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Insulin and its secretagogues are essential for some patients with type 2 diabetes (T2D) to maintain good glycemic control (GC), but severe hypoglycemia (SH) is a concern. This network meta-analysis aimed to find optimal glucose-lowering drug treatment regimens in terms of GC and SH in T2D patients. MEDLINE and EMBASE were used to identify trials that compared two or more treatments including insulins and/or sulfonylurea or glinides and that examined both GC and SH. Treatment hierarchy was expressed as the surface under the cumulative ranking curve (SUCRA) probabilities. We identified 137 eligible trials comprising 42 treatments. The use of insulins and non-insulin glucose-lowering agents except for sulfonylurea or glinide had a higher SUCRA than insulins only for hemoglobin A1c (A1C) (p = 0.01) changes and achievement of A1C

We developed a new Physical Score (PS) consisting of comprehensive physical fitness indicators and elucidated the association between the resultant PS and metabolic diseases, i.e., diabetes, hypertension, dyslipidemia, fatty liver, and metabolic syndrome (MetS), among Japanese. Analyzed were 49,850 persons (30,039 men) aged 30 to 69 y who underwent physical fitness tests. Principal component analysis was performed on the correlation matrix of the physical fitness test results (relative grip strength, single-leg balance with eyes closed, and forward bending) according to sex and age. We defined the PS as the first principal component score. A formula was developed for various age groups comprised of men and women from 30 to 69 years of age from which the PS for each age and sex was calculated. The PS for both men and women was normally distributed with a value of 0 ± 1.15-1.16. Multivariate logistic regression analysis showed that the risk of metabolic diseases increased approximately 1.1-1.6 times per each 1-point reduction in the PS. The association between PS and MetS was particularly strong in that a 1-point reduction in the PS increased the risk of MetS by 1.54 times (95% confidence interval 1.46 to 1.62) in men and by 1.21 times (1.15 to 1.28) in women. The association between a lower PS and disease risk was stronger in younger men for fatty liver and in older men for MetS. Conversely, in women, the association between a lower PS and disease risk was stronger in older women for fatty liver and in younger women for MetS. For diabetes, hypertension, and dyslipidemia, the change in the impact of PS reductions across age groups was small. The PS is a useful and simple non-invasive tool for screening Japanese people for metabolic diseases.

Elevated serum uric acid reportedly increases the risk of development and progression of diabetic retinopathy with conflicting results. However, whether it also increases the incidence of severe vision-threatening diabetic eye diseases has been scarcely investigated. Also unknown is whether there are sex differences in the incidence of advanced retinopathies. To clarify this, we utilized ICD-and medical treatment codes from a nationwide claims database that finally included 13,721 type 2 diabetes patients (mean age 50 y, HbA1c 7.0%, mean follow-up period 5.8 y, 10,962 men) . During the study period, 388 patients developed vision-threatening treatment-required diabetic eye diseases (4.9/1000 person-years) . Multivariate Cox analysis demonstrated that a serum uric acid ≥7.1 mg/dl was significantly positively associated in men with future occurrence of treatment-required diabetic eye diseases, but not in women. Hazard ratios for those with serum uric acid ≥7.1 mg/dl for incident treatment-required diabetic eye diseases were 1.36 (95% confidence interval, 1.01-1.85) in men and 2. (0.71-6.08) in women, compared with the reference group ( Disclosure M. Yamamoto: None. K. Fujihara: None. H. Ishiguro: None. M. Ishizawa: None. M.H. Yamada: None. T. Osawa: None. M. Kitazawa: None. M. Kaneko: None. M. Iwanaga: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding The Japan Society for the Promotion of Science and the Ministry of Health, Labor and Welfare, Japan. (18K17897)

Muscle strength, balance, and flexibility has been associated with the development of type 2 diabetes and atherosclerosis, but little is known whether the physical score (PS) , which integrates these physical fitness indices, can predict future metabolic diseases. We investigated the longitudinal relationship between baseline and changes in PS and future prediabetes and MetS. Analyzed were 5620 men aged 30 to 69 y without MetS who underwent physical fitness tests. Principal component analysis was performed on the correlation matrix of the physical fitness test results according to age. PS was defined as the first principal component score. Associations between PS values at the start of observation (year 0) , change in the PS one year later (year 1) and the onset of prediabetes and MetS at the end of observation (years 4 or 5) were examined by Cox hazard regression analysis. The same analysis was performed for the 3812 men without prediabetes at baseline. No significant difference was found for the development of prediabetes, but a significant difference was found for development of MetS. The hazard ratio for the development of MetS was 1.30 (1.18,1.44) for every 1 decrease in the PS in year 0 and 1.35 (1.13,1.60) for every 1 decrease in the change in PS from year 0 to year 1. PS was a simple and non-invasive indicator to predict MetS. Disclosure T. Sato: None. K. Fujihara: None. M. Yamamoto: None. M. Kitazawa: None. H. Ishiguro: None. T. Osawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

This study aims to examine the impact of the association between metabolic syndrome (MetS) and metabolic dysfunction-associated fatty liver disease (MAFLD) , which both have insulin resistance and are pathophysiologically similar, on the development of new-onset cardiovascular disease, with and without type 2 diabetes mellitus (T2DM) A total of 570,426 participants without a history of cardiovascular disease who were enrolled in the nationwide claims database from 2008-2016 were included in this study. Participants were classified according to the presence or absence of MetS and/or MAFLD, and the risk of developing coronary artery disease (CAD) and/or cerebrovascular disease (CVD) in each category was analyzed using a multivariate Cox proportional hazard model. The same analysis was performed with stratification by the presence or absence of T2DM. During a median follow-up of 5.2 years, 2,252 CAD and 3,128 CVD events occurred. The hazard ratio (HR) (95% CI) for CAD, compared with the group with neither MAFLD nor MetS, was 1.46 (1.32-1.62) for MAFLD only (without MetS) , 2.02 (1.51-2.70) for MetS only (without MAFLD) , and 2.33 (2.10-2. 58) for MAFLD + MetS. For CVD, The HR was 1.41 (1.28-1.55) for MAFLD only, 1.67 (1.38-2.02) for MetS only, and 1.89 (1.72-2.08) for MAFLD + MetS. These results were similar for non-T2DM participants but different for T2DM participants, with no significant increased risk for CAD in MetS only and a significant increased risk for CVD only when both MAFLD and MetS coexisted. The predictive ability for cardiovascular disease development in patients with MetS and MAFLD differed depending on the presence or absence of T2DM. These results suggest that distinguishing between the diagnosis of MetS and MAFLD, taking into account the presence or absence of T2DM, may lead to more accurate identification of patients at high risk of developing cardiovascular disease. Disclosure K. Fujihara: None. M.H. Yamada: None. M. Yamamoto: None. H. Ishiguro: None. M. Kitazawa: None. M. Iwanaga: None. S. Kodama: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding The Japan Society for Promotion of Science (JSPS) KAKENHI Grant Number JP 20K19706)

The association between screen time (ST) , including that for smartphones, and overweight/obesity (OW/OB) in children was examined separately for boys and girls, considering the influence of lifestyle factors including diet, physical activity, and sleep time. A cross-sectional study was conducted in 2242 Japanese children (1278 girls) aged 10-14 years. OW/OB was defined by the International Obesity Task Force. Logistic regression analysis showed that only for girls, total ST (≥4h) , smartphone ST (≥3h) and non-smartphone ST (≥2h) were all independently and significantly associated with overweight/obesity compared to In Japanese girls, smartphone ST, non-smartphone ST, and total ST were all significantly associated with OW/OB. To avoid OW/OB, it is suggested to keep smartphone ST, non-smartphone ST, and total ST to Disclosure K. Fujihara: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. C. Horikawa: None. Y. Ogawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

Insulin and its secretagogues are essential for some patients with type 2 diabetes (T2D) to maintain glycemic control (GC) . However, these drugs are inevitably accompanied by hypoglycemia. Avoiding severe hypoglycemia (SH) is essential considering its poor prognosis. This network meta-analysis aimed to find optimal hypoglycemic treatment regimens for T2D in terms of GC and SH. MEDLINE and EMBASE were used to identify trials comparing 2 or more treatments including insulins and/or SU/glinide and included both GC and SH in study outcomes. Treatment hierarchy was summarized as the surface under cumulative ranking probabilities (SUCRA) . There were 137 eligible trials from which 36 treatments were identified. Insulin plus (+) non-insulin drugs except for SU/glinide (others) had a higher SUCRA for changes in hemoglobin A1c (A1C) compared with only insulins (68.2±5.6% vs. 39.9±6.6%; P=0.01) although the difference in the SUCRA for SH was not significant (P=0.59) . Compared with only insulins, SU/glinide + others had a lower SUCRA for SH (42.4±5.8% vs. 58.5±3.4%, P=0.05) and comparable SUCRA for A1C change (P=1.00) . Cluster analysis indicated that premixed insulin + glucagon-like peptide-1 receptor agonist (Mix-ins+GLP1) consistently belonged to the high-efficacy group for A1C change and achievement of A1C Disclosure S.Kodama: None. K.Kato: None. K.Watanabe: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. T.Sato: None. M.H.Yamada: None. M.Yamamoto: None. Y.Matsubayashi: None. H.Ishiguro: None. M.Iwanaga: None. K.Fujihara: None. T.Yamada: None.

Previous cohort study reported that high physical activity was associated with a low risk of self-reported hearing loss in women. However, no studies have examined the association between physical activity and the development of hearing loss as measured using an objective assessment of hearing loss in men and women. Here, we used cohort data to examine the association between leisure-time physical activity and incidence of objectively assessed hearing loss in men and women. Participants included 27 537 Japanese adults aged 20-80 years without hearing loss, who completed a self-administered physical activity questionnaire between April 2001 and March 2002. The participants were followed up for the development of hearing loss as measured by audiometry between April 2002 and March 2008. During follow-up, 3691 participants developed hearing loss. Compared with the none physical activity group, multivariable adjusted hazard ratios (HRs) for developing hearing loss were 0.93 (95% confidence interval (CI), 0.86-1.01) and 0.87 (0.81-0.95) for the medium (

Summary The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD., Graphical abstract, Highlights • SOCS3 suppresses severe systemic inflammation associated with high-fat diet • SOCS3 deficiency on high-fat diet accelerates excess myeloid hematopoiesis • SOCS3 controls gut dysbiosis on high-fat diet, Immunology; Microbiome

It is unclear whether genetic interactions are involved in the association between vegetable intake and reduced body mass index (BMI) or obesity. We conducted a comprehensive search for single nucleotide polymorphisms (SNPs) which are associated with the interaction between vegetable intake frequency and BMI or obesity. We performed a genome-wide association analysis to evaluate the genetic interactions between self-reported intake of vegetables such as carrot, broccoli, spinach, other green vegetables (green pepper and green beans), pumpkin, and cabbage with BMI and obesity, which is defined as a BMI ≥ 25.0 kg/m2 in the Japanese population (n = 12,225). The mean BMI and prevalence of obesity was 23.9 ± 3.4 kg/m2 and 32.3% in men and 22.1 ± 3.8 kg/m2 and 17.3% in in women, respectively. A significant interaction was observed between rs4445711 and frequency of carrot intake on BMI (p = 4.5 × 10−8). This interaction was slightly attenuated after adjustment for age, sex, alcohol intake, smoking, physical activity and the frequency of total vegetable intake (p = 2.1 × 10−7). A significant interaction was also observed between rs4445711 and frequency of carrot intake on obesity (p = 2.5 × 10−8). No significant interactions that were the same as the interaction between frequency of carrot intake and rs4445711 were observed between the intake frequency of broccoli, spinach, other green vegetables, pumpkin or cabbage and BMI or obesity. The frequency of carrot consumption is implicated in reducing BMI by the intermediary of rs4445711. This novel genetic association may provide new clues to clarify the association between vegetable intake and BMI or obesity.

Background: The extracellular matrix is associated with diabetic complications; however, chondroitin sulfate (CS) role remains unclear. Herein, genetically engineered mice lacking the rate-limiting CS-synthesizing enzyme, CS N-acetylgalactosaminyltransferase-1 (T1), were used to clarify CS effects on diabetic neuropathy. Diabetes was induced by streptozotocin injection in 6-week-old male T1 knockout (T1KO) and wild-type (WT) mice. Results: Previously reported preliminary data at the former ADA meeting revealed that thermal nociception and the number of plantar peripheral nerve fibers were disrupted in diabetic WT mice, whereas in diabetic T1KO were preserved. Moreover, conduction velocity in the sciatic nerve was significantly declined in diabetic WT than in T1KO mice. [A1] Immunohistochemical data revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, whereas those neurons were protected in diabetic T1KO mice. Moreover, DRG gene expression analysis showed that caspase-3 and -9 were reduced in T1KO compared with WT mice. To investigate the mechanisms underlying these events, the role of pericytes, which are important CS-expressing components of the blood-nerve barrier (BNB), was explored. Assessment of the retinal vessels, which represent a good model to evaluate pericyte functions and easier to access than peripheral nerves, revealed a higher proportion of pericyte-deficient retina blood vessels in diabetic WT than in T1KO mice upon administration of a platelet-derived growth factor receptor (PDGFR) β antibody. Therefore, pericytes in T1KO mice were more resistant against PDGFRβ antibody than those of WT mice. Thus, it is possible that the BNB in T1KO mice may be more resistant against external stress, including diabetes. Conclusions: Reduced CS production may induce beneficial effects to prevent diabetic neuropathy by improving pericyte function. Disclosure H. Ishiguro: None. T. Ushiki: None. A. Honda: None. T. Mikami: None. H. Kitagawa: None. K. Sango: None. M. Masuko: None. M. Igarashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

Cell culture media influence the characteristics of human osteogenic periosteal sheets. We have previously found that a stem cell medium facilitates growth and collagen matrix formation in vitro and osteogenesis in vivo. However, it has not yet been demonstrated which culture medium is superior for osteoclastogenesis, a prerequisite for reconstruction of normal bone metabolic basis. To address this question, we compared chemotaxis and osteoclastogenesis in tissue-engineered periosteal sheets (TPSs) prepared with two types of culture media. Periosteal tissues obtained from adult volunteers were expanded with the conventional Medium 199 or with the stem cell medium, MesenPRO. Hematopoietic enhanced-green-fluorescent-protein (EGFP)-nude mice were prepared by γ-irradiation of Balb/c nu/nu mice and subsequent transplantation of bone marrow cells from CAG-EGFP C57BL/6 mice. TPSs were implanted subcutaneously into the chimeric mice and retrieved after intervals for immunohistopathological examination. EGFP+ cells were similarly recruited to the implantation site in both the TPSs prepared, whereas the distribution of CD11b+ cells was significantly lower in the TPS prepared with the stem cell medium. Instead, osteoclastogenesis was higher in the TPS prepared with the stem cell medium than in the one prepared with the conventional medium. These findings suggest that the stem cell medium is preferable for the preparation of more functional TPSs.

Pediatric obesity is associated with clustered cardiometabolic risk and the future incidence of cardiovascular disease. However, few studies have determined the effect of pediatric obesity in Asia, where obesity is less common than in Western countries. We aimed to clarify whether weight status including underweight and slightly overweight is associated with metabolic risk factors in Japanese adolescents.We performed a cross-sectional analysis of 2241 adolescents aged 13-14 years. Participants were classified as underweight, normal weight, slightly overweight, overweight, or obese according to the International Obesity Task Force. The clustered cardiometabolic risk (Z-CMR) was estimated by summing standardized sex-specific Z scores of mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDLC), and HbA1c.Linear regression analysis showed that MAP, non-HDL-C, and Z-CMR were higher in the slightly overweight, overweight, and obese groups than in the normal weight group after adjusting for confounders. Compared with the normal weight group, the slightly overweight, overweight, and obese groups had higher prevalence of high BP [odds ratios (ORs): 1.38 (95% CI, 1.03, 1.85); 2.63 (1.77, 3.91); and 2.39 (1.57, 3.64), respectively]. Compared with the normal weight group, underweight boys, but not girls, had a lower prevalence of high Z-CMR [OR=0.20 (0.05, 0.84)].Adolescents classified as slightly overweight had higher levels of BP, serum lipids, and clustered cardiometabolic risk than those classified as normal weight. This observation showed significant associations between weight status and cardiometabolic risk factors during adolescence even in East Asians.

The bone marrow (BM) microenvironment, known as the BM niche, regulates hematopoiesis but is also affected by interactions with hematopoietic cells. Recent evidence indicates that extracellular matrix components are involved in these interactions. Chondroitin sulfate (CS), a glycosaminoglycan, is a major component of the extracellular matrix; however, it is not known whether CS has a physiological role in hematopoiesis. Here, we analyzed the functions of CS in hematopoietic and niche cells. CSGalNAcT1, which encodes CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, was highly expressed in hematopoietic stem and progenitor cells (HSPCs) and endothelial cells (ECs), but not in mesenchymal stromal cells (MSCs) in BM. In T1 knockout (T1KO) mice, a greater number of HSPCs existed compared with the wild-type (WT), but HSPCs from T1KO mice showed significantly impaired repopulation in WT recipient mice on serial transplantation. RNA sequence analysis revealed the activation of IFN-α/β signaling and endoplasmic reticulum stress in T1KO HSPCs. In contrast, the number of WT HSPCs repopulated in T1KO recipient mice was larger than that in WT recipient mice after serial transplantation, indicating that the T1KO niche supports repopulation of HSPCs better than the WT niche. There was no obvious difference in the distribution of vasculature and MSCs between WT and T1KO BM, suggesting that CS loss alters vascular niche functions without affecting its structure. Our results revealed distinct roles of CS in hematopoietic cells and BM niche, indicating that crosstalk between these components is important to maintain homeostasis in BM.

Although cardiorespiratory fitness (CRF) and muscular fitness (MF) are modifiable factors for metabolic risk, the role of weight status in these factors has not been clarified in the pediatric population. We examined associations between metabolic indices and CRF or MF according to weight categories and compared the prevalence of metabolic abnormalities among four groups stratified by combinations of PF and weight categories. Cross-sectionally analyzed were 1744 Japanese adolescents aged 13-14 years. The PF test included measurements of CRF (20-m shuttle run test), upper-limb strength (handgrip test), lower limb strength (standing long jump test), and muscular endurance (sit-ups). Participants were classified as non-overweight (non-OW) or overweight/obese (OW) according to BMI cutoffs by the International Obesity Task Force. Metabolic risk was defined as ≥1 SD of the clustered metabolic risk (estimated by summing standardized sex-specific Z scores of HbA1c, MAP, and non-HDL-C). After adjusting for BMI and other characteristics, linear regression analysis showed that non-HDL-C was inversely associated with CRF in the non-OW group (P In summary, relationships of metabolic risk with components of PF differed according to weight status. In OW adolescents, MF might be more useful for stratifying metabolic risk than CRF. Disclosure S.Y. Morikawa: None. K. Fujihara: None. R. Nedachi: None. I. Ikeda: None. Y. Takeda: None. M. Takeuchi: None. M. Hatta: None. H. Ishiguro: None. T. Yamada: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

Machine learning (ML) methods receive increasing attention for diabetes risk assessment. This meta-analysis quantitatively assessed the predictive ability of ML algorithms for incident T2DM. Electronic literature searches were done using MEDLINE and EMBASE for longitudinal studies whereby an index test was a model constructed by ML algorithms for predicting incident T2DM. Reference standard was a blood test or physicians’ diagnosis confirming T2DM. The model was restricted to algorithms that required the aid of ML (e.g., neural network, support vector machine, etc.). The 2x2 contingency data (i.e., true-positive, false-positive, false-negative, and true-negative) were pooled with a hierarchical summary receiver operating characteristic model. Pooled sensitivity and specificity (95% confidence interval (CI)) of 8 eligible studies were 0.70 (0.66-0.74) and 0.78 (0.69-0.85), respectively. (Figure) Positive likelihood ratio (PLR) calculated as sensitivity/(1-specificity) and negative likelihood ratio (NLR) calculated as (1-sensitivity)/specificity were 3.25 (95%CI, 2.25-4.58) and 0.38 (95% CI, 0.34-0.43), respectively. We conclude that existing prediction models are not yet satisfactory considering that PLR>5 moderately increases the probability of a disease given a positive test and NLR Disclosure S. Kodama: None. T. Sato: None. M. Yamamoto: None. H. Ishiguro: None. M. Iwanaga: None. K. Fujihara: None. T. Yamada: None. K. Kato: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

An increase in screen time (ST) is reportedly associated with insulin resistance and obesity in children. However, most studies are of TV viewing but not smartphone use. Also, little is known of the relationship between ST and diet. In this study, we clarified the relationships among ST including smartphone use, lifestyle factors including dietary content, and obesity. Cross-sectionally analyzed were 1393 children between 11-15 years of age. ST (min/day) was classified into 4 groups: In conclusion, the increase in ST including smartphone usage was suggested to be associated with various unfavorable lifestyles including dietary habits that could be connected to obesity. Disclosure I. Ikeda: None. K. Fujihara: None. R. Nedachi: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

A 74-year-old man who had type 2 diabetes mellitus of a duration of 20 years was admitted for syncope after eating a high carbohydrate meal. Although he had had episodes of pallor or syncope after carbohydrate-rich meals, such as with large amounts of white rice, several times within a year and he had been taken to hospitals emergently, the etiology of these episodes had remained unclear despite his undergoing several studies. Studies did show severe orthostatic hypotension during the head-up tilt test and a decrease in the coefficient of variation of the R-R interval (CVR-R) on resting electrocardiogram, suggesting severe autonomic nervous dysfunction. Because of the episodes of syncope after eating a carbohydrate-rich meal, we investigated whether he had postprandial hypotension (PPH). The 75 g oral glucose tolerance test revealed a significant decrease in his postprandial blood pressure by about 40 mmHg, leading to the diagnosis of PPH. The carbohydrate-rich meal test induced syncope with systolic blood pressure under 40 mmHg. Then 150 mg caffeine was administered before a second carbohydrate-rich meal. The marked decline in postprandial blood pressure was suppressed and plasma noradrenaline levels were gradually increased over a period of 60 minutes. Caffeine could be useful for prevention of postprandial hypotension-related syncope.

Key Clinical Message Pheochromocytomas are catecholamine‐producing neuroendocrine tumors that arise from the adrenal medulla. The clinical presentation includes headache, palpitation, and hypertension, but pheochromocytomas are sometimes clinically silent. The present case highlights the importance of biochemical testing for pheochromocytoma in patients with adrenal incidentaloma, even if they are completely normotensive and asymptomatic.

Background Bariatric surgery leads to a higher remission rate for type 2 diabetes mellitus than non-surgical treatment. However, it remains unsolved which surgical procedure is the most efficacious. This network meta-analysis aimed to rank surgical procedures in terms of diabetes remission. Methods and findings We electronically searched for randomized controlled trials in which at least one surgical treatment was included among multiple arms and the diabetes remission rate was included in study outcomes. A random-effects network meta-analysis was performed within a frequentist framework. The hierarchy of treatments was expressed as the surface under the cumulative ranking curve value. Results of the analysis of 25 eligible randomized controlled trials that covered non-surgical treatments and eight surgical procedures (biliopancreatic diversion [BPD], BPD with duodenal switch, Roux-en Y gastric bypass, mini gastric bypass [mini-GBP], laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, greater curvature plication and duodenal-jejunal bypass) showed that BPD and mini-GBP had the highest surface under the cumulative ranking curve values among the eight surgical treatments. Conclusion Current network meta-analysis indicated that BPD or mini-GBP achieved higher diabetes remission rates than the other procedures. However, the result needs to be interpreted with caution considering that these procedures were in the minority of bariatric surgeries.

AIM Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients. METHOD Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m2) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HICCIR). Correlation analyses between HICCIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination. RESULTS HICCIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HICCIR decreased in those with both FL and obesity compared with those with only one such complication. CONCLUSION HICCIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC. TRIAL REGISTRATION NUMBER These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351.

Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13–1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08–1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.

Aims/Introduction The present meta-analysis aimed to clarify the association of unstable bodyweight with the risk of type 2 diabetes mellitus, an association that has been controversial among longitudinal studies., Materials and Methods An electronic literature search using EMBASE and MEDLINE was followed up to 31 August 2016. The relative risks (RRs) of type 2 diabetes mellitus in individuals with unstable bodyweight were pooled using the inverse variance method., Results Eight studies were eligible for the meta-analysis. The median duration of measurements of weight change and follow-up years for ascertaining type 2 diabetes mellitus were 13.5 and 9.4 years, respectively. The pooled RR for the least vs most stable category was 1.33 (95% confidence interval 1.12–1.57). Between-study heterogeneity was statistically significant (P = 0.048). Whether type 2 diabetes mellitus was ascertained by blood testing explained 66.0% of the variance in the logarithm of RR (P = 0.02). In three studies in which blood testing was carried out, type 2 diabetes mellitus risk was not significant (RR 1.06, 95% confidence interval 0.91–1.25). Furthermore, publication bias that inflated type 2 diabetes mellitus risk was statistically detected by Egger's test (P = 0.09)., Conclusions Unstable bodyweight might be modestly associated with the elevated risk of type 2 diabetes mellitus; although serious biases, such as diagnostic suspicion bias and publication bias, made it difficult to assess this association.

Pediatric obesity is associated with clustered cardiometabolic risk and the future incidence of diabetes. However, few studies have determined the effect of pediatric obesity in Asia, where obesity is less common than in Western countries. Thus, we clarified whether metabolic risk factors are associated with weight status including slight overweight and underweight among Japanese adolescents. We performed a cross-sectional analysis of 2241 Japanese adolescents (1180 boys) aged 13-14 years whose height, weight, HbA1c, blood pressure (BP), and serum lipids were measured. Participants were classified as underweight, normal weight, slightly overweight, overweight, or obese according to both the universal and Asian cutoffs of the International Obesity Task Force, which correspond to adult BMI cutoffs. The clustered cardiometabolic risk (Z-CMR) was estimated by summing standardized sex-specific Z scores of HbA1c, mean arterial pressure (MAP), and non-high-density lipoprotein cholesterol (non-HDL-C). Linear regression analysis showed that MAP (sex-specific Z score), non-HDL-C (sex-specific Z score), and Z-CMR were higher in the slightly overweight, overweight, and obese groups than in the normal weight group after adjusting for confounders. Compared with the normal weight group, the slightly overweight, overweight, and obese groups had significantly higher odds ratios (ORs) for high BP [OR = 1.38 (95% CI, 1.03-1.85); OR = 2.63 (1.77-3.91); and OR = 2.39 (1.57-3.64), respectively]. Compared with the normal weight group, underweight boys, but not girls, had a significantly lower OR for high Z-CMR [OR = 0.20 (0.05-0.84)]. Our results indicated that adolescents classified as slightly overweight had higher levels of BP, serum lipids (but not HbA1c), and clustered cardiometabolic risk than those classified as normal weight. This observation demonstrated that significant associations between weight status and cardiometabolic risk factors could be seen during adolescence even in East Asia. Disclosure S.Y. Morikawa: None. K. Fujihara: None. D. Ishii: None. R. Nedachi: None. M. Ishizawa: None. H. Ishiguro: None. Y. Matsubayashi: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

Introduction: Suppressors of cytokine signaling (SOCS) are negative regulators of cytokine signaling; SOCS3 controls myeloid hematopoiesis by suppressing G-CSF. SOCS3 haploinsufficiency attenuates diet-induced obesity by enhanced leptin sensitivity while improving insulin resistance. We established SOCS3 conditional knock-out (KO) mice to elucidate how high fat diets (HFD) affect inflammation and obesity in complete SOCS3 deficiency. Methods: Embryonic lethality of complete SOCS3 deficiency was overcome using a conditional Socs3 allele inactivated by tamoxifen (TAM)-inducible cre-recombinase with SOCS3fl/flRosa26-CreERT2T/+ mice. They were fed HFD (60 kcal% fat) or control chaw (10 kcal% fat) starting at 4 weeks of age and TAM or vehicle administration was done at 8 weeks. Results: Although insulin resistance improved and obesity and fatty liver were not confirmed in SOCS3-KO with HFD (S3HFD), the S3HFD group looked moribund around day 30 post-TAM by systemic inflammation; their mean survival was 62.5 days after TAM. Other groups did not look moribund. Significant granulopoiesis was also observed in S3HFD (peripheral blood neutrophil counts 29301 ± 20581/mm3). This myeloid hematopoiesis occurred in the spleen and not the bone marrow. S3HFD exhibited the progression of various granulocytes from progenitor cells (c-kitint∼highLy6G-) to mature granulocytes (c-kit-Ly6G+).Hematopoietic infiltration was confirmed in the liver in S3HFD with granulocytes, monocytes, and macrophages. Inflammasome-associated genes (IL-1β and Caspase1) were elevated in the liver at day 65 post-TAM in S3HFD. Conclusion: SOCS3 deficiency showed myeloid proliferation under HFD without obesity and adiposity. SOCS3-KO may help in the clarification of the specific mechanism of myeloid proliferation and invasion in HFD-induced inflammation. Disclosure K. Cho: None. T. Ushiki: None. H. Ishiguro: None. T. Katagiri: None. T. Suwabe: None. H. Hirai: None. Y. Nakagawa: None. M. Masuko: None. W. Alexander: None. H. Shimano: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

Hematological markers such as hematocrit (Hct), hemoglobin (Hb) or red blood cell (RBC) count were reported to be associated with the development of diabetic retinopathy with conflicting results. Moreover, which of these markers is the best to predict incident retinopathy remains unknown. To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that included 7,182 participants (1,490 women, mean age 50.8 y, HbA1c 6.9%, mean follow-up period 5.5y) classified as having diabetes mellitus or vision-threatening treatment-required diabetic eye diseases (TRDED). Multivariate Cox regression model was used to identify predictors of TRDED. During the study period, 177 patients developed TRDED (4.5/1000 person-years). Cox analysis demonstrated that the lower Hcts were significant predictors TRDED and lower Hcts were more predictive than lower RBC counts. The Hb level was not significantly associated with TRDED. Hazard ratios (HRs) per 1 standard deviation (SD) increase in Hct, RBC count and Hb for incident TRDED were 0.792 (95% confidence interval [CI], 0.666-0.942), 0.874(0.765-0.998), and 0.861 (0.725-1.023) as continuous variables, respectively. The interaction between Hct and RBC count was not statistically significant. Multivariate tertile analysis also revealed that a lower Hct was more predictive of TRDED (HR 2.03 [95% CI, 1.33-3.08] for the bottom [≤43.4%] vs. the top [≥46.7%] tertile [P value = 0.001]) than lower RBC counts (HR 1.54 [95% CI, 0.99-2.38] for the bottom [≤468×104/m3] vs. the top [≥507×104/m3] [P value = 0.054]). These findings demonstrated that lower Hcts were significant predictor of vision-threatening retinopathy for people with diabetes and more useful than the RBC count or Hb. Association of the influence of these three markers on severe retinopathy awaits further investigation. Disclosure M. Yamamoto: None. K. Fujihara: None. T. Osawa: None. M. Harada: None. M. Ishizawa: None. H. Suzuki: None. H. Ishiguro: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

Background Evidence of the role of systolic blood pressure (SBP) in development of severe diabetic retinopathy is not strong, although the adverse effect of low diastolic blood pressure has been a partial explanation. We assessed the predictive ability of incident severe diabetic retinopathy between pulse pressure (PP) which considers both SBP and diastolic blood pressure, compared with SBP. Methods and Results Eligible patients (12 242, 83% men) aged 19 to 72 years from a nationwide claims database were analyzed for a median observational 4.8‐year period. Severe diabetic retinopathy was defined as vision‐threatening treatment‐required diabetic eye diseases. Multivariate Cox regression analysis revealed that hazard ratios (95% CI) of treatment‐required diabetic eye diseases for 1 increment of standard deviation and the top tertile compared with the bottom tertile were 1.39 (1.21–1.60) and 1.72 (1.17–2.51), respectively, for PP and 1.22 (1.05–1.41) and 1.43 (0.97–2.11), respectively, for SBP adjusted for age, sex, body mass index, hemoglobin A1c, fasting plasma glucose, lipids, and smoking status. In a model with SBP and PP simultaneously as covariates, the hazard ratios of only PP (hazard ratios [95% CI], 1.57 [1.26–1.96]) but not SBP (0.85 [0.68–1.07]) were statistically significant. Delong test revealed a significant difference in the area under the receiver operating characteristic curve between PP and SBP (area under the receiver operating characteristic curve [95% CI], 0.58 [0.54–0.63] versus 0.54 [0.50–0.59]; P=0.03). The strongest predictor remained as hemoglobin A1c (area under the receiver operating characteristic curve [95% CI], 0.80 [0.77–0.84]). Conclusions After excluding the significant impact of glycemic control, PP in comparison with SBP is a better predictor of severe diabetic retinopathy, suggesting a role of diastolic blood pressure and arterial stiffness in pathology., See Editorial Dart

Resistance training (RT) is effective for glycemic control in type 2 diabetes mellitus (T2DM) patients. However, the characteristics of an RT program that will maximize its effect and those of patients that will especially benefit from RT are unknown. The objectives of this systematic review were to identify via a comprehensive meta-analysis the characteristics of an RT program for patients with T2DM that might increase the patients’ improvement in glycemic control and the characteristics of patients that will benefit from RT. Electronic-based literature searches of MEDLINE and EMBASE entries from 1 January 1966 to 25 August 2014 were conducted to identify clinical trials examining the effect of RT on glycemic control among patients with T2DM. Study keywords were text words and thesaurus terms related to RT and T2DM. Studies were included if they (1) were clinical trials consisting of two groups with and without RT exercise intervention; (2) had an intervention period of at least 5 weeks; (3) clarified that all patients had T2DM; and (4) reported or made it possible to estimate the effect size [i.e., change in glycosylated hemoglobin (HbA1c) in the RT group minus that in the control group] and its corresponding standard error. The effect size in each study was pooled with a random-effects model. Analyses were stratified by several key characteristics of the patients and RT exercise programs; meta-regression analysis was then used to detect a difference in the effect size among strata within each factor. Linear regression analyses were added by entering each of the following profiles: patients’ baseline characteristics [mean baseline age, body mass index (BMI), and HbA1c levels] and exercise characteristics (total sets per week, total sets per bout of exercise, frequency, and intensity). There were 23 eligible studies comprising 954 patients with T2DM. The pooled effect size (95 % confidence interval) was −0.34 % (−0.53 to −0.16). A program with multiple sets (≥21 vs.

Proteinuria or low eGFR was separately shown to be associated with the development of retinopathy in patients with diabetes. However, it remains unclear whether semi-quantitatively assessed proteinuria by test strips either combined or not combined with low eGFR is predictive of incident retinopathy, especially in its advanced stages.To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that included 6,100 participants (1,074 women, mean age 49.3 y, HbA1c 6.9%) classified as having diabetes mellitus or treatment-required diabetic eye diseases (TRDED) during an 8-y period. Urinary protein was assessed by test strip and a result of ≥1+ indicated proteinuria, which reportedly corresponds to a urine protein concentration of ≥30 mg/dL. Multivariate Cox regression model was used to identify predictors of TRDED. During the study period, 147 patients developed TRDED (4.5/1000 person-years). Cox analysis showed that proteinuria was a significant and independent predictor of TRDED but not the serum creatinine level. Hazard ratios (HRs) for proteinuria, low eGFR (defined as Disclosure M. Yamamoto: None. K. Fujihara: None. T. Osawa: None. M. Harada: None. M. Ishizawa: None. H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. H. Suzuki: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Although the importance of support of patients by family members is emphasized for diabetes care, evidence of achieving adequate glycemic control (GC) through instructing family members to help in self-management care of diabetes patients has not been established. This meta-analysis assessed the effect of family-oriented diabetes programs on GC. The pooled A1C change shown in 31 studies that were retrieved from systematic literature searches for clinical trials presenting data on the net effect of family education on the reduction in glycohemoglobin A1C (A1C) (i.e., difference in A1C change between intervention groups involving family members and that not involving family members [control group]) was -0.45% (PP Disclosure S. Kodama: None. K. Fujihara: None. H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. C. Horikawa: None. Y. Yachi: None. M. Ishizawa: None. S. Matsunaga: None. S. Tanaka: None. K. Kato: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Background: The extracellular matrix is associated with the pathophysiology of diabetic complications; however, the role of chondroitin sulfate (CS) remains unclear. To clarify the effects of CS on diabetic neuropathy (DN), we assessed the effect of genetically reducing CS in mice through disruption of a gene encoding the rate-limiting CS-synthesizing enzyme, i.e., CS N-acetylgalactosaminyltransferase-1 (T1). Methods: T1 knockout (T1KO) mice were generated from the C57BL/6N strain and C57BL/6N were prepared as wild type (WT). Diabetes was induced through streptozotocin injection in 6-week-old male mice. All data were obtained 3 weeks after streptozotocin injection. Results: In the heat radiant test, while thermal nociception in nondiabetic WT and T1KO mice were normal and significantly disrupted in diabetic WT mice, that in diabetic T1KO mice was preserved. The number of plantar peripheral nerve fibers was also significantly decreased in diabetic WT mice; however, that in diabetic T1KO mice were relatively normal. Furthermore, immunohistochemistry revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, which contains a cluster of sensory neuron bodies. In contrast, those neurons were protected in diabetic T1KO mice. Hence, nociception and thermoception are preserved in diabetic T1KO mice. To investigate the mechanisms underlying these events, we analyzed gene expression in DRG through real-time polymerase chain reaction and confirmed the suppression of caspase-3 and caspase-9 in diabetic T1KO mice, compared to those in diabetic WT mice. However, levels of Bcl2, TNF-α, MMP9, and reactive oxygen species-related enzymes (HO-1, NOX) did not differ significantly between WT and T1KO diabetic mice. Conclusions: Reduced CS production is suggested to have potentially beneficial effects on preventing DN by suppressing apoptotic signaling and could be a cutting-edge target of clinical application. Disclosure H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. T. Ushiki: None. A. Kawasaki: None. K. Cho: None. M. Masuko: None. K. Sango: None. M. Igarashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Background Our aim is to examine the dose–response association between cumulative genetic risk and actual risk of type 2 diabetes mellitus (T2DM) and the influence of adjustment for covariates on T2DM risk through a comprehensive meta-analysis of observational studies. Methods Electronic literature search using EMBASE and MEDLINE (from 2003 to 2014) was conducted for cross-sectional or longitudinal studies that presented the odds ratio (OR) for T2DM in each group with categories based on the total number of risk alleles (RAs) carried (RAtotal) using at least two single-nucleotide polymorphisms. Spline regression model was used to determine the shape of the relationship between the difference from the referent group of each study in RAtotal (ΔRAtotal) and the natural logarithms of ORs (log OR) for T2DM. Results Sixty-five eligible studies that included 68 267 cases among 182 603 participants were analysed. In both crude and adjusted ORs, defined by adjusting the risk for at least two confounders among age, gender and body mass index, the slope of the log OR for T2DM became less steep as the ΔRAtotal increased. In the analysis limited to 14 cross-sectional and four longitudinal studies presenting both crude and adjusted ORs, regression curves of both ORs in relation to ΔRAtotal were almost identical. Conclusion Using only single-nucleotide polymorphisms for T2DM screening was of limited value. However, when genotypic T2DM risk was considered independently from risk in relation to covariates, it was suggested that genetic profiles might have a supplementary role related to conventional T2DM risk factors in identifying individuals at high risk of T2DM. Copyright © 2015 John Wiley & Sons, Ltd.

We report a 55-year-old Japanese man who presented with symptomatic hypoglycemia attributable to atypical antipsychotic drugs (APD). He had been taking olanzapine, quetiapine, and paliperidone. One morning, his consciousness level dropped without inducement and his blood glucose was low. His symptoms improved after intravenous glucose infusion. These episodes reoccurred a few times, but ceased after APD were stopped. Physical examination did not find any organic disease that might cause hypoglycemia. Hyperglycemia, dyslipidemia, and body weight gain are well-documented side-effects of APD, but hypoglycemia is rare. There are a variety of hypotheses on how APD cause hypoglycemia: (1) Weight gain and dyslipidemia caused by APD might increase insulin resistance, meaning that excess insulin is secreted, causing hypoglycemia. (2) The quantity of basal insulin secreted by pancreatic beta cells might be enhanced by APD, which might cause hypoglycemia. (3) APD might work as an antagonist of muscarinic receptors such that insulin secretion might continue even after the glucose level has returned to normal, which might cause hypoglycemia. However, the mechanism is not fully understood and more research is needed.

OBJECTIVE To examine the independent and combined associations of cardiorespiratory fitness (CRF) and muscular fitness (MF) with cardiometabolic risk factors in Japanese adolescents. METHODS A cross-sectional study including 993 Japanese adolescents (aged 13-14 years) was undertaken. Height, body mass, blood pressure, lipid profile (non-fasting), and HbA1c were measured. The physical fitness (PF) test included measurements of CRF (20 m multistage shuttle run test), upper limb strength (hand grip strength), lower limb strength (standing long jump), and muscular endurance (sit-ups). The clustered cardiometabolic risk (CCMR) was estimated by summing standardized Z-scores of body mass index (BMI), mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDL-C), and HbA1c. RESULTS Linear regression analysis showed that all PF factors except for muscular endurance were inversely correlated with CCMR (P

Purpose Since the combined effects of proteinuria and a moderately decreased eGFR on incident severe eye complications in patients with diabetes are still largely unknown, these associations were determined in a large historical cohort of Japanese patients with diabetes mellitus. Methods We evaluated the effects of overt proteinuria (OP) (dipstick 1+ and over) and/or moderately reduced estimated glomerular filtration rate (eGFR) (MG) (baseline eGFR 30.0-54.9 mL/min/1.73 m2) on the incidence of treatment-required diabetic eye diseases (TRDED). We divided 7709 patients into four groups according to the presence or absence of OP and MG: no OP without MG (NP[MG-]), OP without MG (OP[MG-]), no OP with MG (NP[MG+]), and OP with MG (OP[MG+]). Multivariate Cox analyses were performed to calculate hazard ratios (HRs) with 95% confidence intervals for combinations of the presence and/or absence of OP and MG on the risk of developing TRDED. Results During the median follow-up period of 5.6 years, 168 patients developed TRDED. HRs for OP and MG for incident TRDED were 1.91 (95% confidence interval, 1.27-2.87) and 1.90 (1.11-3.23), respectively. HRs for incident TRDED were 1.73 (1.11-2.69) and 5.57 (2.40-12.94) for OP(MG-) and OP(MG+), respectively, in comparison with NP(MG-). Conclusions In Japanese patients with diabetes, OP and MG were separately as well as additionally associated with higher risks of TRDED. Results indicate the necessity of the simultaneous assessment of proteinuria and eGFR for appropriate evaluation of risks of severe eye complications in patients with diabetes.

AIMS To determine incidence and predictors of starting dialysis in patients with diabetes emphasizing blood pressure variables. METHODS A nationwide database with claim data on 18 935 people (15 789 men and 3146 women) with diabetes mellitus aged 19 to 72 years in Japan was used to elucidate predictors for starting dialysis. Initiation of dialysis was determined from claims using ICD-10 codes and medical procedures. Using multivariate Cox modelling, interactions between glycaemic and blood pressure values were determined. RESULTS During a median follow-up of 5.3 years, incidence of dialysis was 0.81 per 1000 person-years. Multivariate analysis of a model involving systolic and diastolic blood pressure (SBP and DBP) simultaneously as covariates showed that hazard ratios (HRs) for starting dialysis for each 1-SD elevation in SBP and DBP were 2.05 (95% confidence interval 1.58-2.64) and 0.66 (0.50-0.88), respectively, implying that pulse pressure (PP) was a promising predictor. For confirmation, a model involving SBP and PP simultaneously as covariates demonstrated that HRs for each 1-SD elevation in SBP and PP were 1.09 (0.81-1.48) and 1.54 (1.14-2.08), respectively, with PP the more potent predictor. Compared with HbA1c