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Insulin resistance at diagnosis was investigated in Japanese children with type 2 diabetes mellitus (T2DM).A total of 160 children with T2DM were divided into groups on the basis of percent overweight at time of diagnosis: group A (n = 28),20%; group B (n = 55), 20-39%; group C (n = 37), 40-59%; group D (n = 40), ≥ 60%. Indicators of insulin resistance at diagnosis were compared among the four patient groups, and also between the children with T2DM and the 201 age-matched normal Japanese children.There were no significant differences in plasma glucose (PG) levels among the four patient groups. The mean concentration of fasting plasma immunoreactive insulin (IRI) was significantly higher in group D than in groups A and B (39.2 µU/mL vs 16.2 µU/mL and 24.1 µU/mL, P0.05, respectively). The mean homeostasis model assessment (HOMA-R) was significantly higher in group D than in all the other three groups (17.6 vs 7.8, 10.8 and 12.7, P0.05, respectively). The indicators HOMA-R and fasting IRI were significantly higher in each diabetes group, even in non-obese group A, than in normal children (P0.01, respectively).Japanese children with T2DM had insulin resistance at diagnosis regardless of percent overweight, and the degree of insulin resistance gradually increased with rise in percent overweight.

The etiology of type 1 diabetes (T1D) is heterogeneous and is according to presence or absence of pancreatic autoantibodies divided into two subtypes: type 1A (autoimmune-mediated) and type 1B (non-autoimmune-mediated). Although several genes have been linked to type 1A diabetes, the genetic cause of type 1B diabetes in Japanese individuals is far from understood.The aim of this study was to test for monogenic forms of diabetes in auto antibody-negative Japanese children with T1D.Thirty four (19 males and 15 female) unrelated Japanese children with glutamate decarboxylase (GAD) 65 antibodies and/or IA-2A-negative T1D and diabetes diagnosed at5 yr of age were recruited from 17 unrelated hospitals participating in the Japanese Study Group of Insulin Therapy for children and adolescent diabetes (JSGIT). We screened the INS gene and the KCNJ11 gene which encode the ATP-sensitive potassium cannel by direct sequencing in 34 Japanese children with T1D.We identified three novel (C31Y, C96R, and C109F) mutations and one previously reported mutation (R89C) in the INS gene in five children, in addition to one mutation in the KCNJ11 gene (H46R) in one child. These mutations are most likely pathogenic and therefore the cause of diabetes in carriers.Our results suggest that monogenic forms of diabetes, particularly INS gene mutations, can be detected in Japanese patients classified with type 1B. Mutation screening, at least of the INS gene, is recommended for Japanese patients diagnosed as autoantibody negative at5 yr of age.

The overall annual IDDM incidence rates by area in Japan for 1985-1989 for children 0-14 years of age at diagnosis were from 1.65 to 2.07 per 100,000. The incidence in males and females did not show any temporal trends during the period between 1980 and 1989. The prevalence of IDDM was about 1 per 10,000. The clinical features at diagnosis among Japanese IDDM children identified during the 2-year period between 1979 and 1980 were as follows. Fourteen percent of the cases were in coma and 12% of the cases were asymptomatic at diagnosis. There is a suggestion that slow onset IDDM is often seen in Japan. In these children, the decline of serum CPR levels and the prevalence of ICA (islet cell antibodies) over the course of diabetes was slower than in those with an abrupt onset classical IDDM. During the period from 1975 through 1990 the incidence rates of NIDDM in school children showed as much as an approximate 1.5-fold increase along with a similar increase in the prevalence of obesity. About eighty percent of these NIDDM children were obese. A predominance of female children developing diabetes was seen in both type of diabetes, IDDM and NIDDM, in Japan. Non-obese type NIDDM in children was more common in females than in males. It is interesting to note that the mean height of Japanese children with IDDM was not different from the national average, but children with NIDDM were significantly taller than the national average.

Yorifuji T, Fujimaru R, Hosokawa Y, Tamagawa N, Shiozaki M, Aizu K, Jinno K, Maruo Y, Nagasaka H, Tajima T, Kobayashi K, Urakami T. Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Background: In Asians, mutations in the known maturity-onset diabetes of the young (MODY) genes have been identified in only G mutation was first tested by the polymerase chain reaction restriction fragment length polymorphism analysis for maternally inherited families. Then, all coding exons and exon–intron boundaries of the HNF1A, HNF1B, GCK, and HNF4A genes were amplified from genomic DNA and directly sequenced. Multiplex ligation-dependent probe amplification analysis was also performed to detect whole-exon deletions. Results: After excluding one patient with a mitochondrial 3243A>G, mutations were identified in 38 (48.1%) patients; 18 had GCK mutations, 11 had HNF1A mutations, 3 had HNF4A mutations, and 6 had HNF1B mutations. In patients aged 9 yr of age, mutations were identified less frequently (45.1%), with HNF1A mutations being the most frequent. A large fraction of mutation-negative patients showed elevated homeostasis model assessment (HOMA) insulin-resistance and normal HOMA-β indices. Most of the HNF1B mutations were large deletions, and, interestingly, renal cysts were undetectable in two patients with whole-gene deletion of HNF1B. Conclusion: In Japanese patients with pediatric-onset MODY-type diabetes, mutations in known genes were identified at a much higher frequency than previously reported for adult Asians. A fraction of mutation-negative patients presented with insulin-resistance and normal insulin-secretory capacities resembling early-onset type 2 diabetes.

The aim of this study was to investigate the association between plasma glucose (PG), HbA1c and plasma glucagons levels in children with type 1 diabetes to determine the influence of plasma glucagon on their glycemic control.The study was conducted in 60 Japanese children, aged 13.3 ± 4.6 years, with type 1 diabetes for at least 3 years of diabetes. Most of the subjects had absent pancreatic β-cell function. We compared the glucagon levels among patient groups stratified according to the 2-hour postprandial levels (50, 50-99, 100-199, 200-299, and ≥ 300 mg/dL), and the HbA1c levels (7.0, 7.0-7.9, 8.0-8.9, and ≥ 9%).The mean 2-hour postprandial PG, HbA1c and plasma glucagon levels were 174 ± 97 mg/dL, 7.7 ± 1.3% and 84.0 ± 32.6 pg/mL, respectively. The glucagon levels were highly correlated with the PG levels (r=0.553, P0.0001) and mildly correlated with the HbA1c levels (r=0.301, P=0.0192). Patients with high PG levels had significantly higher levels of glucagon as compared with those with lower PG levels (139.4 ± 47.2, 78.4 ± 17.3, 82.4 ± 21.0, 98.3 ± 29.2 and 93.8 ± 18.3 pg/mL, P=0.0009). On the other hand, there were no significant differences in plasma glucagon levels among patient groups stratified according to HbA1c levels (P=0.1566), however, patients with HbA1c levels ≥ 9% had significantly higher levels of glucagon than those with HbA1c levels7% (113.3 ± 53.4 vs 80.8 ± 18.4 pg/mL, P=0.0291).These results suggest that patients with high PG are likely to have high concentrations of plasma glucagon, which may aggravate glycemic control progressively, leading to elevation of HbA1c levels.

Department of Pediatrics, Uddevalla Hospital, Uddevalla,SwedenCorresponding author:Hans-Jacob Bangstad, MDDepartment of PaediatricsOslo University HospitalUlleval˚Kirkeveien 166Oslo N-0407Norway.Tel: 0047-22118765;fax: 0047-22118663;e-mail: haba@uus.noConflicts of interest: RH has received lecture honoraria fromNovo Nordisk, Lilly, Sanofi-Aventis, Medtronic and Roche. PJ-Chas received lecture fees from Eli Lilly, Novo-Nordisk, Sanofi-Aventis, Abbott, Bayer, Medtronic and Roche.The remainingauthors have declared no potential conflicts.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

Background: Several studies have shown that the autoimmune features in young children with type 1 diabetes differ from those in older pediatric patients as well as adults. The purpose of the present study was to examine the prevalence of β-cell autoantibodies, glutamic acid decarboxylase antibodies (GADA), and antibodies to the protein tyrosine phosphatase-related molecule IA-2 (IA-2A), at the time of diagnosis in Japanese children with type 1 diabetes who were younger than 5 years at diagnosis. Methods: Subjects consisted of 23 Japanese children (nine boys, 14 girls), 3.1 ± 1.3 years of age at diagnosis (range, 1.1–4.8 years). The majority had severe metabolic decompensation accompanied by complete absence of β-cell function at diagnosis. We found 41.7% to have suffered viral infections before disease onset. Results: The prevalence of antibodies to GAD and IA-2 at diagnosis in these subjects was significantly lower than those in older patients diagnosed after 5 years of age (31.6 % vs 86.3% and 47.1% vs 82.5%, P

It has long been understood that psychosocial issues are important to an understanding of diabetes among young people. The diagnosis and management of diabetes places a substantial burden on youths and their families. This burden may disrupt normal developmental processes, and can have a major impact on psychosocial adjustment and successful disease management. The multinational DAWN Study was a pioneering effort to identify psychosocial barriers to optimal health and quality of life of people with diabetes and new ways to overcome those barriers. The DAWN Study interviewed more than 5000 adults with diabetes and almost 4000 diabetes care professionals, but did not include children and young people with diabetes, their families, or their care providers because it was recognized that diabetes in young people presents different psychosocial issues and challenges than diabetes in adults, and that a separate study would be required to identify opportunities to improve outcomes among young people with diabetes and their families. This realization gave rise to theDAWNYouth WebTalk Study. The objectives of this study were to: • gain understanding of the challenges and issues facing young people with diabetes and those with responsibility for supporting them; • identify new avenues for improving the psychosocial management of diabetes among young people; • stimulate new efforts to improve care for young people with diabetes and their families. This paper presents an initial overview of the methods and findings of theDAWNYouthWebTalk Study and discusses some of the implications of those findings.

AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries.METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood.RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen.CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres.

We compared the frequencies of antibodies to GAD (GADA) and IA-2 (IA-2A) and their titers at diagnosis in 48 Japanese children with slowly progressive form of type 1 diabetes (SPT1D) and 70 children with rapidly progressive form of type 1 diabetes (RPT1D). High prevalences of both GADA and IA-2A were found at diagnosis in both the patients with SPT1D (70.8% and 75.0%), and those with RPT1D (71.4% and 71.9%). Most patients, regardless of the form of type 1 diabetes, were positive for both antibodies, though 6 of the 9 patients less than 5 years of age were negative for both antibodies. GADA titers below 50 U/ml were significantly more frequent in the patients with SPT1D (79.4% vs. 38.0%, p=0.0002), and titers above 100 U/ml significantly more frequent in those with RPT1D (38.0% vs. 11.8%, p=0.0081). No significant association was noted between the titers of IA-2A and the clinical form of type 1 diabetes. These results suggest that low GADA titers may reflect mild autoimmune destruction of beta-cells with slow disease progression. Titers of IA-2A do not appear to reflect the degree of autoimmune damage of the beta-cells.

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-alpha, 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.

The efficacy of continuous subcutaneous insulin infusion (CSII) of the rapid-acting insulin analogue, insulin aspart, was evaluated in 26 patients with childhood-onset type 1 diabetes aged between 6 and 18 yr who had been on basal-bolus therapy (multiple daily injection (MDI) of regular human insulin or rapid-acting insulin and intermediate/long-acting insulin). The glycemic control in the patients was evaluated based on changes in the clinical parameters and the patient quality of life (QOL) was evaluated by using the insulin therapy-related QOL questionnaire. Twenty two patients continued CSII during the 6-mo study period. The mean HbA1c was 7.8 ± 1.8% at baseline and it decreased to 7.4 ± 0.8% at 6 mo after the start of the CSII. Overall, no decrease of the QOL post-CSII initiation was noted. The possible superiority of CSII as compared to MDI was suggested for patients who "eat out" or "have to look for an appropriate place for insulin injection." Aside from an inadequate indwelling needle placement detected after the initiation of CSII in several patients, no adverse event associated with NovoRapid(®) was seen. In conclusion, CSII of rapid-acting insulin appears to be a useful therapy for patients with childhood-onset type 1 diabetes.

To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis.This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11-18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005.Mean A1C was 8.2 +/- 1.4%, with substantial variation between centers (mean A1C range 7.4-9.2%; P0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 +/- 2.0% vs. 8.2 +/- 1.4% for those with language difficulties vs. those without, respectively; P0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C.Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.

To clarify the relationship between systemic factors and the development of retinopathy in patients with type 2 childhood diabetes.We evaluated the relationship between retinopathy incidence and systemic factors (i.e., sex, age at diagnosis, and mean HbA(1c)) in 36 patients (11 boys and 25 girls).Ten of the 36 cases (28%) developed retinopathy during a mean observation period of 7 years and 11 months. Retinopathy was found only in female patients. The mean HbA(1c) value correlated significantly with the onset of retinopathy. The incidence of retinopathy in the patients with mean HbA(1c) values less than 8.0% was 0% at 5 and 10 years, and 5% at 15 years. On the other hand, the incidence of retinopathy in the patients with mean HbA(1c) values of 8.0% or more was 44% at 5 years, and 56% at 10 and 15 years after the diagnosis of diabetes.As female patients with mean HbA(1c) values of 8.0% or more have a high risk of developing retinopathy, strict blood glucose control and frequent ophthalmologic examinations are necessary.

The aim of this study was to evaluate the efficacy of long-acting insulin analogue glargine (G) changing from NPH in basal-bolus therapy for Japanese children and adolescents with type 1 diabetes mellitus (DM1). Thirty patients (11 M, 19 F) with DM1 aged 13.3 +/- 4.5 years were included in the study. Mean fasting blood glucose level was significantly decreased (baseline: 142.5 +/- 39.3 vs 127.1 +/- 24.0, 129.0 +/- 29.1, 121.1 +/- 26.0 mg/dl at 3, 6, 12 months, respectively, p

Results The median values of HbA1c (% of glycemic goal

We previously reported that the annual incidences of children with type 2 diabetes as detected by urine glucose screening at school in Tokyo during 1981–1995 were significantly higher than the incidence in 1974–1980 (1). We evaluated recent changes in the annual incidence of childhood type 2 diabetes in Tokyo. The results were analyzed using Fisher’s exact probability test. From 1974 to 2004, a total of 9,242,259 school students were tested for glucosuria to detect diabetes. A total of 236 children were diagnosed as having type 2 diabetes through this screening program. Overall, 83.9% …

The worldwide increase of type 2 diabetes in youth is a critical problem. It is important to prevent the development of type 2 diabetes in high-risk individuals. In many patients with type 2 diabetes, hyperglycemia can be reduced with appropriate changes in diet and exercise. However, some patients with persistent HbA1c levels7.5% need pharmacological therapy to improve their metabolic control. A variety of oral hypoglycemic agents, including alpha-glucosidase inhibitors, sulfonylureas and metformin, are available. Metformin is widely used in pediatric patients and is considered to be the most effective oral agent. In some cases, combination therapy with metformin and sulfonylureas or use of insulin is more effective to stabilize glycemia. The approach to insulin therapy in type 2 diabetes often differs from that used in type 1 diabetes. The therapeutic approach to childhood type 2 diabetes should be individually tailored.

OBJECTIVE—This study investigates the annual incidence and clinical characteristics of type 2 diabetes among school-aged children as detected by urine glucose screening from 1974 to 2002 in the Tokyo metropolitan area. RESEARCH DESIGN AND METHODS— In total, 8,812,356 school children were examined for glucosuria. Morning urine was used for the analysis. When the urine was positive for glucose, an oral glucose tolerance test was carried out to confirm diabetes. RESULTS—In all, 232 students were identified to have type 2 diabetes. The overall annual incidence of type 2 diabetes was 2.63/100,000. The annual incidence after 1981 was significantly higher than that before 1980 (1.73 vs. 2.76/100,000, P < 0.0001). The annual incidence was significantly higher for junior high school students compared with primary school students (0.78 vs. 6.43/100,000, P < 0.0001). The overall male-to-female ratio of students with type 2 diabetes was 1.0:1.19 (P = 0.296), but it was 1.0:1.56 (P = 0.278) for primary school students. Overall, 83.4% of children with diabetes were obese (≥20% overweight). However, nonobese girls ( CONCLUSIONS—We confirmed that the incidence of young people with type 2 diabetes increased after 1981 in the Tokyo metropolitan area. The increase in the frequency of this disorder seemed to be strongly related to an increasing prevalence of obesity. Age and genetic susceptibility may be associated with the occurrence of type 2 diabetes.

Urine glucose screening at school implemented in Japan is useful for detecting childhood type 2 diabetes at the early stage of the disease. Most patients detected by the screening can improve hyperglycemia and reduce overweight within one to three months by changing lifestyle with diet and exercise. For patients who are unable to alter their lifestyle and for those who have hyperglycemia despite maintaining these changes, a variety of oral hypoglycemic agents, including α-glucosidase inhibitors, sulfonylureas, glitinides, metformin, thiazolidenediones, and insulin are available. Metformin is considered to be the most effective oral agent as monotherapy for Japanese young persons with type 2 diabetes, because most of them are obese with insulin resistance. The approach to insulin therapy in patients with type 2 diabetes often differs from that most frequently used in patients with type 1 diabetes. Adjustment of the dose of insulin at each injection using sliding scales or algorithms is not required in most cases. In some cases, combination therapy with metformin and sulfonylureas or use of insulin is more effective for stabilization of blood glucose values. Therapeutic means for childhood type 2 diabetes should be variable depending on each patient’s characteristics.

Idiopathic type 1 diabetes, by definition, has no known etiology. Although only a minority of type 1 diabetic patients fall into this category, it is reported that the majority are of African or Asian descent. Individuals with this form of diabetes are considered to present heterogeneous clinical manifestations (1). Imagawa et al. (2) reported a new subtype of type 1 diabetes characterized by fulminant onset, absolute insulin deficiency, and absence of β-cell autoimmunity in Japanese adults. We reported similar cases of idiopathic …

Objective: to clarify and confirm the renoprotective effects of ACEIs in Japanese type 1 diabetics. Research design and methods: a double-blind randomized study using two ACEIs, imidapril (a prodrug of imdaprilat without an SH-residue) and captopril as well as placebo was performed. Seventy-nine eligible cases were randomized to receive captopril 37.5 mg ( n =26), imidapril 5 mg ( n =26) or their placebos ( n =27) daily in a double-blind manner. Results: urinary albumin excretion (UAE), determined every half year, was significantly decreased by the ACEIs (placebo vs. ACEIs F =11.316, P =0.001, placebo vs. captopril F =4.260, P =0.043, placebo vs. imidapril F =14.341, P 1C levels and systolic blood pressure (BP) between the three groups were not different, glycemic and BP control significantly affected UAE. Systolic BP in the placebo group tended to be higher by 7–10 mmHg throughout the study. Conclusions: these results suggest that the ACE inhibitors, imidapril and captopril, prevent the increase in UAE in micro and macroalbuminuric patients with type 1 diabetes mellitus and that the target BP might be less than 130/80 mmHg.

To clarify the characteristics of idiopathic type 1 (type 1B) diabetes mellitus (DM), we compared the clinical features of immune-mediated type 1 (type 1A) DM and type 1B DM in 85 Japanese children and adolescents with DM. The prevalence of type 1B DM was 16.5%. The patients with type 1B DM were significantly younger at diagnosis and had a higher frequency of preceding viral infection before onset, compared to those with type 1A DM. They displayed more severe metabolic decompensation with a higher frequency of ketoacidosis at diagnosis than patients with type 1A DM. They had strong, HLA-defined genetic susceptibility, similar to that in type 1A DM. Some patients with type 1B DM exhibited a remarkably abrupt onset and rapid loss of beta-cell capacity. From these findings, it is considered that type 1B DM differs from type 1A DM with respect to age at onset and the trigger event, such as viral infection, leading to rapid destruction of beta-cells without autoimmunity in the etiology of the disease.

Non-insulin dependent diabetes (NIDDM) was diagnosed in 188 of more than 7 million Tokyo schoolchildren tested between 1974 and 1994 for glycosuria followed by oral glucose tolerance testing. The incidence rate of NIDDM in youth has continued to increase since 1976. While the daily energy intake has not changed significantly, the consumption of animal protein and fat by the Japanese population has greatly increased during the past two decades, and this change in diet, with low levels of physical activity, may exacerbate insulin resistance and glucose intolerance. Clin Pediatr. 1998;37:111-116

The risks of complications due to chronic diabetes are indicated by an increase in average blood glucose levels and the range of blood glucose level fluctuation. Postprandial hyperglycemia should be the target of glycemic control in clinical practice. There are few studies on the time to peak postprandial glucose levels in children. Therefore, we investigated the time to peak in childhood-onset diabetic patients using a continuous glucose monitor system (CGMS). Twenty-seven patients with childhood-onset diabetes were included (male to female ratio, 9:18): 20 had type 1 diabetes, 3 had type 2 diabetes, and 4 had other types of diabetes. All patients underwent CGM on admission using the CGMS; their blood glucose levels were monitored up to 3 h after each meal. The time to peak postprandial blood glucose levels was retrospectively determined. The CGMS recorded the postprandial glucose levels 266 times. Average peak time of postprandial blood glucose and average blood glucose excursion were 96.3 ± 56.7 min and 86.5 ± 56.7 mg/dL, respectively. The average peak time and average blood glucose excursion were as follows: type 1 diabetes, 91.2 ± 56 min and 80.0 ± 62.3 mg/dL; type 2 diabetes, 92.7 ± 42.6 min and 105.8 ± 52.2 mg/dL; other types of diabetes, 112.1 ± 50.7 min and 82.8 ± 42.7 mg/dL. The average peak time and blood glucose excursion for meals were as follows: breakfast, 108.4 ± 53.7 min and 92.6 ± 60.6 mg/dL; lunch, 93.2 ± 51.8 min and 83.4 ± 48.6 mg/dL; and dinner, 88.3 ± 54.0 min and 83.9 ± 60.0 mg/dL. There was no correlation between time to peak postprandial blood glucose and HbA1c levels. The average time to peak postprandial blood glucose levels was approximately 90 min in both type 1 and 2 diabetes patients. The time to peak postprandial blood glucose levels reported here was delayed as compared to other studies on Japanese healthy adults with childhood-onset diabetes. The time to peak postprandial blood glucose levels in childhood-onset diabetic patients was approximately 90 min. As an indicator of glycemic control in childhood-onset diabetic patients, the CGMS was considered useful for determining the postprandial blood glucose levels in clinical practice.

OBJECTIVE To elucidate the significance of clinical and immunogenic heterogeneity in Japanese children with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS Serial changes in the prevalence of islet cell antibodies (ICAs) and in ICA titer were monitored for 10 years after diagnosis in 34 IDDM children, 17 with abrupt onset and 17 with slow onset, whose durations of disease were > 5 years. RESULTS In slow-onset IDDM children, enough β-cell function was maintained in the early phase of the disease within 2 years after diagnosis. There was a high prevalence of ICAs in children with both forms of IDDM at the time of diagnosis (abrupt onset 94% slow onset 82%). However, the decline in the frequency of ICAs in slow-onset IDDM seemed less marked than in abrupt-onset IDDM after a duration of ≥ 1 year (47 vs. 82%, 1–3 years; 24 vs. 47%, 3–5 years; 24 vs. 47%, 5–7 years; 18 vs. 53%, 7–10 years, P < 0.05). In terms of changes in ICA titer, abrupt-onset IDDM children initially had high ICA levels of 160–320 Juvenile Diabetes Foundation units (JDF U), but these titers decreased rapidly after the 1st year. On the other hand, slow-onset IDDM children tended to continue to be ICA+ for a relatively long period with low titers of 20–40 JDF U. Among 12 children who remained ICA+ for > 5 years, slow onset was noted in 67% while abrupt onset was seen in only 33%. CONCLUSIONS From these results, we speculated that changes in ICA titer reflect the slow autoimmune destruction of pancreatic β-cells. It may be probable that immunogenic factors as well as environmental factors could affect the clinical features in the early phase of IDDM in children.

A 14 year old boy with common variable immunodeficiency (CVID) had regularly recurring episodes of severe infections independently of the serum gamma-globulin level. Serial blood counts revealed that this patient also had cyclic neutropenia. Recently, recombinant human granulocyte colony-stimulating factor (rhG-CSF) was reported to be an effective treatment for this disease. We tried rhG-CSF therapy for this patient and a prompt increase in the neutrophil count was noted. However, the cyclic alterations and duration of the nadir of the neutrophil count were not altered, which suggested that rhG-CSF has a variable efficacy in at least some patients with cyclic neutropenia.

These 62 patients with the Kabuki make-up syndrome (KMS) were collected in a collaborative study among 33 institutions and analyzed clinically, cytogenetically, and epidemiologically to delineate the phenotypic spectrum of KMS and to learn about its cause. Among various manifestations observed, most patients had the following five cardinal manifestations: 1) a peculiar face (100%) characterized by eversion of the lower lateral eyelid; arched eyebrows, with sparse or dispersed lateral one-third; a depressed nasal tip; and prominent ears; 2) skeletal anomalies (92%), including brachydactyly V and a deformed spinal column, with or without sagittal cleft vertebrae; 3) dermatoglyphic abnormalities (93%), including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; 4) mild to moderate mental retardation (92%); and 5) postnatal growth deficiency (83%). Thus the core of the phenotypic spectrum of KMS is rather narrow and clearly defined. Many other inconsistent anomalies were observed. Important among them were early breast development in infant girls (23%), and congenital heart defects (31%), such as a single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus, aneurysm of aorta, transposition of great vessels, and right bundle branch block. Of the 62 KMS patients, 58 were Japanese, an indication that the syndrome is fairly common in Japan. It was estimated that its prevalence in Japanese newborn infants is 1/32,000. All the KMS cases in this study were sporadic, the sex ratio was even, there was no correlation with birth order, the consanguinity rate among the parents was not high, and no incriminated agent was found that was taken by the mothers during early pregnancy. Three of the 62 patients had a Y chromosome abnormality involving a possible common breakpoint (Yp11.2). This could indicate another possibility, i.e., that the KMS gene is on Yp11.2 and that the disease is pseudoautosomal dominant. These findings are compatible with an autosomal dominant disorder in which every patient represents a fresh mutation. The mutation rate was calculated at 15.6 X 10(6).

We treated six newly diagnosed children with insulin-dependent diabetes mellitus (IDDM) with high-dose gammaglobulin therapy in a clinical trial of immunomodulation. Approximately 400 mg/kg/day of polyethylene glycol-treated gammaglobulin was given by intravenous injection for four to five days. After the initial therapy, four out of six patients showed an elevation of serum CPR and a decline of their insulin requirements; this indicates an improvement of insulin secretory function of pancreatic beta cells. A second course of gammaglobulin was given to four patients one year after the initial therapy, and the same results were observed in two out of four patients. These results suggest that high-dose gammaglobulin might provide some protection against the deterioration of endogenous insulin secretion in children with IDDM.

Hyperglycemia and other metabolic derangements resulting from absolute or functional deficiency of insulin are accompanied by typical signs and symptoms of diabetes. The clinical signs and the findings of hyperglycemia over 200 mg/dl should establish a diagnosis of diabetes mellitus. An oral glucose tolerance test (O-GTT) is rarely necessary for diagnosis of diabetes in a child. A small proportion of children, however, present less severe symptoms, and may require an O-GTT. Approximately 14% of IDDM children were in coma at diagnosis in Tokyo, and 11 onset deaths (0.94%) were observed among the 1172 newly diagnosed IDDM cases in Japan. A significant decline in the onset mortality, however, has been observed in the past 20 years in Japan in association with the improvement of early management of childhood diabetes. The clinical distinction of IDDM from NIDDM is often difficult in diabetic children of Oriental origin without obesity. Japanese IDDM can be divided into two forms, abrupt and slow onset forms, but they may be essentially the same disease. There was no difference in the frequency of being tested positive for circulating ICA between the two groups of the patients. But a difference in the frequency of HLA DR4 and DRW9 was noticed between the two groups. Clinical features of 107 children with NIDDM were studied and about 75% of these cases were obese. All of them can be detected by routine urinalysis for glucose. Diet and exercise therapy in most of the newly diagnosed patients resulted in remission but some of them may require insulin or an oral hypoglycemic agent to get better glycemic control.

The initial course of Type 1 (insulin-dependent) diabetes mellitus was studied in two groups of Japanese children, i.e. 21 patients with abrupt onset (Group A) and 19 patients detected by urine glucose screening at school with minimal or no symptoms (Group B). There was no statistical difference in mean age at diagnosis between Group A and B (11 +/- 3 years vs 11 +/- 3 years). Group A patients revealed a rapid deterioration of pancreatic B-cell function, but there was evident recovery of the B-cell function from 3 to 9 months following initial treatment. The B-cell capacity in Group B was self maintained until 24 months after diagnosis. Thereafter, even these patients exhibited a progressive decline in the B-cell function. The two groups had a similar incidence of islet cell antibodies at diagnosis (58% vs 69%). However, human leukocyte antigen studies revealed that patients in Group A had a significantly higher prevalence of DR4 and DRW9 than those in Group B (p less than 0.01). These results suggest that in Japanese children there are two forms of diabetes, an abrupt and a slow onset form, which are clinically different and which also seemed to be genetically independent types, or possibly the same disease diagnosed at different stages.