Retrospective analysis of 23 Chinese children with congenital hyperinsulinism undergoing pancreatectomy.

INTRODUCTION: The aim of the study was to discuss therapeutic effect and prognosis of pancreatectomy in the treatment of congenital hyperinsulinism (CHI). MATERIAL AND METHODS: A total of 23 Chinese children with CHI, who had undergone pancreatectomy, were selected as the study objects. The clinical data, the results of the ¹8Fluoro-L-3-4 dihydroxyphenylalanine positron emission tomography/computerized tomography (¹8F-DOPA PET/CT) scanning, and the diagnosis, treatment, and follow-up were analysed retrospectively. RESULTS: Among the 23 cases, 14 patients were diagnosed with focal-type CHI via a ¹8F-DOPA PET/CT scan prior to the operation, with the lesions removed via partial pancreatectomy. After the operation, ten patients (71%) had normal blood glucose levels, while frequent feeding was required in four patients (29%) to control the hypoglycaemia. Three cases were diagnosed as diffuse-type CHI via preoperative scanning, two of which were treated by subtotal pancreatectomy. The other case was treated by near-total pancreatectomy, and the blood glucose level was normal following the operation. The remaining six cases were not diagnosed via the pancreatic scanning prior to the operation due to the limitation of certain conditions. Here, pancreatectomy was performed directly due to severe hypoglycaemia. CONCLUSIONS: ¹8F-DOPA PET/CT scanning was a reliable method for determining the histological type and localizing the lesion before the operation. Partial pancreatectomy for focal-type CHI had a high cure rate.

Analysis on the pathogenic genes of 60 Chinese children with congenital hyperinsulinemia.

This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children's Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, 8 patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. Conclusions: ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children's families has an important guiding significance for treatment planning and prognosis assessment.

[ABCC8, KCNJ11 and GLUD1 gene mutation analysis in congenital hyperinsulinism pedigree].

OBJECTIVE: To explore the ABCC8, KCNJ11, and GLUD1 gene mutations of the 11 patients diagnosed as congenital hyperinsulinism (CHI). METHODS: A total of 11 CHI children hospitalized in Beijing Children's Hospital from November 2008 to February 2012 and their parents were chosen as the study subjects. Direct sequencing of PCR-DNA was used to analyze the 39 exons of ABCC8 gene, non-translational region and exon of KCNJ11 gene and 6, 7, 10, 11 and 12 exons of GLUD1 gene. RESULTS: An P629PfsX17 heterozygous mutation of ABCC8 gene was detected in case 1 and his father, an W288X heterozygous mutation of ABCC8 gene was detected in case 4 and his father, A640V and Q1196X mutations in ABCC8 gene in case 5 whose father only carried the Q1196X mutation. In case 6 and his father, an R269H mutation was found in GLUD1 gene. The genotype of 4 children's mothers was normal. No mutations were found in other 7 patients and their parents. CONCLUSIONS: The ABCC8 gene mutations are the main pathogenic mechanisms of Chinese children with CHI. In Chinese, P629PfsX17, W288X, A640V and Q1196X heterozygous mutation of ABCC8 gene and R269H heterozygous mutation of GLUD1 gene may lead to CHI. The inheritance mode of the mutations may be paternally or de novo.

[Mutation analysis of the GLUD1 gene in patients with glutamate dehydrogenase congenital hyperinsulinism].

OBJECTIVE: To investigate the glutamate dehydrogenase 1 (GLUD1) gene mutation of three patients diagnosed as glutamate dehydrogenase congenital hyperinsulinism (GDH-HI). METHODS: Three patients diagnosed as GDH-HI and their parents were involved in the study. PCR-DNA direct sequencing was used to analyze the exons 6,7,10,11 and 12 of the GLUD1 gene. RESULTS: In the first case, an R269H heterozygous mutation was found in the GLUD1 gene, with autosomal dominant inheritance. In the second case, there was a de novo S445L heterozygous mutation of the GLUD1 gene. No mutation was detected in the third case. CONCLUSION: In Chinese, R269H, S445L heterozygous mutation of the GLUD1 gene can lead to GDH-HI. Genetic analysis is necessary in making genetic diagnosis of congenital hyperinsulinsm.

[Blood glucose profile in children and adolescents in Beijing area].

OBJECTIVE: There are scant data about normal reference values of blood glucose (BG) in children. This study was conducted to learn the BG profile of children and adolescents in Beijing area. METHOD: The population for survey was selected as a stratified cluster sample from 8 urban and 10 rural areas in Beijing. Fasting capillary blood glucose (FCBG) was determined in 19,593 children and adolescents aged 6 to 18 years in 4 urban and 3 rural areas using haemosaccharometer model II [Roche Diagnostic, (Shanghai) Ltd]. RESULTS: There were 1 9112 (97.5%) individuals with complete records, the mean age was 12.1 +/- 3.3 years (ranged from 6 to 18.9 years); 9514 (49.8%) were boys, 9598 (50.2%) were girls, 9792 were (51.2%) from urban areas and 9320 (48.8%) from rural areas. The average level of FCBG in boys was higher than that in girls (4.7 +/- 0.5 vs. 4.5 +/- 0.5, u = 28.0, P < 0.01). Among urban children, the trend of variation of FCBG was similar between boys and girls, the levels of FCBG increased with age, the peak of FCBG was reached at 12-13 years in urban girls, and from the age of 15 years, the level of FCBG declined. In boys, the FCBG level increased slowly from 13 years of age, there was no significant variation until 17 years old, and declined at the age of 18. Among suburban children, the trend of variation of FCBG was similar between boys and girls, both of them had two peaks, from 6 to 11 years old, FCBG of both boys and girls increased with age, and both reached the first peak at the age of 11 years. While at 13 years of age, there was an obvious drop in FCBG level. From 14 years of age on, there was a rise of FCBG in both boys and girls, and the second peak of FCBG was reached at 15 and 16 years of age in girls and boys respectively. The FCBG level of urban children was higher than that of rural children (4.7 +/- 0.5 vs. 4.6 +/- 0.5, u = 13.8, P < 0.01). The level of FCBG in overweight and obese children was higher than that of normal children. More boys, more obese and more urban children had abnormal FCBG. CONCLUSIONS: The blood glucose level of children was associated with age, gender, obesity and district.

[Clinical significance of pancreatic beta-cell function in obese children with acanthosis nigricans].

OBJECTIVE: The strong relation between type 2 diabetes mellitus and obesity with acanthosis nigricans is widely concerned. This study investigated the pancreatic beta-cell function in obese children with acanthosis nigricans, so as to find out the role of insulin secretion and insulin resistance in obese children with acanthosis nigricans. METHODS: Thirty-five obese children with acanthosis nigricans (19 males and 16 females with mean age 12.8 +/- 1.5 years) were enrolled in this study. Thirty-eight obese children (21 boys and 17 girls with mean age 11.9 +/- 2.6 years) and 39 normal children (20 boys and 19 girls with mean age 11.2 +/- 2.2 years) were recruited as obese and normal control groups. The levels of serum fasting insulin, C-peptide, proinsulin and true insulin were measured in all the subjects. The ratios of proinsulin/insulin and proinsulin/C-peptide were calculated. Homeostasis model assessment was applied to assess the status of insulin resistance and basic function of pancreatic beta-cell. RESULTS: The levels of fasting insulin, C-peptide proinsulin, true insulin, the ratios of proinsulin/insulin and proinsulin/C-peptide, insulin resistance index and insulin secretion index of obese children with acanthosis nigricans, obese control children and normal control children were: 18.5 (5.0-60.5) pmol/L, 12.4 (6.1-35.8) pmol/L and 5.1 (2.0-32.8) pmol/L; 3.9 (1.3-14.0) microg/L, 2.4 (1.1-4.0) microg/L and 1.1 (1.0-4.2) microg/L; 28.8 (9.9-64.2) pmol/L, 9.5 (2.2-34.5) pmol/L and 4.2 (2.0-16.0) pmol/L; 33.0 (6.2-66.0) pmol/L, 10.6 (4.8-29.4) pmol/L and 4.5 (1.3-30.1) pmol/L; 1.2 (0.4-8.9), 0.9 (0.2-1.9) and 0.8 (0.4-2.0); 6.9 (2.5-36.6), 4.7 (1.2-12.3) and 3.6 (1.2-9.6); 5.0 (0.8-14.1), 2.6 (1.3-8.1) and 1.2(0.4-6.9); 303.3 (52.2-1,163.8), 213.6 (84.6-572.0) and 51.1 (19.1-561.4). The levels of fasting insulin, C-peptide, proinsulin, true insulin, the ratios of proinsulin/insulin and proinsulin/C-peptide, insulin resistance index and insulin secretion index in obese children with acanthosis nigricans were significantly higher than those in obese children (P < 0.001) and normal children (P < 0.001). CONCLUSION: Obese children with acanthosis nigricans had higher insulin resistance and pancreatic beta-cell dysfunction; acanthosis nigricans may be a skin sign of high risk of type 2 diabetes mellitus.

[Survey of type 1 diabetes incidence in children from 1997 to 2000 in Beijing area].

OBJECTIVE: The incidence of type 1 diabetes varied in different countries, different nations and different regions. This survey was conducted to clarify the incidence of type 1 diabetes of children in Beijing area between 1997 and 2000, to compare and analyze the difference in incidence of type 1 diabetes between the 2 periods of 1988 - 1996 and 1997 - 2000. METHOD: According to the criteria of WHO Diabetes Mondial (DIAMOND), data were collected from all the children younger than 15 years of age in Beijing area who had the onset of type 1 diabetes during Jan. 1st, 1997 to Dec. 31st, 2000. Using the capture-recapture methods, 95% confidence intervals of incidence were calculated with Poisson's distribution formula. The significance of differences was tested with Chi-square method. RESULTS: The incidences of type 1 diabetes during 1997 - 2000 were around 0.76/100 000 to 1.21/100 000. The average yearly incidence was 1.014/100 000 (95% confidence interval was 0.98/100 000 - 1.16/100 000). There was no significant difference in the incidence between 1988 - 1996 and 1997 - 2000, and it showed the same result when the incidences were adjusted by age according to the Chinese population census in 2000 (The incidence was 0.83/100 000 in 1988 - 1996 and 0.86/100 000 in 1997 - 2000, respectively). The incidence was higher in 10 - 14 year-old group than the younger groups (P = 0.002). There was no significant difference between male and female groups, either. CONCLUSIONS: No significant difference was found between the periods 1988 - 1996 and 1997 - 2000 when the average yearly incidence of type 1 diabetes of children in Beijing was compared. These results were different from the other countries' reports that the incidence of type 1 diabetes was increasing by 3% - 5% per annum. There was no significant difference between male and female groups either and there was a higher incidence of type 1 diabetes in 10 - 14 yr group than the other groups in 1997 - 2000. Although the life-style of Beijing people changed a lot, it didn't affect the incidence of type 1 diabetes in children in this area. But since many people migrated to Beijing from other parts of the country, the changes in constitutive proportions of population might have some impacts on the results of the survey.

[Association of human leukocyte antigen non-classical genes with type 1 diabetes].

OBJECTIVE: HLA-DMA and DMB are non-classical genes whose product (DM molecules) plays an important role in antigen presentation. Our present study was designed to investigate the relationship between human leukocyte antigen-DMA, -DMB and clinical status heterogeneity of type 1 diabetes. METHODS: A total of 80 children (male 36, female 44) with type 1 diabetes were selected as research subjects. Diagnosis of type 1 diabetes was made according to WHO criteria. The range of age at onset of type 1 diabetes was 2.5 - 14 years. Ninety-one healthy adult blood donors were selected as normal controls. Polymerase chain reaction and dot blot hybridization techniques were used to classify DMA and DMB alleles. Patients with type 1 diabetes were classified into different groups according to different clinical status, including sex, age of onset, ketosis onset situation on diagnosis, remained function of islet beta cell, etc. Then distribution of DM susceptive alleles and heterodimer in different clinical groups were studied. RESULTS: The frequencies of DMA * 0103 and DMB * 0103 alleles in patients were significantly increased (50% vs. 8%, 43% vs. 22%, respectively), these two alleles confer susceptibility to type 1 diabetes in Chinese. The frequencies of DMA * 0103/DMB * 0102, DMA * 0103/DMB * 0103 and DMA * 0103/DMB * 0101 heterodimers were also increased in the patients. The above heterodimers confer predisposition to type 1 diabetes. Both DMB * 0103 allele and DM susceptive heterodimers are related to islet beta cell function on diagnosis. The patients with DMB * 0103 allele or DM susceptive heterodimers were significantly increased in the patients with lower C-peptide level on diagnosis (56% vs. 29%; 58% vs. 34% respectively). DM heterodimes were also related to onset age and ketosis-onset-situations of the patients. The patients carrying DM susceptive heterodimers had higher probability to suffer type 1 diabetes before 10 years of age and had the predisposition to ketosis or ketoacidosis on diagnosis. CONCLUSION: HLA- class II non-classical alleles-DMA and DMB may play an important role in pathogenesis of type 1 diabetes, and clinical status heterogeneity of type 1 diabetes may be related to genetic mechanism.