ11 é segura e promove uma melhora persistente no controle metabólico.

KCNJ11 activating mutation in an indian family with remitting and relapsing diabetes.

Objective. To identify the genetic cause of transient neonatal diabetes mellitus in three siblings from an Indian family. Methods. Case reports with clinical and molecular evaluation of an activating mutation in the KCNJ11 gene are presented. We describe an Indian family with two asymptomatic parents with 3 children presenting with hyperglycemia at 6, 1.5 and 1 month of age respectively. Blood glucose levels at presentation were 22.2, 18.3 and 20 mmol/L and the diabetes remitted in all three children by 5 years of age. None of the affected siblings had dysmorphism or neurological abnormalities. Diabetes relapsed in the oldest sibling at 9.4 years of age and she is now euglycemic on 1mg/Kg of Glibenclamide twice a day. Results. A novel heterozygous missense mutation (G53V) in the KCNJ11 gene was identified in all 3 affected children and the father. Conclusions. The report suggests that screening for KCNJ11 mutations is appropriate in patients diagnosed with neonatal diabetes as it provides valuable information concerning possible course of the disease and choice of treatment.