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Context. Esaxerenone is a new mineralocorticoid receptor antagonist (MRA). It is an oral nonsteroidal MRA with high MR-binding specificity and antihypertensive effects in patients with essential hypertension and primary aldosteronism (PA). This study aimed to investigate the underlying characteristics of PA patients who responded best to an esaxerenone treatment. Design. Retrospective cohort study. Patients. The data was obtained from a total of 87 PA patients treated with esaxerenone. The treatment group comprised 33 patients who received esaxerenone as first-line therapy and 54 patients that switched from another MRA to esaxerenone. Measurements. Blood pressure (BP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), serum potassium level, estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and brain natriuretic peptide (BNP) were assessed before and after treatment with esaxerenone. Patients with overall reductions in their systolic or diastolic BP by 10 mmHg, or more, were considered responders. Unpaired t-tests of the biochemical and personal parameters between responders and nonresponders were run to find the most influencing characteristic for treatment success. Results. BP overall decreased after treatment with esaxerenone (systolic BP: P = 0.025 , diastolic BP: P = 0.096 ). Serum potassium levels increased, while eGFR decreased ( P = 0.047 and 0.043, respectively). No patients needed a dose reduction or treatment discontinuation of esaxerenone based on the serum potassium and eGFR criteria. UACR and BNP decreased insignificantly. The responders were significantly older than the nonresponders of the esaxerenone treatment ( P = 0.0035 ). Conclusions. Esaxerenone was effective in older patients with primary aldosteronism.

AIM: To identify predictive factors for surgical site infection (SSI) in patients with type 2 diabetes and develop a prediction tool. MATERIALS AND METHODS: We retrospectively analyzed the perioperative blood glucose management of 105 patients with type 2 diabetes treated from 2016 to 2018 at Chiba University Hospital. The primary outcome was SSI onset within 30 postoperative days; moreover, predictive factors were identified using univariate analysis. Principal component analysis and logistic regression analysis were performed to prepare SSI predictive model using the identified predictive factors. The area under the receiver operating characteristic curve (AUC) was evaluated. Based on the predictive model, we developed a risk engine for SSI prediction. RESULTS: Compared with patients without SSI (n = 70), those with SSI (n = 35) had significantly higher fasting blood glucose levels at referral (169.1 ± 61.8 mg/dL vs. 140.1 ± 56.6, P = 0.036), preoperative mean blood glucose levels (178.3 ± 48.4 mg/dL vs. 155.2 ± 39.7, P = 0.009), preoperative maximum blood glucose levels (280.4 ± 87.3 mg/dL vs. 230.3 ± 92.4, P = 0.009), preoperative blood glucose fluctuations (54.9 ± 24.1 mg/dL vs. 37.7 ± 23.1, P = 0.001), percentage of hospitalization at referral (54.3% vs. 20.0, P

Backgrounds and aim Lipoprotein lipase (LPL) deficiency is a genetic disorder with a defective gene for lipoprotein lipase, leading to very high triglycerides. In the daily practice it is much more common to come across severely hypertriglyceridemia without homozygous or compound heterozygous LPL deficiency (SHTG). Methods We investigated on how to screen homozygous or compound heterozygous LPL deficiency using lipid parameters by meta-analyzing past 20 subjects on this genetic disease reported by Japanese investigators. As a comparison with LPL deficiency, 21 subjects with SHTG from recent two studies were included in this study. Results Serum HDL-C levels were significantly lower in LPL deficiency than in SHTG (0.38 ± 0.13 vs 0.94 ± 0.28 mmol/L (mean ± SD), p Conclusion We found for the first time that serum HDL-C is an extremely useful marker for discriminating LPL deficiency from SHTG in Japanese population.

Introduction Sodium glucose co-transporter 2 (SGLT2) inhibitors are widely used in the management of type 2 diabetes mellitus; they prevent cardiovascular events and reduce fat mass. However, little is known about the effects of SGLT2 inhibitors on type 1 diabetes mellitus as an adjuvant to insulin therapy. Therefore, we aimed to elucidate the effects of SGLT2 inhibitors on body composition of patients with type 1 diabetes mellitus and assess blood glucose variability. Methods A single-center, single-arm, prospective, interventional study was performed on Japanese patients with type 1 diabetes mellitus who were not administered SGLT2 inhibitors prior to this study. These patients were equipped with flash glucose monitoring (FGM) and administered ipragliflozin 50 mg daily. Body composition was evaluated using bioelectrical impedance analysis, and glycemic variabilities were assessed using FGM before and after SGLT2 inhibitor treatment. Results After 52 weeks of treatment, the total fat mass tended to be reduced (− 9.10% from baseline, P = 0.098). In addition, skeletal muscle mass also decreased (− 2.98% from baseline, P = 0.023). Although the basal insulin dose was reduced, SGLT2 inhibitors decreased HbA1c levels. FGM revealed that glycemic variabilities were also reduced, and time within the target glucose range increased (51.7% vs. 62.5%, P = 0.004). Conclusion SGLT2 inhibitors have beneficial effects on glycemic variabilities and fat mass reductions in patients with type 1 diabetes mellitus. However, loss of skeletal muscle is a major concern; therefore, caution is required when using SGLT2 inhibitors in lean patients with type 1 diabetes mellitus. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000042407).

Background: Werner syndrome (WS) is a hereditary premature aging disorder in which various signs of accelerated aging develop after puberty. These signs include gray hair, cataracts, diabetes, myocardial infarction, and malignant tumors. Patients with WS frequently show severe insulin resistance, visceral fat accumulation, and subcutaneous fat atrophy, leading to myocardial infarction due to atherosclerosis. However, the mechanism of accelerated aging and its effect on adipose tissue dysfunction and glucose intolerance remain unclear. Materials and Methods: We evaluated visceral fat area and insulin resistance using the glucose clamp method in four Japanese patients with WS. Stromal vascular fraction (SVF) was obtained from the subcutaneous adipose tissue of WS patients (WSVF) . Healthy individuals and phenotypes were examined. Results: The median glucose infusion rate (GIR) was 3.78 mg/kg/min (interquartile range 3.05, 4.25; insulin infusion rate=1.25 mU/kg/min; normal range >6 mg/kg/min) . All Japanese patients showed severe insulin resistance, sarcopenia, and visceral fat accumulation. The visceral fat area and GIR were inversely correlated (R2=0.72) . In vitro analysis of WSVF revealed early replicative senescence and an increase in SAβgal staining. A significant increase was observed in the expression of senescence-associated secretory phenotypes (SASP) , such as IL1B, IL6, and CXCL8 (p Conclusions: SVF from the adipose tissue of WS patients exhibited cellular senescence and increased inflammatory cytokine production. Cellular senescence and chronic inflammation of adipose tissue induced by SASP may exacerbate insulin resistance in WS patients. Disclosure D.Sawada: None. T.Takatani: None. H.Hamada: None. K.Yokote: None. H.Kato: n/a. Y.Maezawa: None. D.Kinoshita: None. S.Funayama: None. H.Kaneko: None. T.Minamizuka: None. M.Koshizaka: None. T.Shiohama: None. Funding JSPS (20K17485) , AMED (21bm0804016h0005)

Background: Diabetic kidney disease (DKD) is the most common cause of dialysis induction in the United States. Tcf21 is a basic helix-loop-helix transcription factor that is essential for the development of the lungs, heart, and kidneys. Previously, we reported that Tcf21 regulates podocyte development. However, the precise role of Tcf21 in mature individuals and DKD remains unclear. Method: We generated mice that lacked Tcf21 only in podocytes after birth (iKO) using a doxycycline induction system. We also constructed a diabetes mouse model using streptozotocin injections. In addition, we used cultured human podocytes to investigate the effects of Tcf21 overexpression and the factors that regulate Tcf21 expression. Results: When the Tcf21 gene was deleted specifically in podocytes in 3-week-old mice, urinary protein was not observed. In contrast, when diabetes was induced in these mice, massive urinary protein and strong glomerulosclerosis was present in 60% of iKO mice. Ultrastructural analysis revealed glomerular basement membrane thickening and podocyte foot process effacement, suggesting that iKO mice are susceptible to DKD. In addition, RNA-seq analysis of Tcf21-overexpressing podocytes showed accumulation of genes involved in the interferon pathway, extracellular matrix production, senescence, and autophagy in gene ontology analysis. Analysis of individual genes showed upregulation of interferon-related genes such as IFI6 and IFI27, increased expression of PAI-1, which is one of the senescence-associated secreted phenotypes, and decreased expression of HMGA2, whose SNIP is known to correlate with susceptibility to DKD. In addition, Tcf21 expression was suppressed by 58% and 27% after TGF-β and high glucose plus insulin stimulation, respectively. Conclusion: Our results suggest that Tcf21 protects against DKD in mature individuals. Elucidation of the mechanism by which Tcf21 prevents DKD may lead to the identification of novel therapeutic targets. Disclosure N.Teramoto: None. Y.Maezawa: None. T.Minamizuka: None. M.Koshizaka: None. K.Yokote: None.

Aims: Diabetic macular edema (DME) leads to impaired vision. The first line of treatment is intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent. However, there are patients who are refractory to this. We reported patients whose DME were refractory to anti-VEGF agents and showed improvement by using sodium glucose cotransporter 2 inhibitors (SGLT2is) . The effectiveness of SGLT2is for DME was assessed using a health insurance claim database. Methods: The JMDC inc. database covering million Japanese patients between 2005-20was used for analysis. Patients with type 2 diabetes (T2D) with DME were included, and those who were undergo dialysis, had other ocular diseases that may be treated by anti-VEGF agents, or were not on treatment with any antidiabetic drug introduced after 2014 were excluded. Propensity score matching was performed between SGLT2i users and non-users. The frequency and the duration of intravitreal injection of anti-VEGF agent after the period from the start of SGLT2is or other antidiabetic drugs were analyzed. Results: In this study, 340 matched patients with T2D were analyzed. Initiation of SGLT2is revealed a decrease in the frequency of anti-VEGF agent injection (2.7 ± 4.1 vs. 3.8 ± 4.6 times, p < 0.001; the Wilcoxon signed rank test, p < 0.001, 95%CI -0.25 to -0.085; the Poisson regression, p < 0.001, HR 0.80, 95% CI 0.73 to 0.87; the recurrent event analysis) and an extension in the duration for the requirement of the first injection of anti-VEGF agent (the number of patients who received no anti-VEGF agents, 96 vs. 32, p < 0.001; the log-rank test) . Conclusion: Using SGLT2is for patients with T2D complicated by DME extended the duration for the requirement of the first anti-VEGF agent injection and decreased the frequency of anti-VEGF agent injection. SGLT2is may be an option for DME treatment. Disclosure R.Ishibashi: Research Support; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., YL Biologics, ZERIA Pharmaceutical Co.,Ltd. E.Kawakami: None. M.Koshizaka: None. Y.Maezawa: None. K.Yokote: None. Y.Takatsuna: None. T.Tatsumi: None. S.Yamamoto: None. Y.Inaba: None. Y.Shiko: None.

Background: COVID-is a pandemic disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . Diabetes is a major risk factor for the severe progression and outcome of COVID-infection. Although some risk factors have been revealed, determining undetected risk factors for severe infection would enable identifying patients who may benefit from aggressive supportive care and early intervention. Methods: A retrospective observational study of 100 diabetes patients who were admitted with confirmed COVID-infection was conducted. The patients were divided into two groups - severe and moderate - based on intensive care unit (ICU) admission. The differences between the groups were analyzed with multivariable logistic regression to reveal the risk factors. Results: Of 100 patients, the mean (SD) age was 62.1 (13.0) years, 70 (70.0%) were male, and 48 (48.0%) were ≥ 65 years. Among patients with severe COVID-infection, 25 (25%) were admitted to ICU, and one patient died. Patients with severe infection had a significantly lower albumin level (severe 2.81 ± 0.37 g/dL vs. moderate 3.39 ± 0.50, p Conclusions: In patients with diabetes, albumin was an independent predictor for the development of severe COVID-19. Disclosure M.Shoji: None. N.Teramoto: None. A.Hayashi: None. Y.Maeda: None. H.Ochiai: None. A.Tsukagoshi: None. Y.Maezawa: None. M.Koshizaka: None. K.Yokote: None.

Cushing's disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing's disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing's disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing's disease.

Introduction In Japan, several sodium glucose co-transporter 2 (SGLT2) inhibitors have been used for type 1 diabetes mellitus as an adjuvant therapy to insulin therapy; however, there are no clinical reports regarding the satisfaction of its use. Therefore, we conducted a survey among patients with type 1 diabetes undergoing treatment using an SGLT2 inhibitor. Methods This is a single-arm open-label prospective study including 24 patients with type 1 diabetes who were to be initiated on ipragliflozin treatment between March and August 2019. All participants provided written informed consent. They completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) for the survey and 3 months of observation after the administration of an SGLT2 inhibitor (50 mg of ipragliflozin), and changes from baseline diabetes treatment satisfaction were evaluated using modified DTSQ scores (five-step evaluation) and were analyzed. Results The average score for each question on DTSQ significantly increased [mean (standard deviation); 0.25 (0.25) vs 0.83 (0.77), P = 0.004]. Approximately 75% of the patients perceived an improvement in glycemic control over short periods of time. Finally, 54.2% of patients were highly satisfied and would recommend the SGLT2 inhibitor treatment [0.0 (0.0) vs. 0.92 (1.32), P

Background We present here a 72-y-old Japanese woman with lipoprotein lipase (LPL) deficiency and analyzed her lipolytic enzymes in detail before and after pemafibrate treatment. Methods She had a serum triglycerides (TG) of 22.6 mmol/l at a medical checkup at the age of 52 y. She was referred to our hospital at the age of 61 y. Her serum lipoprotein lipase (LPL) concentration was extremely low, suggesting the clinical diagnosis of LPL deficiency. She experienced an event of acute pancreatitis at the age of 65 y. Results Next-generation sequencing analysis revealed a homozygous nonsense mutation in the LPL gene, c.1277G > A (p.Trp409Ter). Her serum TG, LPL and hepatic lipase (HL) concentrations were 15.0 mmol/l, 23 ng/ml and 66 ng/ml, respectively. Fifteen minutes after intravenous heparin injection (30 U/kg), her serum TG, LPL and HL concentrations turned to 14.1 mmol/l, 20 ng/ml and 660 ng/ml, respectively. Eight weeks of pemafibrate treatment (0.2 mg/day) caused a modest reductions in serum TG (15.02 → 13.58 mmol/l) and considerable increases in preheparin HL (66 → 76 ng/ml) and PHP-HL (660 → 1118 ng/ml) concentrations and PHP-HL activities (253 → 369U/l) despite almost no effect on LPL concentrations and activities. Conclusions These findings suggest that HL may contribute to the reduction of plasma TG in LPL deficiency.

Introduction To compare the effects of ipragliflozin, a sodium-glucose transporter 2 inhibitor, with those of metformin on visceral fat (as well as muscles and bones) in Japanese elderly patients with type 2 diabetes (T2D), we conducted a sub-analysis of a prospective, multicenter, blinded-endpoint randomized-controlled study. Methods In total, 103 patients with T2D (body mass index ≥ 22 kg/m2; glycated hemoglobin, 7–10%) and being treated with sitagliptin (a dipeptidyl peptidase-4 inhibitor) were included and randomized to receive ipragliflozin or metformin. The primary outcome was the change in visceral fat area measured using computed tomography 24 weeks following treatment. The secondary outcomes included changes in subcutaneous and total fat area, muscle volume, bone density measured using computed tomography, handgrip strength, bone markers, plasma glucose, insulin, homeostasis model assessment (HOMA)2-beta, HOMA2-R, glycated hemoglobin, lipid panel, uric acid, blood pressure, adiponectin, and high-sensitivity C-reactive protein. All patients aged 65–74 years were selected for sub-analysis. Results The sub-analysis included 15 and 14 patients in the ipragliflozin and metformin groups, respectively. The patients’ backgrounds were well balanced. Visceral fat area reduction was greater in the ipragliflozin group than in the metformin group (− 10.58% vs. − 6.93%; P = 0.034). There were significant differences in the changes in bone absorption markers, uric acid, and total cholesterol levels between the groups. Conclusion Ipragliflozin significantly reduced the visceral fat area compared with metformin when added to sitagliptin in elderly patients with T2D. Long-term and large-scale studies are required to elucidate whether ipragliflozin is suitable for elderly patients. Trial Registration The study was registered at https://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170). Electronic supplementary material The online version of this article (10.1007/s13300-020-00949-0) contains supplementary material, which is available to authorized users.

AIM An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and

A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium‐dependent glucose transporter‐2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%‐10%, and body mass index (BMI) ≥ 22 kg/m2. Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000‐1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)‐resistance, and increased HDL‐cholesterol levels. Metformin significantly reduced HbA1c and LDL‐cholesterol levels and increased HOMA‐beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase‐4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Aim Sarcopenia is defined as a condition that combines decreased skeletal muscle mass with weakness or decreased physical function. It is well known that in older adults, the presence of sarcopenia is a risk of frailty, falls and physical dysfunction. Patients with Werner syndrome are characterized by visceral fat accumulation and thin limbs, but the prevalence of sarcopenia in patients with Werner syndrome has not been investigated. Methods A literature search was conducted using Werner syndrome and skeletal muscle as keywords. We also analyzed data from our 7 Werner syndrome patients. Results A literature search on the relationship between Werner syndrome and skeletal muscle yielded only one article reported from Japan. According to this paper, a decrease in skeletal muscle mass (appendicular skeletal muscle index) was observed in all 9 Werner syndromes investigated. On the other hand, in our 7 Werner syndrome patients, their appendicular skeletal muscle indexes were below the standard value except for one male patient who had continued resistance exercise. Conclusion The decrease in skeletal muscle mass frequently occurs in patients with Werner syndrome. However, resistance exercise may prevent the appearance of sarcopenia and requires early intervention in patients with Werner syndrome. Geriatr Gerontol Int 2021; 21: 139-141.

Aims To evaluate the characteristics of diabetes associated with Werner syndrome. Methods A literature search was done with search term "Werner syndrome" and "Diabetes". Results and conclusions Prevalence of diabetes is extremely high in Werner syndrome. Diabetes associated with Werner syndrome is classified as "accompanied with other diseases and conditions and the one occurring mainly in association with other genetic syndromes." This type of diabetes is marked by accumulated visceral fat and high insulin resistance, despite low body mass index. Thiazolidine derivatives and metformin are effective for glycemic control. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, could be potentially beneficial for patients with Werner syndrome. Furthermore, the establishment of diet therapy as well as exercise therapy is warranted. Geriatr Gerontol Int 2020; ••: ••-••.

Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro. On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.

Accumulation of visceral fat leads to insulin resistance and diabetes. Therefore, it is important to elucidate the mechanism by which adipose progenitor cells (APCs) are maintained and how they differentiate. The bHLH transcription factor 21 (Tcf21) is expressed in visceral, but not in subcutaneous fat, and used as a marker for white adipose tissues. Although Tcf21 promotes IL6 expression in APCs in vitro, little is known about its role in vivo. Therefore, we aimed to clarify the role of Tcf21 in visceral fat using mouse models. Tcf21 was deleted after birth using inducible Cre-LoxP system to circumvent the lethality due to cardiac malformation (iTcf21 KO). The mice were fed high fat diet (HFD) from 6 to 24 weeks of age. Weight gain, blood glucose level, epididymal fat weight, and APC count (0.8x104/g fat for iKO and 2.9x104/g fat for wild type (WT)) of epididymal fat were all low in iTcf21KO compared to WT mice. Insulin sensitivity was increased in iTcf21KO mice. Staining of epididymal fat from Tcf21lacZ/+ mice using X-Gal revealed that Tcf21 was localized in the vascular mural cells. Isolation of Sca1+ Lin- APCs using magnetic activated cell sorting revealed that Tcf21 mRNA was expressed in the APCs, along with Pdgfrb and Periostin. In contrast, Tcf21 expression was attenuated in the adipose tissue of WT mice after HFD, and in adipocyte culture that was differentiated from the vascular stromal fraction (SVF). In addition, Tcf21 expression suppressed by HFD was upregulated in adipocytes undergoing de-differentiation by ceiling culture. Adipocyte induction from SVF resulted in no differences between WT and iTcf21KO mice assessed by oil red O staining. However, adipocyte differentiation and expression of Pparg and Cebpb were suppressed in 3T3-L1 cells in which Tcf21 was overexpressed. These findings suggest that Tcf21 is expressed in the APCs of vascular mural cells, controls the number of APCs, and potentially contributes to the maintenance of their progenitor state through suppression of adipocyte differentiation. Disclosure T. Minamizuka: None. Y. Maezawa: None. H. Udagawa: None. Y. Baba: None. M. Koshizaka: None. Y. Endo: None. K. Yasuda: None. K. Yokote: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker’s Bureau; Self; Abbott, Astellas Amgen, AstraZeneca K.K., Bayer Inc., FUJIFILM Pharmaceuticals U.S.A., Inc., Kaken Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.

Objective: Early prevention of renal dysfunction progression and cardiovascular disease is important in diabetes. We aimed to determine the risk factors for renal dysfunction and cardiovascular disease among medical insurance subscribers between 40 and 74 years of age in Japan. Methods: This retrospective study involved 1585 subjects, including 97 patients with diabetes, who had undergone a specific health checkup in 2013 and 2019. The primary composite outcome included decline in estimated glomerular filtration rate (eGFR) by ≥30%, increase in urine albumin-to-creatinine ratio (UACR) by ≥30 mg/gCre, and increase in the Framingham Risk Score by ≥5%. We categorized the subjects into groups with and without these outcomes. Univariate analysis was conducted using Welch’s t-test, Pearson’s correlation coefficient, and Fisher’s exact test. Based on the univariate analysis, principle component and logistic analyses were performed to determine the predictive risk factors. Results: Significant between-group differences were noted in terms of age, BMI, waist circumference, blood pressure, hemoglobin, hematocrit, triglyceride, HDL-C, LDL-C, AST, ALT, γ-GTP, HbA1c, serum creatinine, eGFR, urine creatinine, UACR, urine protein-to-creatinine ratio, sex, antihypertensive medication, history of anemia, diabetes, smoking, alcohol consumption, weight change, exercise habits, the will to improve and others. Logistic analysis showed that age (odds ratio [95% confidence interval]: 1.04 [1.02-1.06], P Conclusion: Lower HDL-C and higher HbA1c were detected as the risk factors for patients with diabetes and without diabetes. The results of this study indicate that the harmful effects of hyperglycemia and dyslipidemia may have started before the patients actively exhibit metabolic disorders. Disclosure R. Terayama: None. M. Koshizaka: None. T. Shibata: None. T. Ban: None. Y. Maezawa: None. K. Yokote: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker’s Bureau; Self; Abbott, Astellas Amgen, AstraZeneca K.K., Bayer Inc., FUJIFILM Pharmaceuticals U.S.A., Inc., Kaken Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.

Introduction Diabetic macular edema (DME) threatens daily life activities such as reading and driving and reduces the patients’ quality-of-life. Recently, anti-vascular endothelial growth factor (VEGF) agents have become a first-line therapy in DME. However, therapy with anti-VEGF agents has several problems: repeated invasive injections are required; medical costs are high; and a certain proportion of patients with DME are resistant to treatment with anti-VEGF agents. While sodium-glucose co-transporter 2 (SGLT2) inhibitors have been widely used for the treatment of type 2 diabetes mellitus (T2DM), the effects of a combination therapy with anti-VEGF agent and SGLT2 inhibitor on DME are not yet known. Methods This study enrolls subjects with T2DM and DME, randomizes them into either a study agent treatment group (treated with ranibizumab as anti-VEGF agent and luseogliflozin as SGLT2 inhibitor) or a control group (treated with ranibizumab and glimepiride), and observes the subjects for 52 weeks after initiation of treatment. Planned outcomes: The primary endpoint is intergroup difference in the number of intravitreal anti-VEGF injections to the study eye from baseline to week 48. Secondary and exploratory endpoints include safety and ophthalmologic and internal medical clinical parameters. Registration This study is registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN000033961) and Japan Registry of Clinical Trials (jRCTs031180210).

Aims/Introduction Recent randomized clinical trials have suggested that sodium–glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium–glucose cotransporter 2 inhibitors on bone and muscle are unclear. Materials and Methods A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium–glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m2 and hemoglobin A1c 7–10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000–1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate‐resistant acid phosphatase 5b (TRACP‐5b); handgrip strength; abdominal cross‐sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. Results After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross‐sectional muscle area were not significantly different between the two groups. However, TRACP‐5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs −10.30%, P, Ipragliflozin in combination with sitagliptin did not affect bones or muscles adversely compared to metformin. However, ipragliflozin increased the levels of the bone resorption marker, tartrate‐resistant acid phosphatase 5b.

Aims/Introduction The incidence of type 2 diabetes is higher in elderly patients, in whom this disease is associated with dementia, falling, stroke and death. We utilized a continuous glucose monitoring device to analyze the relationship between hypoglycemia and diabetes treatments to identify risk factors for hypoglycemia (defined as a blood glucose level

Objective: In Japan, obesity is defined as a body mass index (BMI) ≥25 kg/m2. Sarcopenic obesity (low BMI with visceral fat accumulation) has high mortality and is common in elderly people. We evaluated the value of visceral fat area (VFA) measurement in elderly type 2 diabetes (T2D) patients for determining sarcopenic obesity. Methods: We analyzed 124 T2D patients who were hospitalized for glycemic control. They were divided into elderly people (aged ≥65 years) (n=74) and non-elderly people (aged Results: We observed the following patient characteristics: the elderly group; 55 men (74.3%), average age 73.2 years, BMI 24.7 kg/m2, and VFA 137.7 cm2; and the non-elderly group; 25 men (50%), average age 49.8 years, BMI 31.8 kg/m2, and VFA 180.7 cm2. Only 6/43 (14.0%) metabolism related items differed significantly between patients with BMI ≥25 kg/m2 and those with BMI Conclusion: Although BMI is a simple and useful index of obesity evaluation, sarcopenic obesity may be overlooked. In elderly patients who tend to have sarcopenic obesity, VFA measurement might be a more useful index of obesity. Disclosure T. Minamizuka: None. Y. Maeda: None. M. Koshizaka: Research Support; Self; Astellas Pharma Inc., Pfizer Health Research Foundation, Taisho Pharmaceutical Co., Ltd. T. Ishikawa: None. Y. Maezawa: None. K. Yokote: None.

Background/Purpose: Perioperative blood glucose management is important for complication prevention and early hospital discharge. The relation between blood glucose fluctuations and infection is few reported. This study aimed to find predictive risk factors to identify high-risk patients with diabetes requiring more extensive management. Methods: A retrospective study was performed on the perioperative blood glucose management of 105 patients. The presence of infection within one month after surgery was the primary outcome, and the predictive factors were identified. For statistical analysis, analysis of variance or Wilcoxon rank sum test was used. Based on univariate analysis, principle component analysis and logistic analysis were performed to prepare a prediction model of infection onset within one month after surgery using predictive risk factors. The area under the receiver operating characteristic curve (AUC) was evaluated. Results: Patients with infection within one month after surgery had higher mean blood glucose levels (185.1±28.7 vs. 168.3±33.6 mg/dL, P=0.013), larger preoperative blood glucose fluctuations (54.9±24.1 vs. 37.7±23.1 mg/dL, P=0.006), lower albumin level (3.6±0.6 vs. 3.9±0.6 g/dL, P=0.046), longer operation time (432.5±179.6 vs. 282.5±178.3 minute, P Discussion: Preoperative blood glucose fluctuations and long operation time were risk factors for infection in perioperative patients with diabetes. This prediction model can detect these high-risk patients. Disclosure M. Koshizaka: Research Support; Self; Astellas Pharma Inc., Pfizer Health Research Foundation, Taisho Pharmaceutical Co., Ltd. R. Ishibashi: None. Y. Maeda: None. T. Ishikawa: None. Y. Maezawa: None. M. Takemoto: None. K. Yokote: None. Funding Pfizer Health Research Foundation

Background There is a lack of evidence that multidrug use triggers adverse events. Therefore, the main purpose of this study was to clarify the relationship between the total number of drugs and number of high-risk prescriptions administered to Japanese elderly patients. Methods Using hospital electronic medical records (EMR), we evaluated the prescriptions of outpatients aged 65 years or older. We defined prescriptions of potentially inappropriate medications (PIMs) and overlapping prescription of drugs with the same mechanism of action (DSAs) as high-risk prescriptions. We analyzed the relationship among total number of drugs and high-risk prescriptions. In addition, we performed a secondary research to determine whether the hospitalization rate and concomitant medication contents differ depending on the high-risk prescriptions. Results Data for 13,630 outpatients were analyzed. A significant positive correlation between the numbers of total drugs and PIMs was found. The prescription frequency of individual PIMs rose as the total number of prescription drugs increased. The odds ratio (OR) of overlapping DSAs was significantly higher in patients using 5 or more drugs. In addition, there were significantly more prescriptions of laxatives among patients with overlapping prescriptions of anticholinergic drugs. The use of almost all PIMs was not an independent risk factor for hospitalization; instead, the number of PIMs was an independent risk factor for hospitalization [OR 1.18 (95% CI, 1.12–1.26)]. Conclusions The number of PIMs and overlapping DSAs were high in patients receiving multidrug treatment. To avoid adverse events and hospitalization, it might be useful to review prescriptions and consider the number of PIMs and overlapping DSAs.

Objective: To determine the effects of SGLT2 inhibitor or metformin on reducing visceral fat in Asian patients with type 2 diabetes inadequately controlled with DPP-4 inhibitor, sitagliptin. Methods: A prospective, multicenter, blinded-endpoint, randomized controlled trial was conducted to evaluate the efficacy of treatment with either SGLT2 inhibitor (ipragliflozin) or metformin added on to sitagliptin for visceral fat reduction and glucose control in patients with type 2 diabetes. Patients who met the eligibility criteria were randomly selected (1:1) to receive ipragliflozin (Ipr; 50 mg daily) or metformin (Met; 1000 mg daily). The primary outcome is the change rate in visceral fat area, measured using computed tomography, after 24 weeks of therapy. Two radiologists, blinded to the information, analyzed the images. Results: A total of 51 patients were in enrolled in the Ipr group and 52 in the Met group. The reduction rate in visceral fat area was significantly greater in the Ipr group (-12.06% vs. -3.65%, group difference of -8.40%; 95% CI of -16.4 to -3.38, P Conclusion: Ipr significantly reduced the visceral fat area compared with Met as the secondary agent used in combination with DPP-4 inhibitors. As the fasting insulin level decreased, the reduction in visceral fat associated with Ipr administration may have contributed to the improvement of insulin resistance. Disclosure M. Koshizaka: None. K. Ishikawa: None. R. Ishibashi: None. Y. Maezawa: None. K. Sakamoto: None. D. Uchida: Speaker's Bureau; Self; Takeda Pharmaceuticals Japan, Tanabe Mitsubishi Pharmaceuticals Japan, Sanofi, MSD K.K., Novo Nordisk Inc. S. Nakamura: None. H. Yokoh: None. A. Kobayashi: None. S. Onishi: None. K. Kobayashi: None. J. Ogino: None. H. Tokuyama: None. F. Shimada: None. E. Ohara: None. T. Ishikawa: None. M. Shoji: None. K. Ide: None. S. Ide: None. Y. Baba: None. T. Horikoshi: None. R. Shimofusa: None. S. Takahashi: None. K. Nagashima: None. M. Takemoto: None. K. Yokote: Research Support; Self; Astellas Pharm Ltd, MSD K.K..

The diaphragm is a skeletal muscle that is involved not only in respiration but also in swallowing and lymphatic functions and maintaining posture. Only a few studies have described diaphragm thickness in patients with diabetes. Diaphragm thickness is usually evaluated using ultrasonography (U.S.). However, because evaluation of diaphragm thickness using U.S. is not routinely performed, it is difficult to assess it in a retrospective manner. Therefore, in this study, we developed a new method to evaluate diaphragm thickness in patients with diabetes using computed tomography (CT) and evaluated the correlation between U.S. and CT findings. Then, we evaluated the relationship among diaphragm thickness, age, and blood glucose metabolism. We prospectively evaluated the diaphragm thickness of 50 patients with diabetes using both U.S. and CT. The diaphragm thickness using CT was evaluated in the zone of apposition on contact with the thoracic cavity between the most frontal and dorsal positions, and the results were expressed as a sum of left and right measurements. The mean diaphragm thickness was 3.35 ± 0.64 mm and 3.73 ± 1.00 mm using U.S. and CT, respectively. The diaphragm thicknesses evaluated using both U.S. and CT were significantly correlated with each other (r = 0.3809, P = 0.0063). Then, we studied the data of 1patients with tuberculosis who had undergone CT and had a high morbidity of diabetes. The diaphragm thickness was positively correlated with body weight (r = 0.2911, P = 0.0088) and negatively with age and HbA1c (r = −0.4493, P < 0.0001; r = −0.5507, P < 0.0001, respectively). Moreover, the diaphragm thickness was significantly less in patients with diabetes than in those without diabetes. A thin diaphragm has been found to be related to poor prognosis among patients with acute pneumonia in intensive care units. Our results indicate that diabetes can accelerate sarcopenia of the diaphragm. Because the diaphragm has multiple functions, sarcopenia of the diaphragm in patients with diabetes might affect prognosis. Disclosure M. Yamamoto: None. M. Takemoto: None. H. Masuyama: None. M. Koshizaka: None. Y. Maezawa: None. K. Yokote: Research Support; Self; Astellas Pharm Ltd, MSD K.K..

Podocalyxin is a cell surface sialomucin, which is expressed in not only glomerular podocytes but also vascular endothelial cells. Urinary podocalyxin is used as a marker for glomerular disease. However, there are no reports describing serum podocalyxin (s-Podxl) levels. Therefore, the association between s-Podxl levels and clinical parameters were examined with 52 patients. s-Podxl level was evaluated using enzyme-linked immunosorbent assay. The median s-Podxl level was 14.2 ng/dL (interquartile range: 10.8–22.2 ng/dL). There were significant correlations (correlation coefficient: r > 0.2) of s-Podxl levels with carotid intima media thickness (IMT) (r = 0.30, p = 0.0307). Multiple logistic regression analysis showed that s-Podxl levels remained significantly associated with carotid IMT > 1 mm (OR: 1.15; 95% CI 1.02–1.31, p = 0.026) after adjustments for traditional cardiovascular risk factors such as age, sex, current smoking status, hypertension, dyslipidemias, and diabetes. In conclusion, s-Podxl is independently associated with carotid IMT and might be used as a novel biomarker for cardiovascular disease.

Background: Visceral fat accumulation is associated with insulin resistance and various metabolic complications. We aimed to determine the effect of ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin with a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) in reducing visceral fat in Asian patients with insufficiently controlled type 2 diabetes. Methods: A prospective, multicenter, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with either ipragliflozin or metformin combined with sitagliptin on visceral fat reduction and glycemic control among Japanese patients with type 2 diabetes, HbA1c 7-10%, and BMI ≥22 kg/m2. Patients who met the eligibility criteria were randomly assigned (1:1) to receive ipragliflozin 50 mg (n=51) or metformin 1000-1500 mg daily (n=52). The primary outcome was rate change in visceral fat area measured by computed tomography at 24 weeks of therapy. Two radiologists, blinded to patients' clinical information and randomized treatment assignment, analyzed the images. Secondary outcomes included effects on blood glucose, fasting insulin level, and lipids. The full analysis set was used for analysis. Findings: Mean percent reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12·06% vs. -3·65%, group difference [95% CI] -8·40%; [-16·4 to -3·38], P=0·040). The ipragliflozin group also showed significant lowering of fasting insulin (-20·73% vs. 0·85%, group difference [95% CI] -21·58%, [2·80 to 34·20], P=0·018), while HbA1c decreased in the metformin group compared with ipragliflozin group. Interpretation: Ipragliflozin significantly reduced the visceral fat area compared with metformin, as the secondary agent used in combination with DPP-4 inhibitor. Since the fasting insulin level decreased, the reduction in visceral fat associated with ipragliflozin administration might have contributed to the improvement in insulin resistance. Trial Registration Number: Trial registration: UMIN 000015170. Funding Statement: To conduct this study, an agreement was signed between Chiba University and Astellas Pharma Inc. (Tokyo, Japan). Astellas Pharma Inc. funded this work. Declaration of Interests: KY received research grants from Astellas Pharma Inc. and MSD K.K. (Tokyo, Japan), and received a lecture fee from Astellas Pharma Inc. and Sumitomo Dainippon Pharma (Tokyo, Japan). No conflicts of interest are declared for other authors. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards (IRBs), Ethics Review Committees, or Ethics Committees of the following institutions: Chiba University Hospital (ID number: G26009), Asahi General Hospital (ID number: 2014091602), National Hospital Organization Chiba Medical Center, Seirei Sakura Citizen Hospital, Chiba Rosai Hospital (ID number: 26-21), Toho University Sakura Medical Center (ID number: 2014-077), Tokyo Women’s Medical University Yachiyo Medical Center (ID number: 150303), Chiba Aoba Municipal Hospital, Kimitsu Chuo Hospital, Funabashi Central Hospital (ID number: H27-1), and Chiba Kaihin Municipal Hospital. In other facilities, approval was provided at Chiba University Hospital (which had the centralized IRB).

There is limited information about the association between diabetes, its treatment, and long-term angiographic and clinical outcomes in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the association of diabetes and its treatment with 1-year angiographic graft failure and 5-year clinical outcomes in patients undergoing CABG.Using data from 3,014 patients in PREVENT IV, we analyzed angiographic and clinical outcomes in patients with and without diabetes and among those who did and did not receive insulin before CABG. Logistic regression and Cox proportional hazards models were used to adjust for differences in baseline variables.Overall, 1,139 (37.8%) patients had diabetes. Of these, 305 (26.8%) received insulin. One-year rates of vein graft failure were similar in patients with and without diabetes but, among diabetics, tended to be higher in patients who received insulin compared with those who did not. At 5 years, rates of death, myocardial infarction, or revascularization were higher among patients with compared with those without diabetes (adjusted hazard ratio 1.57; 95% CI 1.26-1.96; P.001) and, among diabetics, higher among those who received insulin (adjusted hazard ratio 1.15; 95% CI 1.02-1.30; P = .02).Patients with diabetes had similar rates of vein graft failure but worse clinical outcomes than patients without diabetes. Patients who received insulin had significantly worse clinical outcomes than patients who did not receive insulin. Further studies to better understand the mechanism behind these findings and to improve the outcomes of patients with insulin-requiring diabetes undergoing CABG surgery are warranted.

BACKGROUND The pharmacodynamic effects of changing from standard-dose clopidogrel to low-dose (3.75 mg) prasugrel in Japanese patients are largely unknown. METHODS AND RESULTS A total of 53 consecutive Japanese patients with stable coronary artery disease (CAD) who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75 mg prasugrel. At day 14, prasugrel was switched to 75 mg clopidogrel. Platelet reactivity was measured using the VerifyNow assay at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as high on-treatment platelet reactivity (HPR). The prevalence of HPR (18.9% vs. 41.5% vs. 44.2%, P

Background Patients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia. Methods This was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c)

SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size, Dermatology: peptide drug development for skin ulcers Chronic leg ulcers result in substantial impairment of patient quality of life with a socioeconomic impact both in terms of medical care and missed work days. A teams led by Hironori Nakagami at Osaka University originally identified a functional peptide, SR-0379, and evaluated the safety and efficacy of SR-0379 for the treatment of leg ulcers in a physician-initiated, first-in-patient, a multi-center, double-blind, randomized clinical study. In the evaluation of efficiency, the skin ulcer reduction rates were improved for the SR-0379 treated groups in a dose-dependent manner, compared for the placebo group with no causal adverse events. Since treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective in this initial clinical trial, the clinical trial on next stage will be designed toward peptide drug development.

Introduction

Most diabetes and cardiovascular studies have been conducted in white patients, with data being extrapolated to other population groups.For this analysis, patient-level data were extracted from 5 randomized clinical trials in patients with acute coronary syndrome; we compared obesity levels between Asian and white populations, stratified by diabetes status. By using an adjusted Cox proportional hazards model, hazard ratios (HRs) for cardiovascular outcomes after an acute coronary syndrome were determined.We identified 49,224 patient records from the 5 trials, with 3176 Asians and 46,048 whites. Whites with diabetes had higher body mass index values than those without diabetes (median 29.3 vs 27.2 kg/mAlthough Asians with diabetes and acute coronary syndrome are less likely to be obese than their white counterparts, their risk for death or recurrent ischemic events was not lower.

Dipeptidyl peptidase-4 inhibitor (DPP-4i) is commonly used worldwide for the treatment of type 2 diabetes mellitus. In addition to its hypoglycemic activity, DPP-4i might have anti-inflammatory effects. In this study we examined the effects of DPP-4i on the serum levels of soluble CD163 (sCD163), a marker for activated macrophages, in individuals with type 2 diabetes mellitus. We compared these anti-inflammatory effects with those of α glucosidase inhibitor (αGI).Japanese patients with type 2 diabetes mellitus who were stably maintained on ≤2mg/day glimepiride alone were recruited and randomly assigned to receive additional sitagliptin (n=37) or αGI (n=37). Levels of sCD163 were measured before the addition and after a 24-week treatment period.Addition of sitagliptin significantly reduced the serum sCD163 (632 vs. 575ng/mL, p0.05), while αGI did not display this effect (624 vs. 607ng/mL). The changes in levels of sCD163 were not related to changes in either HbA1c or body mass index (BMI).Our results suggested that DPP-4i might exert anti-inflammatory effects in individuals with type 2 diabetes mellitus, which are independent of its effects on glycemia and BMI.

Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factorβand vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

We aimed at elucidating the roles of transforming growth factor (TGF)-β and Smad3 signaling in adipocyte differentiation (adipogenesis) and in the pathogenesis of obesity. TGF-β/Smad3 signaling in white adipose tissue (WAT) was determined in genetically obese (ob/ob) mice. The effect of TGF-β on adipogenesis was evaluated in mouse embryonic fibroblasts (MEF) isolated both from WT controls and Smad3 KO mice by Oil red-O staining and gene expression analysis. Phenotypic analyses of high-fat diet (HFD)-induced obesity in Smad3 KO mice compared to WT controls were performed. TGF-β/Smad3 signaling was elevated in WAT from ob/ob mice compared to the controls. TGF-β significantly inhibited adipogenesis in MEF, but the inhibitory effects of TGF-β on adipogenesis were partially abolished in MEF from Smad3 KO mice. TGF-β inhibited adipogenesis independent from the Wnt and β-catenin pathway. Smad3 KO mice were protected against HFD-induced insulin resistance. The size of adipocytes from Smad3 KO mice on the HFD was significantly smaller compared to the controls. In conclusion, the TGF-β/Smad3 signaling pathway plays key roles not only in adipogenesis but also in development of insulin resistance.

Objective— CCN3 belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of CCN3 in the vessels. Methods and Results— We examined the effects of CCN3 on the proliferation and migration of rat vascular smooth muscle cells (VSMC). CCN3 knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated. CCN3 suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-β did not affect the growth inhibitory effect of CCN3 . Moreover, CCN3 enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by CCN3 . CCN3 also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice. Conclusion— CCN3 suppresses neointimal thickening through the inhibition of VSMC migration and proliferation. Our findings indicate the involvement of CCN3 in vascular homeostasis, especially on injury, and the potential usefulness of this molecule in the modulation of atherosclerotic vascular disease.

Background Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. Patients and methods This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20–40 years). MPA (400 mg/day) and metformin (750–2250 mg/day) were administered for 24–36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set. Results The body mass index was ≥25 kg/m2 in 27 patients (mean, 31 kg/m2; range, 19–51 kg/m2), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7–21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2–18]. At 36 weeks, 29 (81%; 95% CI 65–90) patients achieved CR, and 5 (14%; 95% CI 6–29) patients achieved partial response. During a median follow-up of 38 months (range, 9–66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. Conclusions Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further. Trial registration number UMIN 000002210.

Introduction In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. Methods and analysis A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. Ethics and dissemination The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants. Trial registration number UMIN000015170, R000016861 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000016861); Pre-results

Transforming growth factor-beta (TGF-beta) is known to promote the accumulation of extracellular matrix (ECM) and the development of diabetic nephropathy. Halofuginone, an analog of febrifugine, has been shown to block TGF-beta(1) signaling and subsequent type I collagen production. Here, the inhibitory effect of halofuginone on diabetic nephropathy was examined. Halofuginone suppressed Smad2 phosphorylation induced by TGF-beta(1) in cultured mesangial cells. In addition, the expression of TGF-beta type 2 receptor decreased by halofuginone. Halofuginone showed an inhibitory effect on type I collagen and fibronectin expression promoted by TGF-beta(1). An in vivo experiment using db/db mice confirmed the ability of halofuginone to suppress mesangial expansion and fibronectin overexpression in the kidneys. Moreover, an analysis of urinary 8-OHdG level and dihydroethidium fluorescence revealed that halofuginone reduced oxidative stress in the glomerulus of db/db mice. These data indicate that halofuginone prevents ECM deposition and decreases oxidative stress, thereby suppressing the progression of diabetic nephropathy.