Shigetaka Sugihara

Criteria for medical intervention in obese children: A new definition of ‘Obesity disease’ in Japanese children

The Committee of the Japan Society for the Study of Obesity reported the new criteria for ‘obesity disease’ for Japanese adults in 2000. We defined the criteria for the diagnosis of obesity in children with medical problems, corresponding to the ‘obesity disease’ criteria in adults. Obesity in childhood was defined as follows: percentage of overweight (POW) and body fat exceeded the criteria. ‘Obesity disease in childhood’ was defined as obesity associated with health or medical problems, and with indications for medical intervention. Medical problems with indications for immediate intervention were grouped as A problems, which consisted of (i) hypertension; (ii) sleep apnea or hypoventilation; (iii) Type 2 diabetes mellitus or impaired glucose tolerance; and (iv) increased waist circumference or accumulation of visceral adipose tissue. Metabolic derangements or equivalent associated with obesity were grouped as B problems: (i) liver dysfunction; (ii) hyperinsulinemia; (iii) hypercholesterolemia; (iv) hypertriglyceridemia; (v) low serum high‐density lipoprotein cholesterol; (vi) acanthosis nigricans, and (vii) hyperuricemia. Obese children over 5 years of age with following conditions were diagnosed as ‘obesity disease in childhood’: (i) any ‘A problem’, (ii) POW ≥ 50% and any ‘B problem’, or (3) POW < 50% and more than one ‘B problem’ or equivalent. We decided to take physicosocial problems related to obesity into consideration as the criteria. The resultant criteria are proposed by the Committee for Research of Appropriate Body Build in Children * .

Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children.

Japanese IDDM patients have been demonstrated to have unique and different HLA associations from white patients. To elucidate the effect of HLA-associated genetic factors on the clinical heterogeneity of IDDM in Japanese people, HLA-DRB1, DQA1, and DQB1 genotypes in 88 childhood-onset Japanese IDDM patients were examined by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) or sequence-specific primers (SSP). Of the 88 IDDM patients, 26 (29.5%) had DRB1*0405-DQA1*0302-DQB1*0401/X (DR4-DQ4/X), 38 (43.2%) had DRB1*0901-DQA1*0302-DQB1*0303/X (DR9-DQ9/X), and 9 (10.2%) were DR4/9-DQ4/9 heterozygous in the present study (X does not contain protective alleles). Clinical heterogeneity such as age distribution at onset, prevalence and serum level of anti-GAD antibodies (GADAb), and residual pancreatic β-cell function after diagnosis were compared between patients with HLA-DR4-DQ4 and DR9-DQ9. The frequency of DR9-DQ9 genotype was significantly higher in the younger (0–10 years) than in the older (11–16 years) age-group of onset, but the frequency of DR4-DQ4 was higher in the older (11–16 years) age-group. Although no association of DR-DQ genotypes with the prevalence and serum level of GADAb was found among newly diagnosed patients, long-standing DR9-DQ9 patients had significantly higher levels of GADAb than those with DR4-DQ4. While no difference in time course of serum C-peptide (CPR) levels was detected between GADAb+ and GADAb− patients, a remarkable difference was demonstrated between DR9-DQ9 and DR4-DQ4 patients. The residual pancreatic β-cell function was retained more in patients with DR4-DQ4 than in those with DR9-DQ9 at diagnosis through 12–18 months after diagnosis. These results suggest that the DR9-DQ9 genotype may induce stronger autoimmune destructive response (T-helper 1 function) against target β-cells than the DR4-DQ4 genotype does. Our findings may warrant further studies on the association of diabetogenic autoimmune response with HLA class II molecules and contribute to a clarification of interracial differences in HLA-encoded susceptibility to IDDM.

Bone Maturation Reflects the Secular Trend in Growth

The aim of this study was to compare a series of X-rays from the mid–1990s with another taken in the mid–1980s in order to test the possibility that environmental causes affect the skeletal maturation. The first group of subjects included a total of 1,057 girls and 1,055 boys participating in a project for Japan and China health research in 1986. The second group of subjects included a total of 382 girls and 629 boys participating in a project for bone mineral density research in 1996. The skeletal maturity score using the Tanner-Whitehouse 2-RUS method was used as the fundamental datum. This score was used to represent each group. The Wilcoxon’s rank sum test was applied to examine the significance of the difference between the 1986 and the 1996 groups. The 1996 children had not matured more than the 1986 children; children in both groups reached the given scores at almost the same ages. In girls, there was little difference between the groups at 7 years of age, but it declined from 8 years of age onward. Some apparent differences arose at ages 14 and 15, but ceased by age 16 in girls. In boys, no differences were found in those aged from 7 to 17 years, except for 12-year-olds. We did not detect much of a difference in bone maturation between the 1986 and 1996 groups of children, and no differences in height during the same period. Our findings suggest that bone maturation reflects the secular trend in growth.

Metabolic syndrome in youths

Abstract:  The metabolic syndrome (MetS), characterized by a clustering of cardiovascular disease and type 2 diabetes (T2DM) risk factors, has become prevalent in children and adolescents in recent years. However, the reported prevalence data on the MetS in youths has varied markedly, in large part, because of the disagreement among the variously proposed definitions of the MetS. Obesity is defined by using body mass index, waist circumference, or percent overweight, pointing to the need for standardized use of anthropometric variables to define obesity with a well‐defined reference year for each ethnic population. In addition, slightly different cutoff values are used for triglycerides, high‐density lipoprotein cholesterol, blood pressure, and fasting plasma glucose. Therefore, International Diabetes Federation recently proposed unified, easy‐to‐use criteria for diagnosing the MetS in youths. To provide insight into the mechanisms underlying the MetS in youths, the degree of insulin sensitivity/resistance and its correlation with the serum lipid and blood pressure levels have been evaluated. In addition, the serum levels of adipocytokines, such as adiponectin, leptin, tumor necrosis factor‐α, resistin, interleukin‐6, plasminogen activator inhibitor‐1, and their correlation with childhood obesity have been extensively investigated. Recommendations for future research include exploring ways to assess visceral adiposity, to identify better biochemical markers for prediction of T2DM and disease progression, and to effectively intervene to prevent the MetS in youths.

Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to Type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies

OBJECTIVE Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA‐2 in Japanese children with Type 1 diabetes.

Discharge diagnoses in infants with apparent life‐threatening event

Background : There are various identifiable diseases or conditions that can be associated with an apparent life‐threatening event (ALTE) in infancy. The present study was carried out to investigate the etiology of ALTE based on the discharge diagnoses.

Impact of leptin and leptin-receptor gene polymorphisms on serum lipids in Japanese obese children

Aim:  Leptin is one of the factors affecting serum lipid profile. We investigated the association between serum lipids and leptin/leptin receptor (LEPR) gene polymorphisms in obese Japanese children.

Wolfram Syndrome in the Japanese Population; Molecular Analysis of WFS1 Gene and Characterization of Clinical Features

Background Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. Methodology The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. Principal Findings Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. Conclusion/Significance This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

Threshold values of visceral fat and waist girth in Japanese obese children

Abstract Background : In order to define the diagnostic criteria for visceral adipose tissue (VAT) accumulation and abdominal obesity in Japanese youths, a cross‐sectional, multicenter study was conducted.

Analysis of weight at birth and at diagnosis of childhood‐onset type 2 diabetes mellitus in Japan

Background:  The prevalence of childhood‐onset type 2 diabetes mellitus (T2DM) has increased dramatically over the past two to three decades in Japan, but epidemiological and clinical data remain limited. Several epidemiological studies stress the importance of elucidating the pathophysiology of prenatal nutrition and other intra‐uterine environmental factors and the risk of T2DM in each of the different populations. We examined the associations of weight at birth, weight at diagnosis of T2DM, and clinical characteristics of childhood‐onset T2DM.