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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.

The aim of the study was to compare two continuous glucose monitoring (CGM) systems, intermittently scanned CGM (isCGM) and real-time CGM (rtCGM), to determine which system achieved better glycemic control in pediatric patients.We carried out a retrospective cohort study of children and adolescents with type 1 diabetes, and compared the time in range (70-180 mg/dL), time below range (70 mg/dL) and time above range (180 mg/dL), and estimated glycated hemoglobin levels between patients on isCGM and rtCGM.Of the 112 participants, 76 (67.9%) used isCGM and 36 (32.1%) used rtCGM for glycemic management. Patients on rtCGM had significantly greater time in range (57.7 ± 12.3% vs 52.3 ± 12.3%, P = 0.0368), and had significantly lower time below range (4.3 ± 2.7% vs 10.2% ± 5.4%, P 0.001) than those on isCGM, but there was no significant difference in the time above range (37.4 ± 12.9% vs 38.0% ± 12.5%, P = 0.881) or the glycosylated hemoglobin A1c levels (7.4 ± 0.9% vs 7.5 ± 0.8%, P = 0.734) between the two groups.Pediatric patients with type 1 diabetes on rtCGM also showed more beneficial effects for increase of time in range, with a notable reduction of time below range compared with those on isCGM. Real-time CGM might provide better glycemic control than isCGM in children with type 1 diabetes.

Purpose The aim was to investigate the characteristics of abdominal fat distribution in Japanese adolescents with type 2 diabetes mellitus. Patients and methods Eighty-six Japanese adolescents with simple obesity or type 2 diabetes mellitus treated between 2002 and 2018 were included. The subjects were classified into the simple obesity group (SO group, n=38) and type 2 diabetes mellitus group (DM group, n=23) by matching average age and gender ratio. The metabolic parameters VFA, SFA, and V/S ratio were compared between the 2 groups. Multivariate logistic regression analysis was performed to identify clinical factors associated with type 2 diabetes mellitus. Linear regression analysis was performed between hemoglobin A1c (HbA1c) and visceral fat area (VFA), subcutaneous fat area (SFA), or VFA-to-SFA ratio (V/S ratio) among all enrolled subjects. Finally, correlation analyses were performed to determine the relationships between VFA, SFA, and V/S ratio and metabolic parameters of the DM group. For the metabolic parameters, serum lipids, alanine aminotransferase (ALT), and HbA1c were measured without fasting. The VFA and SFA at umbilical level were investigated using computed tomography. Results VFA and V/S ratio in DM group were higher than those in SO group (p=0.04 and p

Hyperbaric exposure (1.3 atmospheres absolute with 20.9% O2) for 1 h a day was shown to improve exercise capacity. The present study was designed to reveal whether the daily exposure time affects exercise performance and metabolism in skeletal and cardiac muscles. Male mice in the training group were housed in a cage with a wheel activity device for 7 weeks from 5 weeks old. Trained mice were then subjected to hybrid training (HT, endurance exercise for 30 min followed by sprint interval exercise for 30 min). Hyperbaric exposure was applied following daily HT for 15 min (15HT), 30 min (30HT), or 60 min (60HT) for 4 weeks. In the endurance capacity test, maximal work values were significantly increased by 30HT and 60HT. In the left ventricle (LV), activity levels of 3‐hydroxyacyl‐CoA‐dehydrogenase, citrate synthase, and carnitine palmitoyl transferase (CPT) 2 were significantly increased by 60HT. CPT2 activity levels were markedly increased by hyperbaric exposure in red gastrocnemius (Gr) and plantaris muscle (PL). Pyruvate dehydrogenase complex activity values in PL were enhanced more by 30HT and 60HT than by HT. Protein levels of N‐terminal isoform of PGC1α (NT‐PGC1α) protein were significantly enhanced in three hyperbaric exposed groups in Gr, but not in LV. These results indicate that hyperbaric exposure for 30 min or longer has beneficial effects on endurance, and 60‐min exposure has the potential to further increase performance by facilitating fatty acid metabolism in skeletal and cardiac muscles in highly trained mice. NT‐PGC1α may have important roles for these adaptations in skeletal muscle., Effects of the duration of daily hyperbaric exposure on metabolic enzyme activity levels for fatty acid oxidation

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).

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.

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.

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.

New findings What is the central question of this study? Intermittent hyperbaric exposure (1.3 atmospheres absolute with 20.9% O2 ) enhances endurance capacity by facilitating oxidative and glycolytic capacities in skeletal muscle. It remains unclear whether this strategy enhances endurance performance in well-trained individuals. What is the main finding and its importance? Hyperbaric exposure with endurance training enhanced oxidative and glycolytic capacities and protein levels of mitochondrial transcription factor A, dynamin-related protein-1 and heat shock protein 70. Hyperbaric exposure with sprint interval training increased the proportion of type I muscle fibres and promoted capillary growth and muscle fibre hypertrophy. These results may lead to a new strategy for enhancing exercise capacity in well-trained mice. Abstract The study was designed to clarify the mechanisms by which hyperbaric exposure (1.3 atmospheres absolute with 20.9% O2 ) improves endurance and interval exercise capacities in highly trained mice. Male mice in the training group were housed in a cage with a wheel activity device for 7 weeks from 5 weeks old. Voluntary running markedly increased maximal endurance capacity by 6.4-fold. Trained mice were then subjected to either endurance treadmill training (20-32.5 m min-1 ) or sprint interval training (5 s run-10 s rest, 30-42.5 m min-1 ) with (HypET or HypSIT, respectively) and without (ET or SIT, respectively) 1 h hyperbaric exposure for 4 weeks. Maximal endurance capacity was significantly increased by HypET and HypSIT, and maximal interval capacity was significantly enhanced by HypSIT. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression levels were markedly increased after HypET and HypSIT. Activity levels of 3-hydroxyacyl-CoA-dehydrogenase, citrate synthase and phosphofructokinase in the red gastrocnemius muscle were increased more by HypET than by ET. Protein levels of mitochondrial transcription factor A, dynamin-related protein-1 and heat shock protein 70 were increased more by HypET than by ET. The proportion of type I fibres in the soleus muscle was remarkably increased by HypSIT. Capillary-to-fibre ratio values in the white gastrocnemius were increased more by HypSIT than by SIT. These results suggest that hyperbaric exposure has beneficial effects for endurance and interval training to improve exercise capacity in highly trained mice.

Background The prognosis of non-shockable out-of-hospital cardiac arrest is worse than that of shockable out-of-hospital cardiac arrest. We investigated the associations between the etiology and prognosis of non-shockable out-of-hospital cardiac arrest patients who experienced the return of spontaneous circulation after arriving at hospital. Methods and Results All subjects were extracted from the SOS-KANTO 2012 study population. The subjects were 3,031 adults: (i) who had suffered out-of-hospital cardiac arrest, (ii) for whom there were no pre-hospital data on ventricular fibrillation/pulseless ventricular tachycardia until arrival at hospital, (iii) who experienced the return of spontaneous circulation after arriving at hospital. We compared the patients' prognosis after 1 and 3 months between various etiological and presumed cardiac factors. The proportion of the favorable brain function patients that developed pulmonary embolism or incidental hypothermia was significantly higher than that of the patients with presumed cardiac factors (1 month, P

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.

Background: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death). Methods: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death). RESULTS: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P Conclusions: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms.

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.

This study was designed to investigate exercise-induced changes in muscle capillarisation, the mRNA expression of angiogenic genes, and microRNA levels in young and middle-aged rats. Rats in the training groups were subjected to treadmill running 5 days a week for 3 weeks. The exercise protocol for the young (12-week old) group was 20-25 m/min, 40-60 min/day with a gradient of 15%, and for the middle-aged (12-month old) group was 18-20 m/min, 40-60 min/day with a gradient of 5%. The enzyme histochemical identification of capillary profiles was performed on cross-sections of gastrocnemius muscle. Total RNA was isolated, reverse transcription was performed, and mRNA and microRNA levels were determined by real-time PCR. The capillary-to-fibre ratio was significantly increased by exercise training in the young group (by 10%), but only slightly in the middle-aged (by 5%) group. Vascular endothecial growth factor (VEGF) mRNA levels were at significantly higher values after acute exercise (1.6-fold) and the 3-week training protocol (1.9-fold) in the young group, but not in the middle-aged group. VEGF protein expression levels were significantly increased after training in the young group only. Endothelial nitric oxide synthase, VEGF-R2 and thrombospondin-1 mRNA levels were significantly lower in the middle-aged group than in the young group. Anti-angiogenic miR-195 levels were significantly enhanced by exercise training in the middle-aged group only. These results indicated that the exercise-induced adaptation of muscle capillarity was attenuated in middle-aged rats, possibly by the lower induction of VEGF and up-regulation of anti-angiogenic miRNA expression.

The first-line pharmacological treatment for patients with maturity-onset diabetes of the young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for the treatment of patients with these types of MODY. Here we report a case of a pediatric patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A 13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally resulted in good glycemic control. After changing to alogliptin, the patient maintained optimal glycemic control with glycated hemoglobin levels of 6.3–7.0% while maintaining substantial β-cell function. No adverse events associated with alogliptin were observed. These results suggest that DPP-4 inhibitors may be a potential treatment for patients with MODY1 at the early stage of the disease when residual insulin secretion is still being sustained.

We investigated the efficacy and safety of switching to insulin glulisine (GLU) from other rapid-acting insulin analogs (Ra) in children with type 1 diabetes treated with multiple daily injections of insulin or continuous subcutaneous insulin infusion. A total of 26 children with type 1 diabetes were included. Ra in all of these patients was changed to GLU, and they were observed for a 6-month period after having previously finished treatment with other Ra. The mean glycated hemoglobin value decreased from 7.6 ± 1.0 to 7.4 ± 0.9% (P = 0.0034), and mean plasma glucose values after breakfast and supper also improved from 183 ± 50 to 153 ± 32 mg/dL (P = 0.0035), and from 203 ± 29 to 164 ± 23 mg/dL (P

This study implemented a randomized crossover design to evaluate the efficacy and safety of switching from insulin glargine (IGlar) to insulin degludec (IDeg) in 18 children (11 males, 7 females; age 11.0 ± 0.5 years) with type 1 diabetes. All subjects had previously used IGlar once daily at bedtime. We compared fasting plasma glucose (FPG) and HbA1c levels, frequencies of overall and nocturnal (2200 h - 0659 h) hypoglycemia, and basal insulin dose at the baseline with those measured during a 24-week period during which IGlar or IDeg was administered in combination with pre-meal rapid acting insulin analogues. IDeg was initially given at the same dose as IGlar but was subsequently titrated to achieve FPG levels of 90-140 mg/dL. There were no significant changes in FPG and HbA1c levels from the baseline during the 24-week study period with IGlar or IDeg. The daily basal insulin dose did not significantly differ with IGlar or IDeg. Although the frequencies of overall hypoglycemia were similar, nocturnal hypoglycemia significantly decreased at 12 and 24 weeks from the baseline with IDeg use (2 ± 0.4 vs. 0 ± 0.3, 0 ± 0.5 episodes/month, both P

We evaluated the efficacy and safety of insulin glulisine (GLU) used for continuous s.c. insulin infusion (CSII) in 20 children with type 1 diabetes after 1 year of GLU treatment. There were no significant differences in mean plasma glucose before breakfast and before dinner between before and after using GLU, but the levels after breakfast and after dinner significantly improved, from 192.5 ± 31.7 to 162.0 ± 27.3 mg/dL for breakfast, and from 191.1 ± 33.3 to 161.1 ± 24.5 mg/dL for dinner (P

We treated 80 obese and 28 nonobese children diagnosed as having type 2 diabetes mellitus (T2DM). Among these patients, 26 obese and 23 nonobese children were assigned to pharmacologic therapies during the course of diabetes. Pharmacologic therapies were started if the HbA1c (NGSP) value exceeded 7.0% despite dietary and exercise management. For the 26 obese patients, metformin alone or in combination with an additional medication was frequently used. Only 2 patients independently received sulfonylureas (SUs) in the form of glimepiride. In addition, 9 patients were treated with basal insulin supported with oral hypoglycemic drugs (OHDs) or biphasic premix insulin. On the other hand, the 23 nonobese patients were frequently treated with insulin alone or in combination with an additional medication followed by SUs. The nonobese patients tended to require pharmacologic therapies, in particular insulin, at an earlier stage of diabetes as compared with the obese patients. New antidiabetic drugs, DPP-4 inhibitors and GLP-1 receptor agonists, seemed to exert positive effects on glycemic control without occurrence of hypoglycemic episodes in some patients regardless of the type of diabetes. These results suggest that pharmacologic treatment strategies in childhood T2DM should be tailored to individual patient characteristics.

In recent years, many experiments have investigated the impact of dietary amino acid supplementation on improvements in muscle strength and endurance capacity. However, it is unclear whether this supplementation causes vascular remodelling in skeletal muscle. This review focused on the effects of L-arginine and/or L-ornithine supplementation on capillary growth in cardiac and skeletal muscles. Although the chronic administration of 4% L-arginine did not improve capillarization in rat cardiac and hind-leg muscles, it facilitated exercise-induced capillary growth via vascular endothelial growth factor (VEGF) protein upregulation. In middle-aged rats, moderate intensity endurance training for 6 weeks did not cause capillary growth, whereas training with L-arginine supplementation led to an improvement in capillarization in the hind-leg muscle and left ventricle by promoting VEGF and endothelial nitric oxide synthase (eNOS) protein expression. The administration of L-arginine and L-ornithine for 6 weeks caused a marked increase in capillarization in rat skeletal muscle via the downregulation of endostatin and upregulation of VEGF-R2 protein expression. Moreover, this supplementation facilitated exercise-induced improvements in capillarization in the hind-leg muscles via the downregulation of endostatin and upregulation of VEGF and eNOS protein levels. The evidence presented in this review indicates that L-arginine and/or L-ornithine administration may facilitate capillary growth and endurance exercise capacity. Furthermore, this supplementation may be a useful therapeutic intervention for ischemic-related diseases.

This study was designed to (1) investigate the effects of acute short‐duration intermittent hypoxia on muscle mRNA and microRNA expression levels; and (2) clarify the mechanisms by which short‐duration intermittent hypoxia improves endurance capacity. Experiment‐1: Male mice were subjected to either acute 1‐h hypoxia (12% O 2 ), acute short‐duration intermittent hypoxia (12% O 2 for 15 min, room air for 10 min, 4 times, Int‐Hypo), or acute endurance exercise (Ex). The expression of vascular endothelial growth factor‐A mRNA was significantly greater than the control at 0 h post Ex and 6 h post Int‐Hypo in the deep red region of the gastrocnemius muscle. miR‐16 expression levels were significantly lower at 6 and 10 h post Int‐Hypo. Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1 α ) mRNA levels were significantly greater than the control at 3 h post Ex and 6 h post Int‐Hypo. miR‐23a expression levels were lower than the control at 6–24 h post Int‐Hypo. Experiment‐2: Mice were subjected to normoxic exercise training with or without intermittent hypoxia for 3 weeks. Increases in maximal exercise capacity were significantly greater by training with short‐duration intermittent hypoxia (IntTr) than without hypoxia. Both 3‐Hydroxyacyl‐CoA‐dehydrogenase and total carnitine palmitoyl transferase activities were significantly enhanced in IntTr. Peroxisome proliferator‐activated receptor delta and PGC‐1 α mRNA levels were both significantly greater in IntTr than in the sedentary controls. These results suggest that exercise training under normoxic conditions with exposure to short‐duration intermittent hypoxia represents a beneficial strategy for increasing endurance performance by enhancing fatty acid metabolism in skeletal muscle.

Aim To compare the injection frequencies employed and the basal-to-total insulin dose ratios obtained when glargine (G) and detemir (D) are used in children with type 1 diabetes mellitus (T1DM) treated by basal–bolus therapy (BBT).

We examined the correlation between plasma glucose (PG) and hemoglobin A1c (HbA1c) to evaluate the usefulness and limitations of applying the new diagnostic criteria for diabetes to Japanese pediatric patients. Data were collected from 298 school children who took an oral glucose tolerance test (OGTT) at a school-based urinary glucose screening program in the Tokyo Metropolitan Area between 1988 and 2009. Mean (SD) age of the children was 11.9 (2.5) years. Male-to-female ratio was 1:1.1. Children were diagnosed with renal glucosuria (n=146), diabetes mellitus (n=133), or the Japan Diabetes Society (JDS) "borderline type" (n=19). Median (range) values of fasting plasma glucose (FPG), 2-h plasma glucose in an OGTT (OGTT-2h), and HbA1c were 101 (76-378) mg/dL, 146.5 (57-563) mg/dL, and 6.05 (4.7-14.1) %. The correlation between PG and HbA1c was analyzed using least squares regression, and HbA1c was found to highly correlate with PG. From estimated regression equations, mean values of FPG and OGTT-2h corresponding to an HbA1c of 6.5% were calculated to be 111.4 mg/dL and 170.4 mg/dL. The mean values of HbA1c corresponding to an FPG of 126 mg/dL and OGTT-2h of 200 mg/dL were calculated to be 7.5% and 7.8%. The mean values of PG corresponding to HbA1c of 6.5% were lower than found in adults as analyzed by JDS. The mean values of HbA1c corresponding to diabetic type PG were higher than found in adults.

Objective: 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. Methods: 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 (

目的．肺癌術後患者にみられた肺抗酸菌症例についての検討を行った．方法．1996～2007年に当院で経験した，肺癌術後の肺結核症（pulmonary tuberculosis：PTB）および肺非結核性抗酸菌症（pulmonary non-tuberculous mycobacteriosis：PNTM）の24例を対象に，病歴や経過，検査所見，X線所見などを後ろ向きに解析した．結果．肺抗酸菌症の内訳はPTB 14例，PNTM 10例（肺M. avium complex症9例，肺M. kansasii症1例）で，男性（17例），高齢者（15例），術後5年以内（15例），術側肺（18例）に多くみられた．PTB例では肺癌再発（7例），結核治療歴（6例），他臓器癌の既往，performance status（PS）2以上（各5例）などを認め，全身状態の悪化に基づく内因性再燃が示唆された．PNTMでは全身的要因をほとんど認めなかったが，術側肺の発症が9例を占め，手術に伴う肺局所環境の悪化に伴う感染，増悪が示唆された．治療について，PTBでは診断の遅れがなければ治療経過，予後は良好であったが，PNTMでは治療にも関わらず，病変が進展し，肺アスペルギルス症などを併発し，死亡する症例もみられた．結論．肺癌術後患者の管理においては全身状態やX線所見に注意を払い，肺抗酸菌症を的確に診断することが重要である．

We investigated the percentage of total basal insulin dose to total daily insulin dose (%TBD) among Japanese youth of different ages with type 1 diabetes. The study enrolled 69 patients with type 1 diabetes who were treated with multiple daily injections of insulin. The participants were divided into the following age groups: group A, 0 to

Objective: To examine the prevalence of components of the metabolic syndrome (MS) other than hyperglycemia at diagnosis in schoolchildren with type 2 diabetes mellitus (T2DM). Design: The study involved 112 Japanese schoolchildren, 45 males and 67 females aged 12.9 ± 1.5 yr, who were diagnosed as having T2DM. The body weight, blood pressure and fasting serum triglyceride (TG), and high-density lipoprotein cholesterol cholesterol (HDL-C) levels were also measured at diagnosis. The criteria adopted for the diagnosis of MS were as follows; i.e., TG ≥150 mg/dL, HDL-C

We investigated the incidence of the slowly progressive form of type 1 diabetes (SPT1D) detected by the urine glucose-screening tests at schools in the Tokyo Metropolitan Area from 1974 to 2004. During this study period, a total of 9,242,259 school students underwent the screening program. Of them, 54 children, 19 males and 35 females, aged 11.6+/-2.4 years, were diagnosed to have SPT1D by this method. The overall incidence of SPT1D was 0.57/100,000/year, which was about one fifth of that of type 2 diabetes detected by the same method. The incidence was significantly higher in junior high school students than in primary school students (0.32 vs. 1.13/100,000/year, p

Aims Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus (6q24-related transient neonatal diabetes). 6q24-Related transient neonatal diabetes is characterized by the patient being small-for-gestational age, diabetes mellitus at birth, spontaneous remission within the first few months and frequent recurrence of diabetes after childhood. However, it is not clear whether individuals with 6q24 abnormalities invariably develop transient neonatal diabetes. This study explored the possibility that 6q24 abnormalities might cause early-onset, non-autoimmune diabetes without transient neonatal diabetes. Methods The 6q24 imprinted locus was screened for abnormalities in 113 Japanese patients with early-onset, non-obese, non-autoimmune diabetes mellitus who tested negative for mutations in the common maturation-onset diabetes of the young (MODY) genes and without a history of transient neonatal diabetes. Positive patients were further analysed by combined loss of heterozygosity / comparative genomic hybridization analysis and by microsatellite analysis. Detailed clinical data were collected through the medical records of the treating hospitals. Results Three patients with paternal uniparental isodisomy of chromosome 6q24 were identified. None presented with hyperglycaemia in the neonatal period. Characteristically, these patients were born small-for-gestational age, representing 27.2% of the 11 patients whose birth weight standard deviation score (SDS) for gestational age was below −2.0. Conclusions Abnormalities in the imprinted locus on chromosome 6q24 do not necessarily cause transient neonatal diabetes. Non-penetrant 6q24-related diabetes could be an underestimated cause of early-onset, non-autoimmune diabetes in patients who are not obese and born small-for-gestational age.

This study was designed to examine whether dietary l-arginine supplementation modulates exercise-induced angiogenesis and vascular endothelial growth factor (VEGF) expression in female Wistar rats. Exercise training (running) lasted for 6 weeks at 25 m min−1 on a 20% gradient for 10–60 min day−1. Rats in the l-arginine-treated groups drank water containing 4%l-arginine. Histochemical identification of capillary profiles showed that training with l-arginine significantly increased the capillary/fibre (C/F) ratio in the subendocardium of the left ventricle, whereas training alone did not. Because of a significantly higher fibre cross-sectional area, a concomitant, but not significant, decrease in capillary density was also observed. In the hindleg muscles, training with l-arginine significantly increased the C:F ratio, although the degree of change was the same as that observed after training alone. Western blot analysis showed that training with l-arginine significantly increased VEGF protein expression by 1.7-fold in the left ventricle, while the increase with training alone was insignificant. In the soleus muscle, although VEGF protein expression was elevated insignificantly after training (2.8-fold), training with l-arginine significantly increased the protein levels (3.8-fold). Tissue endothelial nitric oxide synthase protein levels did not changed after either training or l-arginine treatment. The present results suggest that l-arginine supplementation causes additional effects on exercise-induced angiogenesis in the rat heart by promoting VEGF expression.

This study was designed to examine the changes in capillary geometry, especially the distribution of arteriolar and venular capillaries, in the skeletal muscles of female Wistar rats after endurance training with and without chronic CoCl(2) administration. Four groups of rats were used: non-treated sedentary, non-treated training, Co(2+)-treated sedentary, and Co(2+)-treated training. Exercise training by running lasted for 5 weeks at 25 m/min on a 20% gradient, 10-60 min/d, 5 d/week. The Co(2+)-treated rats drank water containing 0.01% CoCl(2) for 5 weeks. Morphological findings were obtained from the soleus (SOL), deep (PLd) and superficial (PLs) portions of plantaris, and diaphragm (DIA) muscles. Co(2+) administration significantly increased the blood hemoglobin concentration by approximately 25% with and without training. Only in DIA, the Co(2+) treatment alone significantly increased total capillary density and the capillary-to-fiber ratio (C : F) (p0.05). Both training groups with and without Co(2+) administration showed a significant increase in the C : F in SOL and PLd (p0.05). In PLd, the increase was significantly greater in the Co(2+)-treated training group than in the non-Co(2+)-treated training group (p0.05). Training significantly increased the proportion of arteriolar capillaries while it decreased that of venular capillaries in both SOL and PLd (p0.05). These changes were also observed in PLd after training with Co(2+). The densities of VEGF-positive and TGF-beta1-positive capillaries remained unchanged in all muscle portions examined after either Co(2+) administration or exercise training. These results suggest that chronic Co(2+) administration causes adaptive changes in the oxygen transport system in respiratory muscle and facilitates exercise-induced angiogenesis in hind-leg muscles.

Sulfonylureas (SUs) are recommended as the first-line pharmacological treatment in patients with uncontrolled maturity-onset diabetes of the young type 3 (MODY3). In contrast, glucagon-like peptide-1 (GLP-1) receptor agonists have the advantages of a low risk of hypoglycemia and maintained β-cell function. We report a pediatric patient with MODY3 treated with a GLP-1 receptor agonist, liraglutide. A 12-year-old Japanese girl with MODY3 had been treated with insulin for 6 months since the time of diagnosis. After genetic analysis, we switched her treatment from insulin to liraglutide. After switching to liraglutide, the patient maintained optimal glycemic control with hemoglobin A₁c levels of 6.8%-7.5% and had postprandial C-peptide levels >3.0 ng/mL during a 3-year treatment period. No adverse events associated with liraglutide were observed. GLP-1 receptor agonists are the potential medications for patients with MODY3 who maintain residual insulin secretion.

Early gastric cancer can be macroscopically classified into elevated and depressed types. To clarify the relationship between macroscopic appearance of early gastric cancer and apoptosis or cell proliferation, formalin-fixed paraffin-embedded tissue specimens of 44 intestinal-type early gastric cancers were investigated by the TUNEL method and immunohistochemical techniques. Diffuse type was excluded in this study. When tissue sections of gastric cancer were vertically classified into the 3 compartments of luminar, intermediate and basal, the apoptosis index (%) was significantly higher in the basal compartment of depressed type (1.76 +/- 2.04, mean +/- SD) than in the basal compartment of elevated type (0.63 +/- 0.81, P = 0.01). In depressed type, the apoptosis index (%) was significantly higher in the basal compartment than in the luminar compartment (0.76 +/- 0.85, P = 0.03). Apoptosis-inducing protein, Bax, was expressed more in each of the compartments of depressed type than in those of elevated type, while there were no significant differences in expression of anti-apoptotic protein, Bcl-2, between the two types. Moreover, the apoptosis index (%) of Bax-positive gastric cancer was significantly higher in the basal compartment (P = 0.03), compared to that of Bax-negative gastric cancer, while there were no significant differences in apoptosis index (%) in any compartment between Bcl-2-positive and Bcl-2-negative gastric cancers. There were no significant differences in Ki-67 expression, either between the two types, or among the compartments of depressed type. These results indicate that increased apoptosis with excessive expression of Bax in the basal compartment is involved in the morphogenesis of the depressed type in intestinal-type early gastric cancer.

This study was designed to examine the time-course changes in capillarity, especially the distribution of arteriolar and venular capillaries, in skeletal muscles during endurance training by running in young female Wistar rats. Exercise training by running started at the age of 5 weeks and lasted for 5 weeks at 25 m min(-1) on a 25% gradient, 10-60 min day(-1), 5 days per week. Morphological findings were obtained from the soleus (SOL) and deep portions of the medial gastrocnemius (GASd) muscles. In SOL, the training significantly increased the capillary-to-fibre ratio (C:F), total capillary density, and density of venular capillaries at Week 1. Significant increases in the C:F and total capillary density were also observed at Weeks 4 and 5. The capillary domain area (CDA) values for total capillary and arteriolar and venular capillaries were significantly decreased after 4 weeks of training. In GASd, the training significantly increased the C:F at Week 1 and from Week 3 onwards. It also significantly increased cross-sectional area of all fibre types. Total capillary density and the CDA values showed no significant difference between control and training groups at all points of time. Significant increases in succinate dehydrogenase (SDH) activity were first noted after 2 weeks in GASd and after 3 weeks in SOL. These findings suggest that, in young growing rats, adaptive changes in the oxygen transport system occurred within 1 week after the onset of training mainly in highly oxidative muscles. The changes in arteriolar and venular capillary densities may help to clarify the growth pattern of the capillary network associated with endurance running training.

compared in terms of diabetes duration (13.0 ± 9.9 vs 10.0 ± 9.7: p

The effects of strength training with partial tourniquet ischaemia on skeletal muscle capillarity were examined, particularly in terms of the distribution of arteriolar and venular capillaries and their capillary domain area, in male Wistar rats. A tourniquet applied around the knee joint induced partial ischaemia. Repeated isometric contractions of calf muscles, 1 s on/1 s off for 3 min, induced by electrical stimulation (100 Hz), were conducted 2 days/week for 6 weeks as training. Morphologic data were obtained from four groups; non-treatment control (C), ischaemic (IS), non-ischaemic training (NIT) and ischaemic training (IT). In the superficial portion of gastrocnemius (GASs) muscle, the total capillary density of arteriolar capillaries was significantly greater in the IT-leg than in the C-leg (P < 0.05). In the plantaris (PL) muscle, these values were significantly greater in the IT-leg than in both the C- and NIT-legs (P < 0.05). Only in the GASs was the capillary-to-fibre ratio significantly greater in the IT-leg than in the C-leg (P < 0.05). In GASs and PL, the capillary domain area (CDA) was smaller in the IT-leg than in the C- and NIT-legs. In all muscles examined, mean fibre cross-sectional area was not significantly changed by the experimental treatment. These findings suggest that adaptive changes in the microvascular network, identified as an increase in the arteriolar capillary area and a reduction in diffusion distance, occur in the skeletal muscles after strength training with partial ischaemia. These adaptive changes probably improve the supply of oxygen and nutrients to skeletal muscle tissues.