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Aims/Introduction We examined the impact of scanning frequency with flash glucose monitoring on glycemic control in children and adolescents with type 1 diabetes. Materials and Methods The study included 85 patients, aged 14.0 ± 0.5 years, with type 1 diabetes. The median time in the target glucose range (TIR) and glycosylated hemoglobin (HbA1c) values were 50.0 ± 1.4% and 7.5 ± 0.1%, respectively. Results The median scanning frequency using flash glucose monitoring was 12.0 ± 0.4 times/day. Scanning frequency showed a significant positive correlation with TIR and an inverse correlation with HbA1c. Scanning frequency was identified to be the determinant of TIR and HbA1c by using multivariate analysis. The participants whose scanning frequency was 12 times/day were categorized as the high‐frequency group (n = 45). Patients in the high‐frequency group were more likely to be treated with insulin pumps compared with those in the low‐frequency group; however, this difference was not significant (21.3 vs 5.3%, P = 0.073). The high‐frequency group showed significantly greater TIR than the low‐frequency group (57 ± 1.6 vs 42 ± 1.7%, P = 0.002). Furthermore, the high‐frequency group showed significantly lower HbA1c levels than the low‐frequency group (6.8 ± 0.1 vs 8.0 ± 0.1%, P 12 times/day might contribute to better glycemic outcomes in real‐world practice in children with type 1 diabetes., Patients with a higher scanning frequency had better glycemic control, with greater target glucose range and lower glycosylated hemoglobin level, compared with those with lower scanning frequency. Frequent scanning of >12 times per day using flash glucose monitoring might contribute to better glycemic outcomes in children with type 1 diabetes.

We investigated serum C-peptide immunoreactivity (CPR) levels in registered data from a multi-center collaborative nationwide type 1 diabetes study. The CPR levels were obtained from 576 and 409 children during the early registration (2013/2014) and late observation (2016/2017) periods, respectively. The percentages of children with a CPR < 0.1 or < 0.3 ng/mL increased according to the duration since diagnosis. Among patients with 5 or more years since diagnosis, 69% had a CPR < 0.1 and 95% had a CPR < 0.3 in the early registration period. A significant negative correlation was observed between the HbA1c and the CPR levels, and the HbA1c levels were significantly higher among children with a CPR < 0.1 or < 0.3 than among those with a CPR ≥ 0.6 ng/mL. During the late observation period, the prevalence of a CPR < 0.1 ng/mL was 88% among long-standing patients and 77% among patients aged 18–20 yr. Regarding the characteristics of “Responders” with a sustained CPR ≥ 0.6 ng/mL at 5 or more years since diagnosis, six of the seven were adolescent females; five of the seven had an HLA DR4-DQ4 haplotype. When type 1A diabetes mellitus (T1AD) children transit to adult care centers, most of them may have some difficulty in glycemic control because of the depleted endogenous insulin.

This multicenter prospective cohort study followed up Japanese children who had just started GH therapy using a drug delivery device (GROWJECTOR® L) linked to a newly developed smartphone application and analyzed precise medication adherence data stored in GROWJECTOR® L to evaluate the usefulness of the application in improving GH therapy adherence over a 24-wk observation period. Moreover, a questionnaire survey on GH therapy and the smartphone application was conducted, and factors affecting adherence to GH therapy were assessed. This study enrolled 60 children with short stature who had GH deficiency or Turner syndrome or were small for gestational age from 28 Japanese medical institutions and analyzed 57 of them. The median and mean adherence rates after 24 wk of observation were 96% and 93%, respectively. Although adherence rates were significantly lower from wk 16 to wk 20 than from wk 1 to wk 4, cumulative adherence rates remained high throughout the observation period. The questionnaire analysis revealed that most patients actively used the application. Overall, our results suggest that active discussion regarding the development of healthcare systems that contribute toward improving the patient quality of life is warranted.

We encountered a 12‐year‐old boy with type 2 diabetes who was born small‐for‐gestational age. We described his clinical characteristics and a possible etiological factor for development of hyperglycemia. He developed well with sufficient nutrition and progressed to being overweight at 6 years‐of‐age as a result of a high‐calorie, high‐protein intake diet. He showed a diabetic pattern with a normal insulin response on an oral glucose tolerance test carried out with the urine glucose screening program at schools. He showed a large total fat area of 239.4 cm2; in particular, his visceral fat area was 103.0 cm2 with a high ratio of visceral fat area to subcutaneous fat area (0.76). The present case might show that insulin resistance, possibly as a result of accumulation of a great amount of visceral fat, might be attributed to the pathogenesis of type 2 diabetes in children born small‐for‐gestational age., We described the clinical characteristics and a possible etiological factor for the development of hyperglycemia in a 12‐year‐old boy with type 2 diabetes who was born small‐for‐gestational age.

We investigated the effect of zinc supplementation on growth and serum IGF-1 levels in 10 prepubertal Japanese children with idiopathic short statures, who had serum zinc levels of less than 80 µg/dL. Subjects were started on oral zinc supplementation at a dose of 25 mg once daily. In three children, the doses were increased by 50 mg once daily during the study period of 12 mo. The serum zinc levels rose in all subjects and reached a normal range (beyond 80 µg/dL). However, it was found that zinc supplementation did not promote growth. Although the mean IGF-1 standard deviations significantly increased, the majority did not reach the normal range. There were no significant adverse events other than mild gastrointestinal symptoms in 4 out of 10 subjects during the supplementation period. The most likely reason why growth was not promoted is that the zinc supplementation dosage was not enough to stimulate IGF-1 generation and subsequent growth velocity.

We present the case of a 12‐year‐old Japanese girl, who was positive for markers of both maturity‐onset diabetes of the young and latent autoimmune diabetes in youth. She was initially diagnosed with maturity‐onset diabetes of the young 1 based on the molecular analysis, and she later developed an autoimmune response, leading to β‐cell‐associated antibody‐positive diabetes. She was treated with incretin‐associated drugs and maintained adequate glycemic control. Pathophysiologically, there was an overlap between the two different types of diabetes, because the hyperglycemia and β‐cell stress seen in non‐autoimmune diabetes can cause β‐cell autoimmunity over time., This paper presents the case of a 12‐year‐old Japanese girl, who was positive for markers of both, maturity‐onset diabetes of the young and latent autoimmune diabetes in youth. She was initially diagnosed with type 1 maturity‐onset diabetes of the young, and later developed an autoimmune response, leading to β‐cell‐associated antibody‐positive diabetes We believe that our study makes a significant contribution to the literature, because it suggests that it is necessary to examine the β‐cell‐associated autoantibodies over time in patients with any type of diabetes when there is a drop in endogenous insulin secretion.

Aims/Introduction We compared the results of testing for glutamic acid decarboxylase antibodies (GADAb) using a radioimmunoassay (RIA) and an enzyme‐linked immunosorbent assay (ELISA) in individuals with childhood‐onset type 1 diabetes mellitus. Materials and Methods Serum specimens were collected from 1,024 Japanese children (426 boys and 598 girls) in 2013. The median age at diagnosis was 7 years (0–18 years). The blood specimens were obtained at a median age of 13 years (2–22 years). Results Among the 628 children whose serum specimens were collected within 5 years after diagnosis, the rate of GADAb positivity was 47.9% using RIA and 69.4% using ELISA. The participants were divided into four groups according to their RIA and ELISA results for GADAb as follows: group I (RIA+/ELISA+), group II (RIA+/ELISA−), group III (RIA−/ELISA+) and group IV (RIA−/ELISA−). The clinical and genetic characteristics of group I and group III were quite similar in terms of age at diagnosis, male/female ratio, relatively high positive rates for both autoantibody to protein tyrosine phosphatase IA‐2 and autoantibody to the cation efflux transporter zinc transporter 8, and human leukocyte antigen genotype. Group II contained just five patients, and was characterized by a younger age at diagnosis, low positive rates for both autoantibody to protein tyrosine phosphatase IA‐2 and autoantibody to the cation efflux transporter zinc transporter 8, and a unique human leukocyte antigen genotype. If the positive rates of either autoantibody to protein tyrosine phosphatase IA‐2 or autoantibody to the cation efflux transporter zinc transporter 8 or both were added to the GADAb results using RIA, the percentage of autoimmune type 1 diabetes increased from 47.9% to 78.5%. Conclusions The diagnosis of autoimmune childhood‐onset Japanese type 1 diabetes increased when GADAb results were obtained using a new ELISA method, compared with a previously utilized RIA method., The diagnosis of autoimmune childhood‐onset Japanese type 1 diabetes was increased by the glutamic acid decarboxylase antibodies using a new enzyme‐linked immunosorbent assay in comparison with a previous radioimmunoassay.

BackgroundDiabetic ketoacidosis (DKA) is a common complication of type 1 diabetes mellitus (T1DM). Infants and children with new-onset T1DM may present with DKA, and the risk of cerebral edema is high in infantile DKA.What is new?Neurological deterioration during an episode of DKA is usually attributed to cerebral edema and cerebrovascular accidents. However, cerebral infarction is a very rare complication in infantile DKA.Case presentationWe describe a rare case of infantile cerebral infarction caused by severe DKA in a patient with new-onset T1DM.ConclusionsCerebral infarction is an important intracranial complication in infantile DKA. Careful observation and treatment for DKA during the first 24 h of therapy are necessary in infants with new-onset T1DM because the risk of cerebral infarction is highest during this timeframe.

Background and methods We investigated the frequency of zinc deficiency in Japanese children with idiopathic short stature, and evaluated whether serum zinc levels correlated with background factors, including age and standard deviation scores (SDSs) for height and serum insulin-like growth factor (IGF)-1 levels. The study subjects consisted of 89 Japanese children. Results The mean serum zinc level was 79 ± 12 (49–108) μg/dL. Of all the children, 48.3% had a low zinc level, in the 60–80 μg/dL range, and 6.7% had zinc deficiency with a zinc level below 60 μg/dL. The majority with a low zinc level and zinc deficiency were asymptomatic other than for short stature. We found no significant correlations of serum zinc with age, or the SDSs for height and serum IGF-1 levels, in either the entire subject population or those with a zinc level below 80 μg/dL. Conclusions We found a low zinc level to be common in Japanese children with idiopathic short stature, whereas actual zinc deficiency was rare. However, other as yet unknown mechanisms not associated with the growth hormone (GH)-IGF-1 axis could be involved in growth retardation in idiopathic short stature.

Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance, onset before 25 years of age, absence of β-cell autoimmunity, and sustained pancreatic β-cell function. To date, mutations have been identified in at least 14 different genes, including six genes encoding proteins that, respectively, correspond to MODY subtypes 1-6: hepatocyte nuclear factor (HNF) 4α (HNF4α), glucokinase (GCK), HNF1α (HNF1 α), pancreatic and duodenal homeobox 1 (PDX1), HNF1β (HNF1 β), and neurogenic differentiation 1 (NEUROD1). Diagnostic tools based on currently available genetic tests can facilitate the correct diagnosis and appropriate treatment of patients with MODY. Candidates for genetic testing include nonobese subjects with hyperglycemia, no evidence of β-cell autoimmunity, sustained β-cell function, and a strong family history of similar-type diabetes among first-degree relatives. Moreover, identification of the MODY subtype is important, given the subtype-related differences in the age of onset, clinical course and progression, type of hyperglycemia, and response to treatment. This review discusses the current perspectives on the diagnosis and treatment of MODY, particularly with regard to the six major subtypes (MODY 1-6).

Aims/Introduction Glucokinase–maturity‐onset diabetes of the young (GCK‐MODY; also known as MODY2) is a benign hyperglycemic condition, which generally does not require medical interventions. The only known exception is increased birthweight and related perinatal complications in unaffected offspring of affected women. As previous data were obtained mostly from white Europeans, the present study analyzed the pregnancy outcomes of Japanese women with GCK‐MODY to better formulate the management plan for this population. Materials and Methods The study participants were 34 GCK‐MODY families whose members were diagnosed at Osaka City General Hospital during 2010–2017. A total of 53 pregnancies (40 from 23 affected women, 13 from 11 unaffected women) were retrospectively analyzed by chart review. Results Birthweights of unaffected offspring born to affected women were significantly greater as compared with those of affected offspring (P = 0.003). The risk of >4,000 g birthweight (16%), however, was lower as compared with that previously reported for white Europeans, and none of the offspring had complications related to large birthweight. Insulin treatment of the affected women resulted in a significant reduction in the birthweights of unaffected offspring. Perinatal complications including small‐for‐gestational age birthweight were found only in affected offspring born to insulin‐treated women. Conclusions In Japanese GCK‐MODY families, unaffected offspring born to affected women were heavier than affected offspring. However, insulin treatment of affected women might not be advisable because of the lower risk of macrosomic birth injury, and an increased risk of perinatal complications in affected offspring.

Women with congenital amino acid disorders, including maple syrup urine disease (MSUD), are at risk of metabolic crisis at delivery. There are still only a few case reports of maternal MSUD globally, and we are the first to report the successful perinatal management of a woman with classical MSUD in Japan. A healthy baby was delivered by scheduled cesarean section despite the presence of several uterine fibroids. With precise diet therapy and accurate preparation, she completed the postpartum period without metabolic decompensation. Although her clinical outcome was favorable, she experienced hypoproteinemia at delivery because the available branched-chain amino acid-free medical food did not contain sufficient protein to meet the recommended nutrient intake. Therefore, this case also indicates a potential issue regarding a shortage of variations in specific amino acid-free medical food in Japan, which should be addressed to achieve a better nutrient status of adults with MSUD and other amino acid disorders.

Tall stature is usually defined as a height beyond 97th percentile or more than 2 SD above the mean height for age and sex in a defined population. Familiar tall stature, also known as constitutional tall stature, is the most common cause of tall stature. Overnutrition, obesity, also usually causes overgrowth. Tall stature by itself is not a pathological condition, however, there are a number of disorders associated with tall stature. Some genetic disorders and syndromes may be associated with mental retardation and various complications. Therefore, recognition of tall stature and revealing the underlying pathogenic causes and making the diagnosis are important not to miss the serious conditions and to provide adequate medical care and genetic counseling. Pathological causes for tall statute include endocrine disorders, such as excessive growth hormone secretion, hyperthyroidism, precocious puberty and lipodystrophy, chromosome disorders, such as Trisomy X (47, XXX female), Klinefelter syndrome (47, XXY), XYY syndrome (47, XYY male) and Fragile X syndrome, and syndromes and metabolic disorders, such as Marfan syndrome, Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, Sotos syndrome and Homocystinuria. Children may require growth reductive treatment if the predicted adult height would be excessive and unacceptable. Some hormonal, high doses of sex steroids, or surgical, bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula, treatment is currently available to reduce adult height.

Background We compared insulin resistance and glucose metabolism during growth hormone (GH) therapy between 43 short children born small-for-gestational age (SGA) and 42 children identifies as growth hormone deficiency (GHD). Methods The study compared fasting plasma glucose (FPG), fasting immunoreactive insulin (IRI) and homeostasis model assessment insulin resistance index (HOMA-IR) during 24-month GH therapy between the two groups. Results Mean FPG, fasting IRI, and HOMA-IR values at 3-month GH therapy were significantly higher than those before and at 12- and 24-month GH therapy in both groups. These markers were significantly higher in short children born SGA than GHD children until 12-month GH therapy but were not different at 24-month GH therapy in both groups. Conclusions The increased secretion of insulin observed in short children born SGA might be a compensatory mechanism for the prevention of hyperglycemia that can progress to diabetes mellitus. However, these metabolic markers gradually declined after 3 months of GH therapy and returned to baseline values at 24 months. These results suggest that short children born SGA have greater insulin resistance than GHD children at the early period of GH therapy, however, increased insulin resistance is improved over a long period. (194 words).

Severe hypoglycemia is defined as a condition with serious cognitive dysfunction, such as a convulsion and coma, requiring external help from other persons. This condition is still lethal and is reported to be the cause of death in 4–10% in children and adolescents with type 1 diabetes. The incidence of severe hypoglycemia in the pediatric population was previously reported as high as more than 50–100 patient-years; however, there was a decline in the frequency of severe hypoglycemia during the past decades, and relationship with glycemic control became weaker than previously reported. A lot of studies have shown the neurological sequelae with severe hypoglycemia as cognitive dysfunction and abnormalities in brain structure. This serious condition also provides negative psychosocial outcomes and undesirable compensatory behaviors. Various possible factors, such as younger age, recurrent hypoglycemia, nocturnal hypoglycemia, and impaired awareness of hypoglycemia, are possible risk factors for developing severe hypoglycemia. A low HbA1c level is not a predictable value for severe hypoglycemia. Prevention of severe hypoglycemia remains one of the most critical issues in the management of pediatric patients with type 1 diabetes. Advanced technologies, such as continuous glucose monitoring (CGM), intermittently scanned CGM, and sensor-augmented pump therapy with low-glucose suspend system, potentially minimize the occurrence of severe hypoglycemia without worsening overall glycemic control. Hybrid closed-loop system must be the most promising tool for achieving optimal glycemic control with preventing the occurrence of severe hypoglycemia in pediatric patients with type 1 diabetes.

BACKGROUND We aimed to investigate the significance of the C-peptide levels on a glucagon stimulation test (GST) conducted soon after diagnosis as a predictive marker for residual β-cell function over time in Japanese children with type 1 diabetes (TD1). METHODS We retrospectively enrolled 65 Japanese children (25 male, 40 female; age

We assessed the significance of recommendations from the international consensus on continuous glucose monitoring (CGM)-derived metrics in Japanese children and adolescents with type 1 diabetes. Eighty-five patients (age, 13.5 ± 4.7 years) who wore the FreeStyle® Libre for a 28-day period were enrolled in this study. Seventy-three patients were treated with multiple daily injections of insulin and 12 with insulin pump therapy without using a sensor-augmented pump or a predictive low-glucose suspend-function pump. We evaluated the relationship between CGM-derived metrics: time in range (TIR: 70-180 mg/dL), time below range (TBR: 180 mg/dL), and laboratory-measured HbA1c and estimated HbA1c (eA1c) levels calculated from the mean glucose values. The TIR was 50.7 ± 12.2% (23-75%), TBR was 11.8 ± 5.8% (2-27%), and TAR was 37.5 ± 13.5% (9-69%). The TIR was highly correlated with HbA1c level, eA1c level, and TAR, but not with TBR. An HbA1c level of 7.0% corresponded to a TIR of 55.1% (95% CI: 53.7-56.5%), whereas a TIR of 70% corresponded to an HbA1c level of 6.1% (95% CI: 5.9-6.3%). The results of eA1c levels were similar to those observed for HbA1c levels. From these findings, we conclude that low rates of a recommended TIR of 70% may be due to less use of advanced technology and insufficient comprehensive diabetes care. Ethnic characteristics including lifestyle and eating customs may have contributed to the result. CGM-derived targets must be individualized based on ethnic characteristics, insulin treatment and diabetes care, and needs of individuals with diabetes.

BACKGROUND We assessed the association between scanning frequency of flash glucose monitoring (FGM) and continuous glucose monitoring (CGM)-derived glycemic markers in children and adolescents with type 1 diabetes. METHODS Subjects consisted of 85 children and adolescents with type 1 diabetes using FGM. We assessed the association between scanning frequencies of FGM- and CGM-derived metrics: Time in range (TIR) (70-180 mg/dL), time below range (TBR) ( 180 mg/dL), and other glycemic markers - laboratory-measured HbA1c and CGM-estimated glucose and HbA1c (eA1c) levels in the subjects. RESULTS The mean number of scans was 11.5 ± 3.5 (5-20) times per day, and scanning was most frequently conducted during a period of 18-24 h. Scanning frequency showed significant positive correlation with TIR (r = 0.719, P < 0.0001) and inverse correlation with time above range (r = -0.743, P < 0.0001), but did not correlate with TBR. There were also significant inverse correlations between scanning frequency and glucose, HbA1c, and eA1c levels (r = -0.765, -0.815, and -0.793, respectively, P < 0.0001). CONCLUSIONS Frequent glucose testing with FGM decreased hyperglycemia with increased TIR, but did not reduce TBR. Coping with a rapid fall of glucose and unexpected hypoglycemia with more advanced technology might contribute to a reduction in TBR.

Introduction: We evaluated the frequencies of various glycemic markers derived from continuous glucose monitoring in Japanese children and adolescents with type 1 diabetes and assessed the significance of hypoglycemia duration. Methods: We enrolled 85 children and adolescents (36 boys and 49 girls) with type 1 diabetes who used FreeStyle® Libre in the present study. Frequencies of blood glucose levels as time within target range (TIR; 70–180 mg/dL), time below target range (TBR; 180 mg/dL) were assessed during a 3-month study period. Furthermore, we evaluated the intraday frequencies of TBR and TBER. Results: The mean frequencies of TIR, TBR, and TAR were 52.7 ± 11.3%, 10.8 ± 5.4%, and 36.5 ± 10.8%, respectively, whereas the mean frequency of TBER was 1.1 ± 0.9% (0–3.0%); there was no clinical episode of severe hypoglycemia. The mean frequency of TBR was significantly greater in 0–6 h (16.9 ± 5.2%) than in 6–12 h (7.8 ± 2.9%) and 18–24 h (6.8 ± 4.8%; p < 0.01) time zones, respectively. Discussion/Conclusion: We found similar TIR and comparatively higher TBR frequencies, particularly during sleep, than those that were previously reported. Possible reasons for the higher frequency of TBR include differences in the quality of insulin treatment and diabetes care between the present study and the European studies. The utilization of advanced technologies, such as a predictive low-glucose suspend-function pump or closed-loop therapy, can reduce the frequency of TBR, with a consequent increase in TIR frequency and comprehensive improvement in glycemic control.

OBJECTIVE: To evaluate the safety and effectiveness of metformin monotherapy for 52 weeks, including 24 weeks of treatment and a 28-week extension period for evaluation of long-term safety, in 37 Japanese pediatric patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: This study design was an open-label, non-randomized, multicenter trial. The primary effectiveness endpoint was the changes from baseline to the final visit at 24 weeks in HbA1c. The secondary endpoints were the rate for achieving the treatment goal, and the changes in glycated albumin, fasting blood glucose, fasting insulin, HOMA-IR, and fasting serum lipids. Metformin was administrated at the dose of 500 mg/day up to a maximum of 2000 mg/day taken in two or three divided doses. RESULTS: The mean change of HbA1c at the final visit at 24 weeks for 20 metformin-naïve patients (Group A) was − 0.66 ± 0.95% and that of 17 already-on metformin patients (Group B) was − 0.98 ± 1.62%. These figures proved the effectiveness of metformin as defined before the study. Secondary effectiveness endpoints were also improved. The improvement of blood glucose, fasting insulin and serum lipid levels proved the effectiveness of metformin without increasing body weight. Adverse effects such as nausea and diarrhea were observed in 35 of the 37 subjects and drug-related adverse events were observed in 19 patients. However, these events were not serious and did not increase with long-term treatment. CONCLUSIONS: Metformin is safe and effective for Japanese pediatric patients with T2DM.

Aims To evaluate comprehensively the use of the glycated albumin to HbA1c ratio for estimation of glycaemic control in the previous month. Methods A total of 306 children with Type 1 diabetes mellitus underwent ≥10 simultaneous measurements of glycated albumin and HbA1c . Correlation and concordance rates were examined between HbA1c measurements taken 1 month apart (ΔHbA1c ) and glycated albumin/HbA1c ratio fluctuations were calculated as Z-scores from the cohort value at enrolment of this study cohort (method A) or the percent difference from the individual mean over time (method B). Results Fluctuations in glycated albumin/HbA1c ratio (using both methods) were weakly but significantly correlated with ΔHbA1c , whereas concordance rates were significant for glycaemic deterioration but not for glycaemic improvement. Concordance rates were higher using method B than method A. Conclusions The glycated albumin/HbA1c ratio was able to estimate glycaemic deterioration in the previous month, while estimation of glycaemic improvement in the preceding month was limited. Because method B provided a better estimate of recent glycaemic control than method A, the individual mean of several measurements of the glycated albumin/HbA1c ratio over time may also identify individuals with high or low haemoglobin glycation phenotypes in a given population, such as Japanese children with Type 1 diabetes, thereby allowing more effective diabetes management.

The principal treatment for children and adolescents with type 2 diabetes is dietary and exercise management. However, the blood glucose levels of some patients receiving this treatment fail to improve; thus, pharmacological treatment is eventually required. The pathophysiology of type 2 diabetes in pediatric patients appears to be similar to that in adults; thus, the range of antidiabetic drugs used in adults is likely to be effective in pediatric patients as well. However, in the majority of countries, including Japan, only metformin, glimepiride, and insulin have been approved for use in pediatric patients. Indeed, the evidence for the usefulness of antidiabetic drugs other than metformin and insulin in children and adolescents is limited at this time. Therefore, the efficacy and safety of various antidiabetic drugs, including DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, which are used in adult patients, should be evaluated in the pediatric population in a large number of centers worldwide. In addition, it is critical that researchers and clinicians establish treatment guidelines for children and adolescents with type 2 diabetes in all racial groups worldwide.

BACKGROUND We conducted an annual urine glucose screening program at schools, and diagnosed schoolchildren with diabetes at an early stage of the disease. We also identified some cases of renal glucosuria (RG), based on positive urine glucose with normal glucose tolerance. METHODS During 2000-2015, 3 309 631 schoolchildren participated in the screening program. The positive rate for glucosuria in the first test was approximately 0.1%, whereas on repeat urine test it was approximately 0.05%. In total 350 schoolchildren were positive for glucosuria on detailed examination. Oral glucose tolerance test (OGTT) was also used to evaluate glucose intolerance. RESULTS One hundred and two schoolchildren (29.7%) were diagnosed with diabetes, whereas RG was identified in 246 (70.3%) with normal glucose metabolism. In regard to the characteristics of RG, the percentage of boys was 50.3%, and the mean age at diagnosis was 11.2 ± 2.4 years. Twenty-eight children (11.4%) were overweight (body mass index standard deviation score [BMI-SDS] > +2.0 SD), whereas five (2.0%) were underweight (BMI-SDS < -2.0 SD). First-degree family history was suspected in 176 cases (71.5%). All RG subjects had normal glucose tolerance in the absence of insulin resistance and decreased insulin secretion (homeostasis model assessment for β-cell function, 78.8 ± 59.5%) on OGTT. CONCLUSIONS RG is not rare in Japanese schoolchildren with glucosuria. This disorder seems to have a strong genetic background, and to involve less growth retardation and weight loss than expected despite continuous excretion of glucose in urine.

OBJECTIVE The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

The aim of this study was to clarify the incidences of and the risk factors for severe retinopathy requiring photocoagulation therapy and albuminuria in Japanese patients with childhood-onset type 1 diabetes mellitus. A total of 756 patients from a cohort study by the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes were included in the study. Patients were registered in 1995 or 2000, and HbA1cwas measured every 4 months and analyzed in central hospital for an average of 6 years. The presence of severe retinopathy requiring laser photocoagulation and the presence of albuminuria was checked for during the period 2010–2011. During a median of 18 (range: 15–21) years, 34 out of 756 patients underwent laser photocoagulation and 57 out of 605 patients developed albuminuria. A Cox proportional hazards model showed that the risk of severe retinopathy requiring laser photocoagulation increased by 1.15 (95% confidence interval [CI] 1.03–1.29, p = 0.012) with each increase of a year in the age at onset, by 4.03 (95% CI 1.20–13.5, p = 0.024) in females, and by 2.05 (95% CI 1.69–2.49, p

Background Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). Objectives We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. Methods Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. Results We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. Conclusions This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.

Optical coherence tomography angiography (OCTA) was performed on patients with juvenile-onset type 1 diabetes (T1DM) but with no diabetic retinopathy to measure the foveal avascular zone (FAZ) area. Retrospective single-facility study Twenty-nine patients (58 eyes) with juvenile-onset T1DM were studied. Images (3 mm x 3 mm cube centered on the fovea) were acquired using an OCTA device. Age at examination was 16.1 ± 8.7 years; onset age was 6.4 ± 3.5 years; duration of diabetes was 9.7 ± 8.3 years. Twenty-four age-matched healthy individuals were studied as controls. FAZ area was significantly larger in T1DM patients than in controls (0.29 ± 0.09 vs. 0.25 ± 0.08 mm2, P = 0.0234). Parafoveal vessel density was not significantly different between patients and controls (50.43 ± 4.24 vs. 50.07 ± 4.64, P = 0.8842). By generalized linear model analysis, annual HbA1c (P = 0.0190), number of serious hypoglycemic attacks (P = 0.0210), and onset age (P = 0.0447) were identified as variables significantly associated with FAZ area. Age, gender, duration of disease, total cholesterol, high or low-density lipoprotein, triglycerides, and body mass index were not significantly associated with FAZ area. Patients with juvenile-onset T1DM and no diabetic retinopathy had increased FAZ, but no significant difference in parafoveal vessel density compared to healthy controls. Larger FAZ area was associated with higher annual HbA1c, more episodes of severe hypoglycemic attacks, and older onset age.

Background: Visceral fat accumulation is strongly associated with type 2 diabetes (T2DM). In contrast to visceral fat, subcutaneous fat might even be beneficial against metabolic abnormalities. Objective: To investigate the association between simple obesity or T2DM and the ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) in Japanese adolescents. Design/Methods: An age- and sex-matched retrospective study was conducted in Tokyo Metropolitan Hiroo Hospital, Nihon University Hospital, and Nihon University Itabashi Hospital with ethics approval. Sixty-one adolescents with simple obesity or T2DM aged 10 to 15 years who have been visiting in these outpatient clinics between 2002 and 2018 were enrolled in this study. Simple obesity was defined as BMI ≥95%ile but without T2DM. VFA and SFA were investigated using CT at the umbilical levels. Subjects were classified into 2 groups: simple obesity group (n=38) and T2DM group (n=23). Results: Comparisons between the 2 groups are shown in Table 1. In simple obesity group, ALT, TC, HDLC or non-HDLC levels were significantly different that those in T2DM group. SFA and V/S ratio in simple obesity group were significantly higher and lower than those in T2DM group, respectively. Conclusion: V/S ratio is different between simple obesity and T2DM in Japanese adolescents. V/S ratio is the most useful predicter of T2DM in adolescents. Disclosure Y. Abe: None. T. Urakami: None. K. Yoshida: None. M. Aoki: None. M. Hara: None. I. Morioka: None.

The economic burden of diabetes in Japan is already serious and will become greater in the future. We review the economic impact of diabetes in Japan to examine viable options for mitigating its effects. Medical costs for diabetes have been increasing by US $1 million annually, reaching US $11 million in 2009, of which US $7 million was accounted for by people aged 65 years or older. The quality of treatment of diabetes in Japan is higher than in other regions in the world. This can be more effective for achieving glycemic control, but is also more expensive compared with conventional treatment. Because of the high cost of diabetes in Japan, a coordinated response is needed. Intervention trials for people with prediabetes aimed at preventing the occurrence of diabetes seem to be the most cost-effective method for lowering the medical costs of diabetes, rather than the use of new, expensive antidiabetic drugs in patients with established diabetes.

Aims/Introduction Although genome-wide association studies have identified more than 50 susceptibility genes for type 1 diabetes, low-frequency risk variants could remain unrecognized. The present study aimed to identify novel type 1 diabetes susceptibility genes by newly established methods. Materials and Methods We performed whole-exome sequencing and genome-wide copy-number analysis for a Japanese family consisting of two patients with type 1 diabetes and three unaffected relatives. Further mutation screening was carried out for 127 sporadic cases. The functional consequences of identified substitutions were evaluated by in silico analyses and fluorescence-activated cell sorting of blood samples. Results Whole-exome sequencing and genome-wide copy-number analysis of familial cases showed co-segregation of the p.V863L substitution in CD101, the human homolog of an autoimmune diabetes gene in the nonobese diabetic mouse, with type 1 diabetes. Mutation screening of CD101 in 127 sporadic cases detected the p.V678L and p.T944R substitutions in two patients. The p.V863L, p.V678L, and p.T944R substitutions were absent or extremely rare in the general population and were assessed as “probably/possibly damaging” by in silico analyses. CD101 expression on monocytes, granulocytes, and myeloid dendritic cells of mutation-positive patients was weaker than that of control individuals. Conclusions These results raise the possibility that CD101 is a susceptibility gene for type 1 diabetes. This article is protected by copyright. All rights reserved.

Background There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). Objectives To elucidate the characteristics of Japanese patients with KATP-NDM. Methods By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. Results Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. Conclusion Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

Objective Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D). Methods Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort). Results Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P

Aims The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. Methods We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. Results Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15–14.47) and 1.64 (corrected P value 5.3 × 10-5; 95% CI 1.34–2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. Conclusions The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Background We previously showed that glycated albumin (GA) is a useful glycemic control indicator in patients with neonatal diabetes mellitus (NDM), and that age-adjusted GA (Aa-GA) can reflect more accurately glycemic control status. Here, we investigated whether the age at diagnosis influences Aa-GA at diagnosis of NDM. Methods Eight patients with NDM whose GA was measured at diagnosis (age at diagnosis: 39 ± 18 days; GA: 31.3 ± 7.6%; Aa-GA: 47.1 ± 10.3%; plasma glucose: 525 ± 194 mg/dl) were included. Aa-GA was calculated as follows: Aa-GA = GA × 14.0/[1.77 × log-age (days) + 6.65]. Correlations of GA or Aa-GA at diagnosis with its logarithmically transformed age in days (log-age), plasma glucose, and their product were investigated. Results GA at diagnosis was not significantly correlated with log-age or plasma glucose. On the other hand, Aa-GA at diagnosis was significantly positively correlated with plasma glucose (R = 0.75, P = 0.031) and was more strongly positively correlated with the product of plasma glucose and log-age (R = 0.82, P = 0.012) although it was not correlated with log-age. Conclusion Aa-GA at diagnosis is influenced by both age in days and plasma glucose. This finding is likely to show the aspect that age in days is almost equal to diabetes duration because glycemic control indicators including GA reflect the weighted mean of plasma glucose.

We evaluated the efficacy and safety of switching to insulin degludec (IDeg) from insulin glargine (IGlar) as basal-bolus therapy in young people with type 1 diabetes. The subjects were 36 patients, 21.3±1.0 years of age, with type 1 diabetes. IGlar had previously been injected once daily in 25 patients and twice daily in 11. They were then switched from IGlar to once-daily injection of IDeg. Both fasting plasma glucose (FPG) and HbA1c levels decreased significantly from 134±3.9 mg/dL and 7.9±0.2% at baseline to 116±2.2 mg/dL and 7.4±0.2% at 12 months after starting IDeg (P

Methylation defects in the imprinting locus at chromosome 6q24 result in transient neonatal diabetes and small-for-gestational age (SGA) births (1). These phenotypes are primarily ascribed to the overexpression of PLAGL1, a paternally expressed gene on 6q24 that regulates cell cycle and apoptosis (2). Paternal uniparental disomy involving 6q24, as well as copy-number gains of paternal PLAGL1 alleles and epimutations in maternal alleles, have been identified as the causes of hypomethylation at the differentially methylated region (DMR) of PLAGL1 (3, 4). Recently, Yorifuji et al. reported the identification of 6q24 uniparental disomy in three patients with childhood-onset non-autoimmune diabetes mellitus (5). The three patients were identified through methylation-specific PCR analysis of the PLAGL1 DMR of 113 patients clinically suspected of having maturity-onset diabetes of the young (MODY). These results expanded the phenotypic consequences of 6q24 methylation defects to include MODY-like manifestations without a history of neonatal diabetes. However, the frequency of 6q24 methylation defects among patients with childhood-onset non-autoimmune diabetes remained unknown.

It is well known that the incidence of youth-onset type 2 diabetes is increasing worldwide. On the other hand, most studies have shown that the majority of youth-onset type 2 diabetes occurs in obese individuals, generally with a body mass index (BMI) greater than the 90th or 95th centile for sex- and age-matched children and adolescents. However, we identified some Japanese children with nonobese type 2 diabetes and BMI less than 90th centile by a urine glucose screening program at schools in the Tokyo Metropolitan Area. According to the results obtained from the screening, clinical characteristics of patients with nonobese type 2 diabetes seemed to be different from those in obese type 2 diabetes. Nonobese patients tended to show lower insulin secretion abilities and milder, but evident, insulin resistance from the time of diagnosis. Female, low birth weight (small for gestational age), and genetic background, not related to β-cell-associated autoimmunity, may play a role in development of nonobese type 2 diabetes. In addition, nonobese patients tend to progress earlier to pharmacological treatment including oral hypoglycemic drugs and insulin. Further studies are needed to confirm to these findings and clarify the pathophysiology of children with nonobese type 2 diabetes.

BackgroundTreatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients.MethodsThe registration data including hemoglobin A1c(HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort).ResultsThe proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p1cvalues between the two cohorts.ConclusionsThe popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by a remarkably abrupt onset. In Japan, FT1DM accounts for approximately 20% of acute-onset adult type 1 diabetes mellitus cases; however, reports of pediatric-onset FT1DM are rare. We aimed to determine the frequency and clinical characteristics of FT1DM in Japanese children and adolescents by conducting a 2-phase questionnaire survey among the members of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) regarding their clinical experience with FT1DM. Responses were obtained from 54 of the 79 participating hospitals (68.4%). Of these, 8 hospitals managed a total of 15 pediatric patients with FT1DM (4 patients in each of 2 hospitals, 2 patients in 1 hospital, and 1 patient in each of 5 hospitals). The distribution of patient age was biphasic, with peaks in children younger than 5 years and older than 8 years of age. The clinical characteristics of FT1DM in this population (such as the duration from onset of symptoms to diagnosis, severity of symptoms, preceding flu-like episodes, and abnormal laboratory data) did not differ from those of patients with adult-onset FT1DM. The frequency of pediatric-onset FT1DM is low compared with that of adult-onset FT1DM. The genetic background and susceptibility patterns of pediatric patients with FT1DM may differ from those typical of adults with FT1DM, but both age groups share similar clinical characteristics.

OBJECTIVE To analyze changes in the annual incidence of school students with type 2 diabetes detected by urine glucose screening at schools in the Tokyo Metropolitan Area during 1975-2015. METHODS Trend in temporal changes in the annual incidence rate were analyzed using a joinpoint regression model and the joinpoints. Annual percent change (APC) was calculated for each segmented line regression. Average annual percent change (AAPC) was also calculated for the whole period analyzed. RESULTS In total, 301 students, including 64 primary school students and 237 junior high school students, were diagnosed with type 2 diabetes. The overall incidence of type 2 diabetes (per 100 000/year) during the entire study period was 2.58 in all students, 0.80 in primary school students, and 6.41 in junior high school students. AAPC during the entire study period was estimated at -1.5 (not significant), and the incidence significantly increased during 1975-1982 (APC = 17.49, P < 0.05), but tended to decrease during 1982-2015 (APC = -1.01). In primary school students, the incidence significantly increased during1975-2010 (APC = 3.30, P < 0.05), and tended to decrease during 2010-2015 (APC = -29.61). In junior high school students, the incidence did not significantly change during the entire study period (APC = 0.06). CONCLUSIONS We found increasing trend in the overall incidence of school students with type 2 diabetes during 1975-1982, but a decreased tendency in recent years. This could be due to changes observed during the same time period in the primary school students. Lifestyle changes might contribute to improved incidence of childhood type 2 diabetes.

AIM To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. METHODS PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. RESULTS One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. CONCLUSIONS The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation.