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1. 2型糖尿病终末期肾病和死亡危险因素的性别差异:一项回顾性队列研究

Author: Megumi Oshima, Yasunori Iwata, Tadashi Toyama, Shinji Kitajima, Akinori Hara, Norihiko Sakai, Miho Shimizu, Kengo Furuichi, Masakazu Haneda, Tetsuya Babazono, Hiroki Yokoyama, Kunitoshi Iseki, Shinichi Araki, Toshiharu Ninomiya, Shigeko Hara, Yoshiki Suzuki, Masayuki Iwano, Eiji Kusano, Tatsumi Moriya, Hiroaki Satoh, Hiroyuki Nakamura, Hirofumi Makino, and Takashi Wada
Subjects: 性别差异, 2型糖尿病, 终末期肾脏疾病, 白蛋白尿, 死亡, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Background This study investigated the sex differences in the risk of end‐stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. Methods This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. Results During a median follow‐up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02–1.75; p = .034) and death (HR 1.64; 95% CI 1.24–2.16; p = .001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo‐ and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. Conclusions In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.
Published: 2023
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2. Extracellular RNA transfer from non‐malignant human cholangiocytes can promote cholangiocarcinoma growth

Author: Yu Ota, Kenji Takahashi, Shin Otake, Yosui Tamaki, Mitsuyoshi Okada, Irene Yan, Kazunobu Aso, Satoshi Fujii, Tushar Patel, and Masakazu Haneda
Subjects: epithelial‐mesenchymal transition, extracellular vesicles, microRNA, secretome, tumor microenvironment, Biology (General), QH301-705.5
Abstract: Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor‐derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, nontransformed cells. We examined the impact of EVs within the cellular secretome from nonmalignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro‐fibrogenic mediator TGF‐β. We identified miR‐195 as a TGF‐β responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion, and migration. The effects of miR‐195 involve modulation of the epithelial–mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV‐mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma.
Published: 2021
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3. Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Author: Kenichi Shikata, Masakazu Haneda, Toshiharu Ninomiya, Daisuke Koya, Yoshiki Suzuki, Daisuke Suzuki, Hitoshi Ishida, Hiroaki Akai, Yasuhiko Tomino, Takashi Uzu, Motonobu Nishimura, Shiro Maeda, Daisuke Ogawa, Satoshi Miyamoto, Hirofumi Makino, and the Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) collaborative group
Subjects: Diabetic kidney disease, Diabetic nephropathy, Diabetic Nephropathy Remission and Regression Team Trial in Japan, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P
Published: 2021
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4. Increment of plasma glucose by exogenous glucagon is associated with present and future renal function in type 2 diabetes:a retrospective study from glucagon stimulation test

Author: Yasutaka Takeda, Yukihiro Fujita, Ryoichi Bessho, Mao Sato, Tomoe Abe, Tsuyoshi Yanagimachi, Hidemitsu Sakagami, Atsuko Abiko, Yumi Takiyama, Tsuguhito Ota, and Masakazu Haneda
Subjects: Glucagon, ΔGlucose, Free fatty acid, Renal function, Gluconeogenesis, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Background Glucagon stimulation test (GST) is often employed to assess the insulin reserve of the pancreatic beta cells in diabetic subjects. The clinical significance of the increment of plasma glucose (Δglucose) by exogenous glucagon during GST has not been elucidated. We investigated the relationship between Δglucose and clinical parameters including the liver and renal function in type 2 diabetic subjects, since we hypothesized that Δglucose is associated with the liver and renal function reflecting the capacity for gluconeogenesis in the organs. Methods A total of 209 subjects with type 2 diabetes who underwent GST during admission were included in this cross-sectional study. We defined the difference between plasma glucose at fasting and 6 min after intravenous injection of 1 mg glucagon as Δglucose. We assessed correlations between Δglucose and clinical parameters such as diabetic duration, BMI, HbA1c, beta cell function, serum free fatty acids (FFA) which is known to stimulate gluconeogenesis, liver function, the indices of liver function, renal function, and urinary albumin excretion (UAE). Results In correlation analysis, Δglucose positively correlated to FFA and estimated glomerular filtration rate (eGFR), but inversely to serum creatinine and cystatin C, although Δglucose showed no correlation with both liver function and the indices of residual liver function. Multiple regression analysis revealed that Δglucose was an independent determinant for the eGFR after 1 year, equally BMI, HbA1c, serum lipids, and UAE, which are known as the predictors for the development of chronic kidney disease. Conclusion Our results suggest that Δglucose during GST might be related to gluconeogenesis in the kidney and could be the determinant of future renal function in type 2 diabetes.
Published: 2019
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5. Combined changes in albuminuria and kidney function and subsequent risk for kidney failure in type 2 diabetes

Author: Toshiharu Ninomiya, Hiroki Yokoyama, Shin-ichi Araki, Hirofumi Makino, Kunitoshi Iseki, Kengo Furuichi, Megumi Oshima, Tadashi Toyama, Takashi Wada, Miho Shimizu, Hiroyuki Nakamura, Norihiko Sakai, Yasunori Iwata, Shinji Kitajima, Akinori Hara, Yoshiki Suzuki, Hiroaki Satoh, Tetsuya Babazono, Tatsumi Moriya, Masayuki Iwano, Masakazu Haneda, Shigeko Hara, and Eiji Kusano
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Introduction Changes in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD.Research design and methods Using data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk.Results Among 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of 5 and 2.5–5 mL/min/1.73 m2/year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m2/year compared with those with a minor change in UACR and eGFR.Conclusions Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.
Published: 2021
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6. Secular changes in clinical manifestations of kidney disease among Japanese adults with type 2 diabetes from 1996 to 2014

Author: Shinji Kume, Shin‐ichi Araki, Satoshi Ugi, Katsutaro Morino, Daisuke Koya, Yoshihiko Nishio, Masakazu Haneda, Atsunori Kashiwagi, and Hiroshi Maegawa
Subjects: albuminuria, diabetic kidney disease, diabetic nephropathy, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (
Published: 2019
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7. Impacts of Diabetes and an SGLT2 Inhibitor on the Glomerular Number and Volume in db/db Mice, as Estimated by Synchrotron Radiation Micro-CT at SPring-8Research in context

Author: Yumi Takiyama, Toshihiro Sera, Masanori Nakamura, Kanaki Ishizeki, Yasuaki Saijo, Tsuyoshi Yanagimachi, Manami Maeda, Ryoichi Bessho, Takao Takiyama, Hiroya Kitsunai, Hidemitsu Sakagami, Daisuke Fujishiro, Yukihiro Fujita, Yuichi Makino, Atsuko Abiko, Masato Hoshino, Kentaro Uesugi, Naoto Yagi, Tsuguhito Ota, and Masakazu Haneda
Subjects: Medicine, Medicine (General), R5-920
Abstract: Background: Recent large-scale clinical studies demonstrate that sodium-glucose cotransporter 2 (SGLT2) inhibitors protect the diabetic kidney. However, clinical and animal studies have not shown the changes of the total glomeruli in the whole kidney treated with SGLT2 inhibitors. Methods: We performed computed tomography (CT) imaging on mice using synchrotron radiation to investigate the impact of luseogliflozin, a SGLT2 inhibitor, on the number and volume of glomeruli in the whole kidney. Findings: We did not observe a significant difference in the total glomerular number (Nglom) among mice. Luseogliflozin redistributed the number of glomeruli in different regions, accompanied by the normalization of diabetes-augmented renal volume (Vkidney). Diabetic db/db mice had a larger glomerular volume in the mid-cortex than did control db/m mice, and luseogliflozin increased the glomerular volume in all renal cortical zones of the whole kidney in db/db mice. According to the multivariate regression analysis, hemoglobin A1c level was the most relevant determinant of Vkidney, not Nglom or mean glomerular volume (Vglom), indicating that hyperglycemia induced renal (tubular) hypertrophy, but not glomerular enlargement. Luseogliflozin increased hypoxia in the juxtamedullary region, sustained upregulated renal renin expression and plasma renin activity, and failed to decrease albuminuria by downregulating megalin in db/db mice. Interpretation: Based on our findings, SGLT2 inhibitors may alter glomerular distribution and size in addition to their glucose-lowering effects, presumably by affecting oxygen metabolism and humoral factors. Fund: Funding for this research was provided by The Japan Society for the Promotion of Science, the Japan Diabetes Foundation, and Asahikawa Medical University. Keywords: Sodium glucose cotransporter-2 inhibitor, Diabetic nephropathy, Glomerular number, Glomerular volume, Megalin, Hypoxia
Published: 2018
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8. A Low-Carbohydrate Diet Improves Glucose Metabolism in Lean Insulinopenic Akita Mice Along With Sodium-Glucose Cotransporter 2 Inhibitor

Author: Yukihiro Fujita, Kuralay K. Atageldiyeva, Yasutaka Takeda, Tsuyoshi Yanagimachi, Yuichi Makino, and Masakazu Haneda
Subjects: low-carbohydrate diet, sodium-glucose cotransporter 2 inhibitor, ketogenesis, islet morphology, Akita mice, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ObjectiveA low-carbohydrate diet (LC) can be beneficial to obese subjects with type2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) presents prompt glucose-lowering effects in subjects with T2DM. We investigated how LC and SGLT2i could similarly or differently influence on the metabolic changes, including glucose, lipid, and ketone metabolism in lean insulinopenic Akita mice. We also examined the impacts of the combination.MethodsMale Akita mice were fed ad libitum normal-carbohydrate diet (NC) as a control or low-carbohydrate diet (LC) as an intervention for 8 weeks with or without SGLT2i treatment. Body weight and casual bold glucose levels were monitored during the study, in addition to measuring TG, NEFA, and ketone levels. We quantified gene expressions involved in gluconeogenesis, lipid metabolism and ketogenesis in the liver and the kidney. We also investigated the immunostaining analysis of pancreatic islets to assess the effect of islet protection.ResultsBoth LC and SGLT2i treatment reduced chronic hyperglycemia. Moreover, the combination therapy additionally ameliorated glycemic levels and preserved the islet morphology in part. LC but not SGLT2i increased body weight accompanied by epididymal fat accumulation. In contrast, SGLT2i, not LC potentiated four-fold ketone production with higher ketogenic gene expression, in comparison with the non-treated Akita mice. Besides, the combination did not enhance further ketone production compared to the SGLT2i alone.ConclusionsOur results indicated that both LC and SGLT2i reduced chronic hyperglycemia, and the combination presented synergistic favorable effects concomitantly with amelioration of islet morphology, while the combination did not enhance further ketosis in Akita mice.
Published: 2020
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9. Establishment of novel specific assay for short‐form glucose‐dependent insulinotropic polypeptide and evaluation of its secretion in nondiabetic subjects

Author: Yasutaka Takeda, Yukihiro Fujita, Tsuyoshi Yanagimachi, Nobuhiro Maruyama, Ryoichi Bessho, Hidemitsu Sakagami, Jun Honjo, Hiroki Yokoyama, and Masakazu Haneda
Subjects: cookie meal test, DPP‐4 inhibitor, ELISA, GIP (1–30), oral glucose tolerance test, Physiology, QP1-981
Abstract: Abstract The short‐form glucose‐dependent insulinotropic polypeptide (GIP) (1–30) is released from islet alpha cells and promotes insulin secretion in a paracrine manner in vitro. However, it is not well elucidated how GIP (1–30) is involved in glucose metabolism in vivo, since a specific assay system for GIP (1–30) has not yet been established. We first developed a sandwich enzyme‐linked immunosorbent assay (ELISA) specific for GIP (1–30) by combining a novel antibody specific to the GIP (1–30) C terminus with the common antibody against GIP N terminus. Then, we explored cross‐reactivities with incretins and glucagon‐related peptides in this ELISA. GIP (1–30) amide, but not GIP (1–42), GLP‐1, or glucagon increased absorbance in a dose‐dependent manner. We next measured plasma GIP (1–30) concentrations in nondiabetic participants (ND) during a 75‐g oral glucose tolerance test or cookie meal test (carbohydrates 75 g, lipids 28.5 g, proteins 8.5 g). Both glucose and cookie load increased GIP (1–30) concentrations in ND, but the increases were much lower than those of GIP (1–42). Furthermore, the DPP‐4 inhibitor significantly increased GIP (1–30) concentrations similarly to GIP (1–42) in ND. In conclusion, we for the first time developed an ELISA specific for GIP (1–30) and revealed its secretion in ND.
Published: 2020
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10. Receptor-Mediated Bioassay Reflects Dynamic Change of Glucose-Dependent Insulinotropic Polypeptide by Dipeptidyl Peptidase 4 Inhibitor Treatment in Subjects With Type 2 Diabetes

Author: Tsuyoshi Yanagimachi, Yukihiro Fujita, Yasutaka Takeda, Jun Honjo, Hiroki Yokoyama, and Masakazu Haneda
Subjects: glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, glucagon, receptor-mediated bioassay, dipeptidyl peptidase 4, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Objective: We recently observed a greater increase in plasma levels of bioactive glucose-dependent insulinotropic polypeptide (GIP) than glucagon-like peptide 1 (GLP-1) using the receptor-mediated bioassays in the subjects with normal glycemic tolerance (NGT) treated with dipeptidyl peptidase 4 (DPP-4) inhibitors, which may be unappreciated using conventional enzyme-linked immunosorbent assays (ELISAs) during oral glucose tolerance test. Thus, we determined incretin levels in addition to glucagon level using the bioassays in type 2 diabetes mellitus (T2DM) subjects with or without treatment of DPP-4 inhibitor, to evaluate whether these assays can accurately measure bioactivity of these peptides.Methods: We performed single meal tolerance test (MTT) by using a cookie meal (carbohydrate 75.0 g, protein 8.0 g, fat 28.5 g) in the subjects with NGT (n = 9), the subjects with T2DM treated without DPP-4 inhibitor (n = 7) and the subjects with T2DM treated with DPP-4 inhibitor (n = 10). All subjects fasted for 10–12 h before the MTT, and blood samples were collected at 0, 30, 60, and 120 min. We used the cell lines stably cotransfected with human-form GIP, GLP-1 or glucagon receptor, and a cyclic adenosine monophosphate–inducible luciferase expression construct for the bioassays. We measured active GIP, active GLP-1, and glucagon by the bioassays. To evaluate the efficacy of bioassay, we measured identical samples via ELISA kits.Results: During the single MTT study, postprandial active GIP bioassay levels of T2DM with DPP-4 inhibitor treatment were drastically higher than those of NGT and T2DM without DPP-4 inhibitor, although the DPP-4 inhibitor-treated group showed moderate increase of active GIPELISA and active GLP-1bioassay, while active GLP-1bioassay levels of T2DM subjects without DPP-4 inhibitor were comparable to those of NGT subjects. During the serial MTT, administration of DPP-4 inhibitor significantly increased active GIPbioassay levels, but not active GLP-1bioassay.Conclusions: In comparison to conventional ELISA, receptor-mediated bioassay reflects dynamic change of GIP polypeptide by DPP-4 inhibitor treatment in subjects with type 2 diabetes.
Published: 2020
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11. Expression of transcription factors in MEN1-associated pancreatic neuroendocrine tumors

Author: Yasutaka Takeda, Yukihiro Fujita, Kentaro Sakai, Tomoe Abe, Tomonobu Nakamura, Tsuyoshi Yanagimachi, Hidemitsu Sakagami, Jun Honjo, Atsuko Abiko, Yuichi Makino, and Masakazu Haneda
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation.
Published: 2017
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12. Dipeptidyl peptidase-4 inhibitor treatment induces a greater increase in plasma levels of bioactive GIP than GLP-1 in non-diabetic subjects

Author: Tsuyoshi Yanagimachi, Yukihiro Fujita, Yasutaka Takeda, Jun Honjo, Hidemitsu Sakagami, Hiroya Kitsunai, Yumi Takiyama, Atsuko Abiko, Yuichi Makino, Timothy J. Kieffer, and Masakazu Haneda
Subjects: Internal medicine, RC31-1245
Abstract: Objective: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) possess multiple bioactive isoforms that are rendered non-insulinotropic by the enzyme dipeptidyl peptidase-4 (DPP-4). Recently, some ELISA kits have been developed to specifically measure “active” GIP and GLP-1, but it is unclear if these kits can accurately quantify all bioactive forms. Therefore, it remains uncertain to what extent treatment with a DPP-4 inhibitor boosts levels of biologically active GIP and GLP-1. Thus, we evaluated our novel receptor-mediated incretin bioassays in comparison to commercially available ELISA kits using plasma samples from healthy subjects before and after DPP-4 inhibitor administration. Methods: We utilized cell lines stably co-transfected with human GIP or GLP-1 receptors and a cAMP-inducible luciferase expression construct for the bioassays and commercially available ELISA kits. Assays were tested with synthetic GIP and GLP-1 receptor agonists and plasma samples collected from subjects during a 75 g oral glucose tolerance test (OGTT) performed before or following 3-day administration of a DPP-4 inhibitor. Results: A GIP isoform GIP(1–30)NH2 increased luciferase activity similarly to GIP(1–42) in the GIP bioassay but was not detectable by either a total or active GIP ELISA kit. During an OGTT, total GIP levels measured by ELISA rapidly increased from 0 min to 15 min, subsequently reaching a peak of 59.2 ± 8.3 pmol/l at 120 min. In contrast, active GIP levels measured by the bioassay peaked at 15 min (43.4 ± 6.4 pmol/l) and then progressively diminished at all subsequent time points. Strikingly, at 15 min, active GIP levels as determined by the bioassay reached levels approximately 20-fold higher after the DPP-4 inhibitor treatment, while total and active GIP levels determined by ELISA were increased just 1.5 and 2.1-fold, respectively. In the absence of DPP-4 inhibition, total GLP-1 levels measured by ELISA gradually increased up to 90 min, reaching 23.5 ± 2.4 pmol/l, and active GLP-1 levels determined by the bioassay did not show any apparent peak. Following administration of a DPP-4 inhibitor there was an observable peak of active GLP-1 levels as determined by the bioassay at 15 min after oral glucose load, reaching 11.0 ± 0.62 pmol/l, 1.4-fold greater than levels obtained without DPP-4 inhibitor treatment. In contrast, total GLP-1 levels determined by ELISA were decreased after DPP-4 inhibitor treatment. Conclusion: Our results using bioassays indicate that there is a greater increase in plasma levels of bioactive GIP than GLP-1 in subjects treated with DPP-4 inhibitors, which may be unappreciated using conventional ELISAs. Keywords: Receptor-mediated incretin bioassays, Glucose-dependent insulinotropic polypeptide, Glucagon-like peptide-1, Dipeptidyl peptidase-4
Published: 2017
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13. Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Author: Shinji Kume, Motoyuki Kondo, Shiro Maeda, Yoshihiko Nishio, Tsuyoshi Yanagimachi, Yukihiro Fujita, Masakazu Haneda, Keiko Kondo, Akihiro Sekine, Shin-ich Araki, Hisazumi Araki, Masami Chin-Kanasaki, Satoshi Ugi, Daisuke Koya, Sawako Kitahara, Kiyosumi Maeda, Atsunori Kashiwagi, Takashi Uzu, and Hiroshi Maegawa
Subjects: First-phase GSIS, Pancreatic β cell, Starvation, Diabetes, Insulin secretion, Medicine, Medicine (General), R5-920
Abstract: Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes.
Published: 2016
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14. Estimated glomerular filtration rate decline and risk of end-stage renal disease in type 2 diabetes.

Author: Megumi Oshima, Tadashi Toyama, Masakazu Haneda, Kengo Furuichi, Tetsuya Babazono, Hiroki Yokoyama, Kunitoshi Iseki, Shinichi Araki, Toshiharu Ninomiya, Shigeko Hara, Yoshiki Suzuki, Masayuki Iwano, Eiji Kusano, Tatsumi Moriya, Hiroaki Satoh, Hiroyuki Nakamura, Miho Shimizu, Akinori Hara, Hirofumi Makino, Takashi Wada, and Research Group of Diabetic Nephropathy, Ministry of Health, Labour, and Welfare of Japan
Subjects: Medicine, Science
Abstract: BACKGROUND:According to studies by the National Kidney Foundation and Food and Drug Administration, 30% and 40% declines in estimated glomerular filtration rate (eGFR) could be used as surrogate endpoints of end-stage renal disease (ESRD). However, the benefits of using these endpoints in diabetic patients remain unclear. METHODS:This cohort study comprised Japanese patients with type 2 diabetes; those with repeated serum creatinine measurements during a baseline period of 2 years (n = 1868) or 3 years (n = 2001) were enrolled. Subsequent risks of ESRD following eGFR declines were assessed. RESULTS:In the 2-year baseline analysis, the cumulative prevalence of -20%, -30%, -40%, and -53% changes in eGFR were 23.9%, 11.1%, 6.8%, and 3.7%, respectively. There were 133 cases (7.1%) of subsequent ESRD during a median follow-up period of 6.5 years. In the 3-year baseline analysis, the corresponding proportions were 28.1%, 14.0%, 7.7%, and 3.9%, respectively, with 110 participants (5.5%) reaching ESRD during a median follow-up period of 5.5 years. The adjusted hazard ratios of subsequent ESRD following -53%, -40%, -30%, and -20% changes in eGFR during the 2-year baseline period were 22.9 (11.1-47.3), 12.8 (6.9-23.7), 8.2 (4.3-15.5), and 3.9 (2.2-7.0), respectively when compared with the no changes in eGFR. In the 3-year baseline analysis, the corresponding risks were 29.7 (10.8-81.9), 18.4 (7.6-44.7), 12.8 (5.2-32.2), and 5.4 (2.3-12.8), respectively. In the subgroup analysis, similar trends were observed in patients with macroalbuminuria at baseline. CONCLUSIONS:Declines in eGFR were strongly associated with subsequent risk of ESRD in Japanese type 2 diabetic patients. In addition to 30% and 40% declines, a 20% decline in eGFR over 2 years could be considered as a candidate surrogate endpoint of ESRD in diabetic kidney disease.
Published: 2018
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15. Sodium-Glucose Cotransporter 2 Inhibitor and a Low Carbohydrate Diet Affect Gluconeogenesis and Glycogen Content Differently in the Kidney and the Liver of Non-Diabetic Mice.

Author: Kuralay Atageldiyeva, Yukihiro Fujita, Tsuyoshi Yanagimachi, Katsutoshi Mizumoto, Yasutaka Takeda, Jun Honjo, Yumi Takiyama, Atsuko Abiko, Yuichi Makino, and Masakazu Haneda
Subjects: Medicine, Science
Abstract: A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.
Published: 2016
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16. Comparative Effects of Direct Renin Inhibitor and Angiotensin Receptor Blocker on Albuminuria in Hypertensive Patients with Type 2 Diabetes. A Randomized Controlled Trial.

Author: Takashi Uzu, Shin-Ichi Araki, Atsunori Kashiwagi, Masakazu Haneda, Daisuke Koya, Hiroki Yokoyama, Yasuo Kida, Motoyoshi Ikebuchi, Takaaki Nakamura, Masataka Nishimura, Noriko Takahara, Toshiyuki Obata, Nobuyuki Omichi, Katsuhiko Sakamoto, Ryosuke Shingu, Hideki Taki, Yoshio Nagai, Hiroaki Tokuda, Munehiro Kitada, Miwa Misawa, Akira Nishiyama, Hiroyuki Kobori, Hiroshi Maegawa, and Shiga Committee for Preventing Diabetic Nephropathy
Subjects: Medicine, Science
Abstract: In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to
Published: 2016
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17. Role of IGFBP7 in Diabetic Nephropathy: TGF-β1 Induces IGFBP7 via Smad2/4 in Human Renal Proximal Tubular Epithelial Cells.

Author: Jun Watanabe, Yumi Takiyama, Jun Honjyo, Yuichi Makino, Yukihiro Fujita, Masatoshi Tateno, and Masakazu Haneda
Subjects: Medicine, Science
Abstract: Tubular injury is one of the important determinants of progressive renal failure in diabetic nephropathy (DN), and TGF-β1 has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. The aim of this study was to identify novel therapeutic target molecules that play a role in the tubule damage of DN. We used an LC-MS/MS-based proteomic technique and human renal proximal epithelial cells (HRPTECs). Urine samples from Japanese patients with type 2 diabetes (n = 46) were used to quantify the candidate protein. Several proteins in HRPTECs in cultured media were observed to be driven by TGF-β1, one of which was 33-kDa IGFBP7, which is a member of IGFBP family. TGF-β1 up-regulated the expressions of IGFBP7 mRNA and protein in a dose- and time-dependent fashion via Smad2 and 4, but not MAPK pathways in HRPTECs. In addition, the knockdown of IGFBP7 restored the TGF-β1-induced epithelial to mesenchymal transition (EMT). In the immunohistochemical analysis, IGFBP7 was localized to the cytoplasm of tubular cells but not that of glomerular cells in diabetic kidney. Urinary IGFBP7 levels were significantly higher in the patients with macroalbuminuria and were correlated with age (r = 0.308, p = 0.037), eGFR (r = -0.376, p = 0.01), urinary β2-microglobulin (r = 0.385, p = 0.008), and urinary N-acetyl-beta-D-glucosaminidase (NAG) (r = 0.502, p = 0.000). A multivariate regression analysis identified urinary NAG and age as determinants associated with urinary IGFBP7 levels. In conclusion, our data suggest that TGF-β1 enhances IGFBP7 via Smad2/4 pathways, and that IGFBP7 might be involved in the TGF-β1-induced tubular injury in DN.
Published: 2016
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18. Predictive properties of plasma amino acid profile for cardiovascular disease in patients with type 2 diabetes.

Author: Shinji Kume, Shin-ichi Araki, Nobukazu Ono, Atsuko Shinhara, Takahiko Muramatsu, Hisazumi Araki, Keiji Isshiki, Kazuki Nakamura, Hiroshi Miyano, Daisuke Koya, Masakazu Haneda, Satoshi Ugi, Hiromichi Kawai, Atsunori Kashiwagi, Takashi Uzu, and Hiroshi Maegawa
Subjects: Medicine, Science
Abstract: Prevention of cardiovascular disease (CVD) is an important therapeutic object of diabetes care. This study assessed whether an index based on plasma free amino acid (PFAA) profiles could predict the onset of CVD in diabetic patients. The baseline concentrations of 31 PFAAs were measured with high-performance liquid chromatography-electrospray ionization-mass spectrometry in 385 Japanese patients with type 2 diabetes registered in 2001 for our prospective observational follow-up study. During 10 years of follow-up, 63 patients developed cardiovascular composite endpoints (myocardial infarction, angina pectoris, worsening of heart failure and stroke). Using the PFAA profiles and clinical information, an index (CVD-AI) consisting of six amino acids to predict the onset of any endpoints was retrospectively constructed. CVD-AI levels were significantly higher in patients who did than did not develop CVD. The area under the receiver-operator characteristic curve of CVD-AI (0.72 [95% confidence interval (CI): 0.64-0.79]) showed equal or slightly better discriminatory capacity than urinary albumin excretion rate (0.69 [95% CI: 0.62-0.77]) on predicting endpoints. A multivariate Cox proportional hazards regression analysis showed that the high level of CVD-AI was identified as an independent risk factor for CVD (adjusted hazard ratio: 2.86 [95% CI: 1.57-5.19]). This predictive effect of CVD-AI was observed even in patients with normoalbuminuria, as well as those with albuminuria. In conclusion, these results suggest that CVD-AI based on PFAA profiles is useful for identifying diabetic patients at risk for CVD regardless of the degree of albuminuria, or for improving the discriminative capability by combining it with albuminuria.
Published: 2014
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19. GW501516, a PPARδ agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFκB pathway in mice.

Author: Xu Yang, Shinji Kume, Yuki Tanaka, Keiji Isshiki, Shin-ichi Araki, Masami Chin-Kanasaki, Toshiro Sugimoto, Daisuke Koya, Masakazu Haneda, Takeshi Sugaya, Detian Li, Ping Han, Yoshihiko Nishio, Atsunori Kashiwagi, Hiroshi Maegawa, and Takashi Uzu
Subjects: Medicine, Science
Abstract: Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(-). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases.
Published: 2011
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20. Octreotide-Treated Diabetes Accompanied by Endogenous Hyperinsulinemic Hypoglycemia and Protein-Losing Gastroenteropathy

Author: Nobuhiko Takahashi, Miho Nagamine, Mitsuko Fukuda, Wataru Motomura, Atsuko Abiko, Masakazu Haneda, Mikihiro Fujiya, Masahiro Ieko, and Yutaka Kohgo
Subjects: Medicine
Abstract: Occurrence of hypoglycemia in diabetes patients is very rare. We report here a case of frequent hypoglycemic attacks caused by inappropriate endogenous hyperinsulinemia in a female patient with poorly controlled diabetes and protein-losing gastroenteropathy. The blood glucose profiles of the patient were unstable. Results of the fasting test performed to investigate the cause of hypoglycemia suggested endogenous hyperinsulinism. Repeated selective arterial calcium injection tests suggested that hyperinsulinemia might be extrapancreatic in origin. However, efforts to detect a responsible lesion such as insulinoma were unsuccessful. Octreotide was used for the treatment of hypoglycemia and protein-losing gastroenteropathy. After treatment, although her leg edema caused by hypoalbuminemia persisted, hypoglycemia almost disappeared.
Published: 2011
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21. Sex differences in risk factors for end‐stage kidney disease and death in type 2 diabetes: A retrospective cohort study

Author: Megumi Oshima, Yasunori Iwata, Tadashi Toyama, Shinji Kitajima, Akinori Hara, Norihiko Sakai, Miho Shimizu, Kengo Furuichi, Masakazu Haneda, Tetsuya Babazono, Hiroki Yokoyama, Kunitoshi Iseki, Shinichi Araki, Toshiharu Ninomiya, Shigeko Hara, Yoshiki Suzuki, Masayuki Iwano, Eiji Kusano, Tatsumi Moriya, Hiroaki Satoh, Hiroyuki Nakamura, Hirofumi Makino, and Takashi Wada
Subjects: Endocrinology, Diabetes and Metabolism
Published: 2023

22. Empagliflozin in Patients with Chronic Kidney Disease

Author: Herrington, William G, Staplin, Natalie, Wanner, Christoph, Green, Jennifer B, Hauske, Sibylle J, Emberson, Jonathan R, Preiss, David, Judge, Parminder, Mayne, Kaitlin J, Ng, Sarah Y A, Sammons, Emily, Zhu, Doreen, Hill, Michael, Stevens, Will, Wallendszus, Karl, Brenner, Susanne, Cheung, Alfred K, Liu, Zhi-Hong, Li, Jing, Hooi, Lai Seong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Maggioni, Aldo P, Pontremoli, Roberto, Deo, Rajat, Goto, Shinya, Rossello, Xavier, Tuttle, Katherine R, Steubl, Dominik, Petrini, Michaela, Massey, Dan, Eilbracht, Jens, Brueckmann, Martina, Landray, Martin J, Baigent, Colin, Haynes, Richard, The EMPA-KIDNEY Collaborative Group: Colin Baigent, Martin J Landray, Christoph Wanner, William G Herrington, Richard Haynes, Jennifer B Green, Sibylle J Hauske, Martina Brueckmann, Mark Hopley, Maximillian von-Eynatten, Jyothis George, Susanne Brenner, Alfred K Cheung, David Preiss, Zhi-Hong Liu, Jing Li, Laiseong Hooi, Wen Liu, Takashi Kadowaki, Masaomi Nangaku, Adeera Levin, David Cherney, Roberto Pontremoli, Aldo P Maggioni, Natalie Staplin, Jonathan Emberson, Stefan Hantel, Shinya Goto, Rajat Deo, Katherine R Tuttle, Michael Hill, Parminder Judge, Kaitlin J Mayne, Sarah Y A Ng, Xavier Rossello, Emily Sammons, Doreen Zhu, Peter Sandercock, Rudolf Bilous, Charles Herzog, Paul Whelton, Janet Wittes, Derrick Bennett, Patricia Achiri, Chrissie Ambrose, Cristina Badin, Jill Barton, Richard Brown, Andy Burke, Sebastian Butler, Rejive Dayanandan, Pia Donaldson, Robert Dykas, Lucy Fletcher, Kate Frederick, Hannah Kingston, Mo Gray, Emily Harding, Akiko Hashimoto, Lyn Howie, Susan Hurley, Ryonfa Lee, Nik Luker, Kevin Murphy, Mariko Nakahara, John Nolan, Michelle Nunn, Sorcha Mulligan, Akiko Omata, Sandra Pickworth, YanRu Qiao, Shraddha Shah, Karen Taylor, Alison Timadjer, Monique Willett, Liz Wincott, Qin Yan, Hui Yu, Louise Bowman, Fang Chen, Robert Clarke, Michelle Goonasekera, Waseem Karsan, Marion Mafham, Christina Reith, Mohammed Zayed, Ritva Ellison, Rowan Moys, Will Stevens, Kevin Verdel, Karl Wallendszus, Chris Bowler, Anna Brewer, Andy Measor, Guanguo Cui, Charles Daniels, Angela Field, Bob Goodenough, Ashley Lawson, Youcef Mostefai, Dheeptha Radhakrishnan, Samee Syed, Shuang Xia, Ruth Adewuyi-Dalton, Thomas Arnold, Anne-Marie Beneat, Anoushka Bhatt, Chloe Bird, Andrew Breach, Laura Brown, Mark Caple, Tatyana Chavagnon, Karen Chung, Sarah Clark, Luminita Condurache, Katarzyna Eichstadt, Marta Espino Obrero, Scarlett Forest, Helen French, Nick Goodwin, Andrew Gordon, Joanne Gordon, Cat Guest, Tina Harding, Michal Hozak, Matthew Lacey, David MacLean, Louise Messinger, Stewart Moffat, Martin Radley, Claire Shenton, Sarah Tipper, Jon Tyler, Lesley Weaving, James Wheeler, Elissa Williams, Tim Williams, Hamish Woodhouse, Angela Chamberlain, Jo Chambers, Joanne Davies, Denise Donaldson, Pati Faria-Shayler, Denise Fleming-Brown, Jennifer Ingell, Carol Knott, Anna Liew, Helen Lochhead, Juliette Meek, Isabel Rodriguez-Bachiller, Andrea Wilson, Patrick Zettergren, Rach AitSadi, Ian Barton, Alex Baxter, Yonghong Bu, Lukasz Danel, Sonja Grotjahn, Rijo Kurien, Michael Lay, Archie Maskill, Aleksandra Murawska, Rachel Raff, Allen Young, Rebecca Sardell, Vladimir Cejka, Marcela Fajardo-Moser, Christian Hartner, Doris Poehler, Janina Renner, Franziska Scheidemantel, Miya Bryant, Anita Hepditch, Cassandra Johnson, Erin Latore, Yolanda Miller, Lauren Price, Merilee Whalen, Ashleigh Wheeler, Jenny Ingell, Yu An, Yinghua Chen, Peiling Chen, Hao Dai, Hong Du, Fang Feng, Qing Guo, Libo Hou, Wuhanbilige Hundei, Binbin Jin, Yan Li, Jiamin Liu, Xia Song, Yanping Wang, Yanwu Yu, Ning Zhang, Lingshan Zhao, Hui Zhong, Cheng Beng Goh, Ye Mun Low, Soon Yi Sor, Farah Hanis Zulkipli, Sarojini Sivanandam, Natsuki Arai, Ai Fukasawa, Mizue Furukawa, Keisuke Habuki, Shoko Hayashi, Wakako Isari, Saki Kanegae, Maria Kawai, Reiki Kobayashi, Takako Kuramae, Chika Kuribayashi, Sawako Maeno, Satoshi Masumoto, Tomoko Morisaki, Minoru Oda, Kazue Sawada, Kenta Sugamori, Ayana Tatsuzawa, Aiko Tomita, Kazuyuki Yuasa, Hiroko Inazawa, Amanda Axler, Kerri Gallo, Ester Baldini, Barbara Bartolomei Mecatti, Francesca Bianchini, Martina Ceseri, Laura Cipressa, Gianna Fabbri, Andrea Lorimer, Donata Lucci, Sharang Ghavampour, Anja Knoppe, Hans Schmidt-Gurtler, Hubert Dumann, Sybille Merscher, Margret Patecki, Georg Rainer Schlieper, Anke Torp, Bianca Weber, Maja Zietz, Bernd Hohenstein, Urs Benck, Diliana Draganova, Thomas Weinreich, Lothar Wolf, Jasmine Gaidu, Hanna Reiner, Mandy Visnjic, Daniel Steffl, Marie Breitenfeldt, Annette Kraemer-Guth, Christine Braun, Simone Hagge, Michael Schomig, Stephan Matthias, Dominik Stoffler, Beate Schumacher, Thomas Sitter, Louise Fuessl, Julia Krappe, Jerome Loutan, Volker Vielhauer, Luciano Andriaccio, Magdalena Maurer, Bernhard Winkelmann, Martin Dursch, Linda Seifert, Linda Tenbusch, Julia Weinmann-Menke, Simone Boedecker, Wiebke Kaluza-Schilling, Daniel Kraus, Carina Krieger, Margit Schmude, Anne Schreiber, Ewelina Eckrich, Diethelm Tschope, Abdulwahab Arbi, Young Lee-Barkey, Bernd Stratmann, Natalie Prib, Sina Rolfsmeier, Irina Schneider, Lars Rump, Johannes Stegbauer, Christine Pötz, Mara Schemmelmann, Claudia Schmidt, Michael Koch, Sendogan Aker, Annika Küpper, Manuela Martin, Thiemo Pfab, Christian Albert, Michael Haase, Barbara Zander, Claudia Schneider-Danwitz, Wolfgang Seeger, Wolf-Adam Seeger, Britta Zemann, Christoph Stellbrink, Kristin Marx, Ekaterina Stellbrink, Britta Brettschneider, Stephanie Watson, Marion Iselt, Gerhard Klausmann, Inga-Nadine Kummer, Auguste Kutschat, Simone Streitenberger, Matthias Girndt, Silke Markau, Ina Girakossyan, Claudia Hanf, Joachim Beige, Ralph Wendt, Ulrike Schmidt, Andreas Schneider, Roland Veelken, Claudia Donhauser, Luis Becker, Nexhat Miftari, Ricarda Wolfling, Sarah Morlok, Christian Hugo, Alexander Paliege, Jens Passauer, Julian Stumpf, Annegret Fleischer, Kerstin Haaser, Bernhard Kraemer, Jan Jochims, Bernd Kruger, Claudia Foellinger, Anastassiya Reisler, Frank Strutz, Stefan Haack, Ursula Hohenstatt, Martin Busch, Konstantin Herfurth, Gunter Wolf, Rainer Paul, Hermann Haller, Jessica Kaufeld, Jan Menne, Elisabeth Bahlmann-Kroll, Angela Bergner, Horst Weihprecht, Aydin Er, Florian Sonntag, Elif Turan, Michael Wittmann, Franziska Klauser, Eva Voigt, Volker Schettler, Egbert Schulz, Madlen Rohnstock, Elke Schettler, Bernd Schroppel, Rene van Erp, Martin Kachele, Ulla Ludwig, Lena Schulte-Kemna, Waltraud Kmietschak, Elke Preiss, Martina Ruocco, Gunnar Heine, Martin Brzoska, Sebastian Gabel, Christina Büttner, Asma Sabarai, Bernhard Banas, Tobias Bergler, Yvonne Ehrl, Franz Putz, Antonia Schuster, Stefanie Kuhn, Torsten Schramm, Stefan Degenhardt, Gerhard Schmidt, Lea Weiland, Ulrike Giebeln-Hudnell, Jan Kielstein, Gabriele Eden, Brigitte Fuchs, Gina Morig, Manuela Winkler, Harald Darius, Charalampos Kriatselis, Carl-Philipp Roesch, Astrid Maselli, Dominik Alscher, Markus Ketteler, Moritz Schanz, Severin Schricker, Bianka Rettenmaier, Andrea Schwab, Pablo Pergola, Irene Leal, Melissa Cagle, Anna Romo, Anthony Torres, Sucharit Joshi, Kulli Barrett, Alexis Africano, Vicki Dodds, Dorleena Gowen, Ashlee Morris, Juan Fernandez, Guillermo Jimenez, Ricardo Viera, Kendaling Bruce, Ryan Barrios, Maylin Garcia, Kerelyn Garcia, Iradis Leal, David Tietjen, David Bains, Carlo Castillo, Genielle Brewer, Justin Davis, Natalie Freking, Brittany Golson, Sally Ham, Jesslyn Roesch, Pusadee Suchinda, Shameem Beigh, Usah Lilavivat, Joyce Bilton, Kim Bocchicchia, Jeffrey Turner, Neera Dahl, Aldo Peixoto, Yasemin Kavak, Lauren Liberti, Hari Nair, Nicolas Page, Stephanie Rosenberg, Kathryn Simmons, Tamara Isakova, Rebecca Frazier, Rupal Mehta, Anand Srivastava, Patrick Fox, Jonathan Hecktman, Alexander Hodakowski, Carlos Martinez, Rachel Phillips, Alexis Stevenson, Reem Mustafa, Kyle Jansson, Cassandra Kimber, Jason Stubbs, Ahmad Tuffaha, Sri Yarlagadda, Debbie Griffin, Elisabeth Laundy, Zhuo Tang, Radica Alicic, Ann Cooper, Lisa Davis, Ashwini Gore, Rebecca Goldfaden, Leslie Harvill, Lisa Hichkad, Barry Johns, Thomas Jones, Kayla Merritt, Jennifer Sheldon, Jennifer Stanfield, Lindsay Alexander, Kaitlyn Preston, Lindsey Wood, Rajesh Pradhan, Roger DeRaad, Kelli McIntosh, Louis Raymond, Michael Shepperd, Susan McLaughlin, Mary Seifert, Andrew Shepherd, Joseph Aiello, William Durham, Laurie Loudermilk, John Manley, Sabrina Burnette, Stephanie Evans, Tara Johnson, Lance Sloan, Judy Ann Acosta, Stacy Gillham, Katia Sloan, SueAnn Squyres, Michael Rocco, Amret Hawfield, Ben Bagwell, Lauren Richmond, Joseph Soufer, Subha Clarke, Amanda Aliu, Kristine Calabrese, Amanda Davis, Veronica Poma, Tracy Spinola, James Magee, Ricardo Silva, Rushab Choksi, Lorraine Dajani, John Evans, Anil George, Prasanth Krish, Gerard Martins, Mae Sheikh-Ali, David Sutton, Freda Driver, Abraham Hanburry, Laura Hume, Amber Hurst, Matthew Taddeo, Marla Turner, Veronica Yousif, Srinivasan Beddhu, Laith Al-Rabadi, Nikita Abraham, Amalia Caamano, Judy Carle, Victoria Gonce, Kaitlyn Staylor, Na Zhou, Shweta Bansal, Manoj Bhattarai, Kumar Sharma, Subrata Debnath, Aliseiya Garza, Chakradhar Velagapudi, Sergio Rovner, Javier Almeida, Pablo Casares, Verlaine Stewart-Ray, Rene Almaraz, Renata Dayrell, Ana Moncada, Ricardo Pulido, Roxana Rodriquez, Wasim Deeb, Kathryn DeGoursey, Rodel Gloria, Trevor Greene, Robert Miller, Edward Pereira, Miguel Roura, Debbie Domingo, Sasha Dorestin, William Hodge, Cathy Jackson, Deborah Lund, Katrina Taylor, Kenneth Boren, Brittany Cleveland, Sandra Gaiser, Mandeep Sahani, Logan Aldrich, Exodus Edmerson, Edmond Limon, Cole Valletta, Patricia Vasquez, Christopher Provenzano, Navkiranjot Brar, Heather Henderson, Bellovich Keith, Qur Khai, Quresh Khairullah, Gail Makos, Joel Topf, Sherry Gasko, Rosemarie Henschel, Kaitlin Knapp, Teresa Kozlowski, Paula LaFleur, Ashwathy Varughese, Hui Xue, Patricia Wu, Olga Arechiga, Shan Darbeau, Michael Fechter, Stephanie Martinez, Lenita Hanson, Nyla Cooper, Arelis Madera, Jay Cadorna, Rita Sheridan, Helen Sparks, Bradley Eilerman, Susanne Bodine, Wael Eid, Rebecca Flora, Amber Avery, Cashmere Hardy, Mihaela Biscoveanu, Steven Nagelberg, Tracey Cummins, Frederic Rahbari-Oskoui, Anju Oommen, Zohreh Forghani, Stacie Hitchcock, Darya Hosein, Diane Watkins, Minesh Patel, Anthony Lambert, Elizabeth Newman, Autumn Wood, Tammy Ross, Stephany Topping, Jeffrey Mulhern, Lorna Murphy, Ann Vasseur, Gregory Greenwood, Alexander Hadley, Denise Laurienti, Christopher Marshall, Nicholas McLean, Scott Satko, Brandy Caudill, Jacob Maris, Janice Rogers, Cindy Vanhoy, George Thomas, Georges Nakhoul, John O'Toole, Jonathan Taliercio, Leslie Cooperman, Marina Markovic, Barbara Tucky, Devasmita Dev, Alia Hasan, Hima Yalamanchili, Namita Jain, Lesley McNeil, Eric Wines, Jean Park, Adline Ghazi, Mia Hamm, Tejas Patel, Amy Mottl, Emily Chang, Vimal Derebail, Emmie Cole, Anne Froment, Sara Kelley, Jordan Osmond Foster, Vahid Mahabadi, Golriz Jafari, Anita Kamarzarian, Wendy Arriaga, Daisy Arteaga, Rosario Machicado, Genesis Naverrete, Prashant Kumar, Imran Nazeer, Karina Urquia, Tammi Glider, Vickie Jones, Savannah Rucker, Jennifer Wiley, Rahul Pandey, Jesus Arroyo, Harish Pariani, Mohammad Ahmad, Shahin Mozaffari, Erika Perez, Matthew Budoff, Sion Roy, Divya Birudaraju, Ahmed Ghanem, Sajad Hamal, Stephen Aronoff, Elisa Joye Petr, Richard Sachson, Jaime Wiebel, Sana Akram, Laurie Jones, Curtis Knight, Maurie Tarlac, Shahbaz Ahmed, Harold Szerlip, Akinwande Akinfolarin, Ankit Mehta, Shana Camp, Cindy Castro, Zanaida Cooper, Jessica Terry, Ahmed Awad, Bhavya Kothapalli, Ryan Lustig, Serine Alfaress, Hyder Jasim, Mary Parrigon, Dennis Karounos, Sadiq Ahmed, Maggie Berry, Ruth Oremus, Carlos Hernandez-Cassis, Elias Ugwu, Nazia Junejo, Nancy Suazo, Mark Segal, Amir Kazory, Sherry Brown, Tristan Daniels, Sofia Dayi, Renee Hogan, Kathy McCray, Jennifer Stickley, Mahboob Rahman, Mirela Dobre, Lavinia Negrea, Aparna Padiyar, Nishigandha Pradhan, Arash Rashidi, Nagaraju Sarabu, Vicki Donley, Tricia Young, Godson Oguchi, Judepatricks Onyema, Kahla Damianik, Jack Dienes, Judith Plummer-Morgan, Marilyn Roman, Mauver Skipper, Stacey-Ann Villaruel, Krystle Williams, Danny Sugimoto, Jeffrey Dugas, Ismeal Ahmed, Jamie Bhairoo, Dolores Rijos, Huzaifa Salim, Madita Gavrila, Kathryn Lafferty, Ria Rabara, Sally Ruse, Maria Weetman, James Bushnell, Albert Power, Alison Jenkins, Stefanie Jones, Amanda Scott, Cath Byrne, Mark Jesky, Alison Cowley, Emma McHaffie, Holly Waterfall, Jo Taylor, Laura Bough, Thomas Phillips, Barbara Winter-Goodwin, Sui Phin Kon, Iain MacDougall, Eirini Lioudaki, Sapna Shah, Claire Sharpe, Francisco Aguilar, Abegail Hernandez Pena, Conception Pugay, Amelia Te, Hugh Finn, Wasim Hanif, Samiul Mostafa, Alice Aitken, Katharine Draxlbauer, Evelina Grobovaite, Jennifer Kearney, Theresa McCarthy, Giorgio Gentile, Duncan Browne, Palanichamy Chellamuthu, Tabinda Dugal, Terri Chant, Laura Jones, Emily Laity, Megan Miners, James Muir, Elizabeth Swanson, Andrew Frankel, James Tomlinson, Marlon Alegata, Rashid Almasarwah, Anthoula Apostolidi, Maria Vourvou, Thomas Walters, Maarten Taal, Hari Dukka, Nitin Kolhe, Carly McDonald, Kelly White, Shiva Ugni, Smita Gunda, Rotimi Oluyombo, Vicki Brindle, Ping Coutts, Tracy Fuller, Evelyn Nadar, Suresh Ramadoss, Nichola Motherwell, Susannah Pajak, Louise Tonks, Sunil Bhandari, Richard Bodington, Adil Hazara, Dominic Fellowes, Christopher Wong, Christopher Goldsmith, Sherald Barnes, Ann Bennett, Claire Burston, Samantha Hope, Nicola Hunt, Lini Kurian, Richard Fish, Daniela Farrugia, Judy Lee, Emma Sadler, Hannah Turner, Christopher Hill, Henry Brown, Agnes Masengu, Peter Maxwell, Nina Bleakley, Hugh Murtagh, William Petchey, Vivian Yiu, Joanne Kellett, Angharad Williams, Helen Clarke, Victoria Carnall, Sarah Benyon, Caroline Blake, Stephanie Estcourt, Jane Piper, Neal Morgan, Carolyn Hutchinson, Teresa McKinley, Alastair Woodman, Judi Graham, Niall Leonard, John Smyth, Vicki Adell, Samantha Hagan, Ben Caplin, Amin Oomatia, Eleanor Damian, Toluleyi Sobande, Tim Doulton, Michael Delaney, Mahmoud Montasser, Jenny Hansen, David Loader, Angela Moon, Frances Morris, Smeeta Sinha, Chukwuma Chukwu, Amy Hudson, Diane Campbell, Melanie Kershaw, Stephanie Whittaker, Ayesha Irtiza-Ali, Farid Ghalli, Heba Nosseir, Allison Leslie, Kate Trivedi, Donald Fraser, Mohammad Alhadj Ali, Sian Griffin, Farah Latif, Justyna Witczak, Alexa Wonnacott, Lynda Jeffers, Yvette Webley, Paul Phelan, Eve Miller-Hodges, Ailsa Geddes, Margaret Glenwright, Amy Hunter, Thomas Pickett, Jim Moriarty, Linda Hill, Amanda Tyler, Waqar Ayub, Gail Evans, Sue Hewins, Davina Hewitt, Kerry Read, Samira Bell, Leanne Cosgrove, Rachel Craik, Shona Murray, Nitin Bhandary, Holly Coles, Rashmi Easow, Maya Joseph, Arif Khwaja, Yvonne Jackson, Angeline Mbuyisa, Rachel Sellars, Nihil Chitalia, Cynthia Mohandas, Anca Gherman, Charlotte Kamundi, Olumide Olufuwa, Kieran McCafferty, Adedolapo Adeleke, Cara Healy, Damini Jeyarajah, Edward Kinsella-Perks, Richard Smith, Brian Camilleri, Carol Buckman, Jenny Finch, Vanessa Rivers, Andrew Connor, Sheila Carr, Lisa Shainberg, Andrew Lewington, Richard Baker, Suzannah Dorey, Kay Tobin, Rosalyn Wheatley, Debasish Banerjee, Richard Hull, Sharirose Abat, Riny Paul, Mahzuz Karim, Zay Htet, Saad Tufail, Ravi Varma, Karen Convery, Deirdre Fottrell-Gould, Lisa Hudig, Emily Tropman, Thahir Abdul-Samad, Anne Grace, Marie Phipps, Rebecca Suckling, Subash Somalanka, Bhrigu Sood, Pauline Swift, Sarah Acheampong, Kwame Ansu, Martia Augustin, Anna Sampson, Lynn Vinall, Kim Wren, Shamila Wanninayake, Nicholas Wooding, Heather Edwards, Lydia Owen, Stephanie Bolton, Marion Carson, Michael Matthews, Nigel Brunskill, Jorge Jesus-Silva, Alex Howson, Mary Quashie-Akponeware, Hilary Tindall, Chidambaram Nethaji, Helen Eldon, Rajan Patel, Patrick Mark, Alastair Rankin, Michael Sullivan, Kirsty 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Andrea, Pergola, Pablo, Leal, Irene, Cagle, Melissa, Romo, Anna, Torres, Anthony, Joshi, Sucharit, Barrett, Kulli, Africano, Alexi, Dodds, Vicki, Gowen, Dorleena, Morris, Ashlee, Fernandez, Juan, Jimenez, Guillermo, Viera, Ricardo, Bruce, Kendaling, Barrios, Ryan, Garcia, Maylin, Garcia, Kerelyn, Leal, Iradi, Tietjen, David, Bains, David, Castillo, Carlo, Brewer, Genielle, Davis, Justin, Freking, Natalie, Golson, Brittany, Ham, Sally, Roesch, Jesslyn, Suchinda, Pusadee, Beigh, Shameem, Lilavivat, Usah, Bilton, Joyce, Bocchicchia, Kim, Turner, Jeffrey, Dahl, Neera, Peixoto, Aldo, Kavak, Yasemin, Liberti, Lauren, Nair, Hari, Page, Nicola, Rosenberg, Stephanie, Simmons, Kathryn, Isakova, Tamara, Frazier, Rebecca, Mehta, Rupal, Srivastava, Anand, Fox, Patrick, Hecktman, Jonathan, Hodakowski, Alexander, Martinez, Carlo, Phillips, Rachel, Stevenson, Alexi, Mustafa, Reem, Jansson, Kyle, Kimber, Cassandra, Stubbs, Jason, Tuffaha, Ahmad, Yarlagadda, Sri, Griffin, Debbie, Laundy, Elisabeth, Tang, Zhuo, Alicic, Radica, Cooper, Ann, Davis, Lisa, Gore, Ashwini, Goldfaden, Rebecca, Harvill, Leslie, Hichkad, Lisa, Johns, Barry, Jones, Thoma, Merritt, Kayla, Sheldon, Jennifer, Stanfield, Jennifer, Alexander, Lindsay, Preston, Kaitlyn, Wood, Lindsey, Pradhan, Rajesh, Deraad, Roger, Mcintosh, Kelli, Raymond, Loui, Shepperd, Michael, Mclaughlin, Susan, Seifert, Mary, Shepherd, Andrew, Aiello, Joseph, Durham, William, Loudermilk, Laurie, Manley, John, Burnette, Sabrina, Evans, Stephanie, Johnson, Tara, Sloan, Lance, Ann Acosta, Judy, Gillham, Stacy, Sloan, Katia, Squyres, Sueann, Rocco, Michael, Hawfield, Amret, Bagwell, Ben, Richmond, Lauren, Soufer, Joseph, Clarke, Subha, Aliu, Amanda, Calabrese, Kristine, Davis, Amanda, Poma, Veronica, Spinola, Tracy, Magee, Jame, Silva, Ricardo, Choksi, Rushab, Dajani, Lorraine, Evans, John, George, Anil, Krish, Prasanth, Martins, Gerard, Sheikh-Ali, Mae, Sutton, David, Driver, Freda, Hanburry, Abraham, Hume, Laura, Hurst, Amber, Taddeo, Matthew, Turner, Marla, Yousif, Veronica, Beddhu, Srinivasan, Al-Rabadi, Laith, Abraham, Nikita, Caamano, Amalia, Carle, Judy, Gonce, Victoria, Staylor, Kaitlyn, Zhou, Na, Bansal, Shweta, Bhattarai, Manoj, Sharma, Kumar, Debnath, Subrata, Garza, Aliseiya, Velagapudi, Chakradhar, Rovner, Sergio, Almeida, Javier, Casares, Pablo, Stewart-Ray, Verlaine, Almaraz, Rene, Dayrell, Renata, Moncada, Ana, Pulido, Ricardo, Rodriquez, Roxana, Deeb, Wasim, Degoursey, Kathryn, Gloria, Rodel, Greene, Trevor, Miller, Robert, Pereira, Edward, Roura, Miguel, Domingo, Debbie, Dorestin, Sasha, Hodge, William, Jackson, Cathy, Lund, Deborah, Taylor, Katrina, Boren, Kenneth, Cleveland, Brittany, Gaiser, Sandra, Sahani, Mandeep, Aldrich, Logan, Edmerson, Exodu, Limon, Edmond, Valletta, Cole, Vasquez, Patricia, Provenzano, Christopher, Brar, Navkiranjot, Henderson, Heather, Keith, Bellovich, Khai, Qur, Khairullah, Quresh, Makos, Gail, Topf, Joel, Gasko, Sherry, Henschel, Rosemarie, Knapp, Kaitlin, Kozlowski, Teresa, Lafleur, Paula, Varughese, Ashwathy, Xue, Hui, Wu, Patricia, Arechiga, Olga, Darbeau, Shan, Fechter, Michael, Martinez, Stephanie, Hanson, Lenita, Cooper, Nyla, Madera, Areli, Cadorna, Jay, Sheridan, Rita, Sparks, Helen, Eilerman, Bradley, Bodine, Susanne, Eid, Wael, Flora, Rebecca, Avery, Amber, Hardy, Cashmere, Biscoveanu, Mihaela, Nagelberg, Steven, Cummins, Tracey, Rahbari-Oskoui, Frederic, Oommen, Anju, Forghani, Zohreh, Hitchcock, Stacie, Hosein, Darya, Watkins, Diane, Patel, Minesh, Lambert, Anthony, Newman, Elizabeth, Wood, Autumn, Ross, Tammy, Topping, Stephany, Mulhern, Jeffrey, Murphy, Lorna, Vasseur, Ann, Greenwood, Gregory, Hadley, Alexander, Laurienti, Denise, Marshall, Christopher, Mclean, Nichola, Satko, Scott, Caudill, Brandy, Maris, Jacob, Rogers, Janice, Vanhoy, Cindy, Thomas, George, Nakhoul, George, O'Toole, John, Taliercio, Jonathan, Cooperman, Leslie, Markovic, Marina, Tucky, Barbara, Dev, Devasmita, Hasan, Alia, Yalamanchili, Hima, Jain, Namita, Mcneil, Lesley, Wines, Eric, Park, Jean, Ghazi, Adline, Hamm, Mia, Patel, Teja, Mottl, Amy, Chang, Emily, Derebail, Vimal, Cole, Emmie, Froment, Anne, Kelley, Sara, Osmond Foster, Jordan, Mahabadi, Vahid, Jafari, Golriz, Kamarzarian, Anita, Arriaga, Wendy, Arteaga, Daisy, Machicado, Rosario, Naverrete, Genesi, Kumar, Prashant, Nazeer, Imran, Urquia, Karina, Glider, Tammi, Jones, Vickie, Rucker, Savannah, Wiley, Jennifer, Pandey, Rahul, Arroyo, Jesu, Pariani, Harish, Ahmad, Mohammad, Mozaffari, Shahin, Perez, Erika, Budoff, Matthew, Roy, Sion, Birudaraju, Divya, Ghanem, Ahmed, Hamal, Sajad, Aronoff, Stephen, Joye Petr, Elisa, Sachson, Richard, Wiebel, Jaime, Akram, Sana, Jones, Laurie, Knight, Curti, Tarlac, Maurie, Ahmed, Shahbaz, Szerlip, Harold, Akinfolarin, Akinwande, Mehta, Ankit, Camp, Shana, Castro, Cindy, Cooper, Zanaida, Terry, Jessica, Awad, Ahmed, Kothapalli, Bhavya, Lustig, Ryan, Alfaress, Serine, Jasim, Hyder, Parrigon, Mary, Karounos, Denni, Ahmed, Sadiq, Berry, Maggie, Oremus, Ruth, Hernandez-Cassis, Carlo, Ugwu, Elia, Junejo, Nazia, Suazo, Nancy, Segal, Mark, Kazory, Amir, Brown, Sherry, Daniels, Tristan, Dayi, Sofia, Hogan, Renee, Mccray, Kathy, Stickley, Jennifer, Rahman, Mahboob, Dobre, Mirela, Negrea, Lavinia, Padiyar, Aparna, Pradhan, Nishigandha, Rashidi, Arash, Sarabu, Nagaraju, Donley, Vicki, Young, Tricia, Oguchi, Godson, Onyema, Judepatrick, Damianik, Kahla, Dienes, Jack, Plummer-Morgan, Judith, Roman, Marilyn, Skipper, Mauver, Villaruel, Stacey-Ann, Williams, Krystle, Sugimoto, Danny, Dugas, Jeffrey, Ahmed, Ismeal, Bhairoo, Jamie, Rijos, Dolore, Salim, Huzaifa, Gavrila, Madita, Lafferty, Kathryn, Rabara, Ria, Ruse, Sally, Weetman, Maria, Bushnell, Jame, Power, Albert, Jenkins, Alison, Jones, Stefanie, Scott, Amanda, Byrne, Cath, Jesky, Mark, Cowley, Alison, Mchaffie, Emma, Waterfall, Holly, Taylor, Jo, Bough, Laura, Phillips, Thoma, Winter-Goodwin, Barbara, Phin Kon, Sui, Macdougall, Iain, Lioudaki, Eirini, Shah, Sapna, Sharpe, Claire, Aguilar, Francisco, Hernandez Pena, Abegail, Pugay, Conception, Te, Amelia, Finn, Hugh, Hanif, Wasim, Mostafa, Samiul, Aitken, Alice, Draxlbauer, Katharine, Grobovaite, Evelina, Kearney, Jennifer, Mccarthy, Theresa, Gentile, Giorgio, Browne, Duncan, Chellamuthu, Palanichamy, Dugal, Tabinda, Chant, Terri, Jones, Laura, Laity, Emily, Miners, Megan, Muir, Jame, Swanson, Elizabeth, Frankel, Andrew, Tomlinson, Jame, Alegata, Marlon, Almasarwah, Rashid, Apostolidi, Anthoula, Vourvou, Maria, Walters, Thoma, Taal, Maarten, Dukka, Hari, Kolhe, Nitin, Mcdonald, Carly, White, Kelly, Ugni, Shiva, Gunda, Smita, Oluyombo, Rotimi, Brindle, Vicki, Coutts, Ping, Fuller, Tracy, Nadar, Evelyn, Ramadoss, Suresh, Motherwell, Nichola, Pajak, Susannah, Tonks, Louise, Bhandari, Sunil, Bodington, Richard, Hazara, Adil, Fellowes, Dominic, Wong, Christopher, Goldsmith, Christopher, Barnes, Sherald, Bennett, Ann, Burston, Claire, Hope, Samantha, Hunt, Nicola, Kurian, Lini, Fish, Richard, Farrugia, Daniela, Lee, Judy, Sadler, Emma, Turner, Hannah, Hill, Christopher, Brown, Henry, Masengu, Agne, Maxwell, Peter, Bleakley, Nina, Murtagh, Hugh, Petchey, William, Yiu, Vivian, Kellett, Joanne, Williams, Angharad, Clarke, Helen, Carnall, Victoria, Benyon, Sarah, Blake, Caroline, Estcourt, Stephanie, Piper, Jane, Morgan, Neal, Hutchinson, Carolyn, Mckinley, Teresa, Woodman, Alastair, Graham, Judi, Leonard, Niall, Smyth, John, Adell, Vicki, Hagan, Samantha, Caplin, Ben, Oomatia, Amin, Damian, Eleanor, Sobande, Toluleyi, Doulton, Tim, Delaney, Michael, Montasser, Mahmoud, Hansen, Jenny, Loader, David, Moon, Angela, Morris, France, Sinha, Smeeta, Chukwu, Chukwuma, Hudson, Amy, Campbell, Diane, Kershaw, Melanie, Whittaker, Stephanie, Irtiza-Ali, Ayesha, Ghalli, Farid, Nosseir, Heba, Leslie, Allison, Trivedi, Kate, Fraser, Donald, Alhadj Ali, Mohammad, Griffin, Sian, Latif, Farah, Witczak, Justyna, Wonnacott, Alexa, Jeffers, Lynda, Webley, Yvette, Phelan, Paul, Miller-Hodges, Eve, Geddes, Ailsa, Glenwright, Margaret, Hunter, Amy, Pickett, Thoma, Moriarty, Jim, Hill, Linda, Tyler, Amanda, Ayub, Waqar, Evans, Gail, Hewins, Sue, Hewitt, Davina, Read, Kerry, Bell, Samira, Cosgrove, Leanne, Craik, Rachel, Murray, Shona, Bhandary, Nitin, Coles, Holly, Easow, Rashmi, Joseph, Maya, Khwaja, Arif, Jackson, Yvonne, Mbuyisa, Angeline, Sellars, Rachel, Chitalia, Nihil, Mohandas, Cynthia, Gherman, Anca, Kamundi, Charlotte, Olufuwa, Olumide, Mccafferty, Kieran, Adeleke, Adedolapo, Healy, Cara, Jeyarajah, Damini, Kinsella-Perks, Edward, Smith, Richard, Camilleri, Brian, Buckman, Carol, Finch, Jenny, Rivers, Vanessa, Connor, Andrew, Carr, Sheila, Shainberg, Lisa, Lewington, Andrew, Baker, Richard, Dorey, Suzannah, Tobin, Kay, Wheatley, Rosalyn, Banerjee, Debasish, Hull, Richard, Abat, Sharirose, Paul, Riny, Karim, Mahzuz, Htet, Zay, Tufail, Saad, Varma, Ravi, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Tropman, Emily, Abdul-Samad, Thahir, Grace, Anne, Phipps, Marie, Suckling, Rebecca, Somalanka, Subash, Sood, Bhrigu, Swift, Pauline, Acheampong, Sarah, Ansu, Kwame, Augustin, Martia, Sampson, Anna, Vinall, Lynn, Wren, Kim, Wanninayake, Shamila, Wooding, Nichola, Edwards, Heather, Owen, Lydia, Bolton, Stephanie, Carson, Marion, Matthews, Michael, Brunskill, Nigel, Jesus-Silva, Jorge, Howson, Alex, Quashie-Akponeware, Mary, Tindall, Hilary, Nethaji, Chidambaram, Eldon, Helen, Patel, Rajan, Mark, Patrick, Rankin, Alastair, Sullivan, Michael, Forsyth, Kirsty, Mcdougall, Rowan, Dasgupta, Tanaji, Davies, Louisa, Ryder, Maggie, Grimmer, Philip, Macdonald, Clare, Webster, Mary, Newcastle, Newcastle, Ellam, Timothy, Wong, Edwin, Meshykhi, Christine, Webster, Andrea, Wilson, Peter, Vilar, Enric, Berdeprado, Jocelyn, Doctolero, Eunice, Wilkinson, Lily, Mccarroll, Frank, Ammar, Hesham, Kuan, Ying, Moran, Conor, Shivashankar, Girish, Campbell, Ryan, Glowski, Deborah, Mcdermott, Paula, Ali, Amar, Patel, Zuber, Bond, Christine, Whalley, Gillian, Zhang, Haitao, Yang, Liu, Zhang, Lihua, Kan, Tingting, Zhu, Ling, Zhao, Jinghong, Hou, Weiping, Wu, Jing, Cheng, Hong, Bian, Weijing, Zhao, Zhirui, Shao, Fengmin, Cao, Huixia, Jiao, Xiaojing, Niu, Peiyuan, Niu, Jianying, Chen, Yu, Zhang, Lihong, Zhu, Shenglang, Lin, Haiyan, Yao, Shaopeng, Chen, Jiehui, Jiang, Ying, Hu, Ying, Xiao, Huaying, Yang, Fuye, Zhang, Xinzhou, Guo, Baochun, Jin, Qiu, Liu, Lixia, Xiao, Xiangcheng, Xie, Yanyun, Meng, Ting, Xu, Chuanwen, Huang, Jie, Xu, Yanmei, Kong, Weixin, Wang, Xiaoliang, Liu, Qianpan, Wang, Xueying, Gao, Ming, Hu, Xiumei, Lu, Ying, Wang, Li, Peng, Kun, Wang, Wei, Gong, Qiuhong, Cai, Jianfang, Li, Xiaojue, Liu, Xuejiao, Zhou, Shuhan, Liu, Hong, Weng, Yao, Tang, Shuai, Yao, Yao, Zhao, Shi, Cheng, Chen, Wei, Wei, Li, Na, Aqashiah Mazlan, Sadanah, Zubaidah Bahtar, Alia, Katiman, Elliyyin, Othman, Noraini, Mushahar, Lily, Mazlan, Nurdiana, Sharafina Safiee, Nur, Ramasamy, Sarasa, Seng Wong, Hin, Ahmad Rosdi, Hajar, Zhao Zhi Tan, Esther, Fan Tay, Ju, Seng Teng, Kok, Yahaya, Hasnah, Jiun Liu, Wen, Wee Ee, Lik, Kay Leong Khoo, Kenneth, Mohd Yusoff, Yuana, Safhan Mohamad Nor, Fariz, Kamil Ahmad, Mohd, Ramli Seman, Mohd, Hui Hong Tan, Clare, Lui Sian Ngu, Laura, Yoke May Chan, Jaime, Peji, Javelin, Loong Loh, Chek, Yan Lee, Yee, Ramanaidu, Sridhar, Mean Thong, Kah, Hong Wong, Yik, Junus, Suria, Hua Ching, Chen, Faisal Asmee, Mohammad, Ruziana Ku Md Razi, Ku, Leong Low, Chun, Sze Bing Sim, Christopher, Duan Tham, Zhang, Kamila Abdullah, Noor, Meng Chen, Tai, Chieh Chan, Yong, Chang, Eason, Yean Kang, Huan, Quan Lee, Kai, Ann Lee, Sue, Kheng Lee, Aik, Vinathan, Jeevika, Abdul Cader, Rizna, Mustafar, Ruslinda, Kamaruzaman, Lydia, Mohd, Rozita, Ismail, Rahimah, Men Leong, Chong, Koon Low, Chee, Wei Wong, Liang, Adnan, Norlezah, Ibrahim, Sabariah, Zaimi Abdul Wahab, Mohamad, Bavanandan, Sunita, Shen Lim, Yik, Hazlina Wan Mohamad, Wan, Munirah Jaafar, Siti, Ashykeen Mohd Fauzi, Nur, Sudin, Aziee, Kun Lim, Soo, Chung Gan, Chye, Hing, Albert, Ahmad Faizal Alaidin Razali, Wan, Fong Liew, Yew, Bao Tyng Chan, Chelsia, Chih Cheng, Mei, Chen Ong, Yu, Meng Ong, Loke, Amalina Mohamed Affandi, Farah, Rahmat, Korina, Chai Peng, Ban, Amat, Masayu, Hadafi Ahmad, Nuzaimin, Yee Mah, Doo, Loon Tye, Yi, Azhari, Zaid, Nabilah Mohamad Zaini, Siti, Aidil Musa, Mohd, Ahmad Miswan, Norazinizah, Ramli, Rafizanur, Aziah Ahmad, Nor, Leong Goh, Bak, Izah Ahmad, Nurul, Huda Ibrahim, Fairol, Jian Ng, Tze, Shanmuganathan, Malini, Lian Tay, Li, Harun, Zaiha, Ramli, Salmi, 'Ain Yusof, Nurul, Abd Rahman, Rossenizal, Iqbal Abdul Hafidz, Muhammad, Hidayati Mohd Sharif, Nur, Yasmoon Awang, Irda, Nakashima, Eitaro, Imamine, Rui, Minatoguchi, Makiko, Miura, Yukari, Nakaoka, Miduki, Suzuki, Yoshiki, Yoshikawa, Hitomi, Shin, Koki, Fujita, Kanae, Iwasa, Misuzu, Sasajima, Haruka, Sato, Airi, Hamamoto, Yoshiyuki, Fujita, Yuki, Haraguchi, Takuya, Hyo, Takanori, Izumi, Kiyohiro, Komiya, Toshiyuki, Kubota, Sodai, Kurose, Takeshi, Kuwata, Hitoshi, Nakatani, Susumu, Oishi, Kaori, Okamoto, Saki, Okamura, Kaori, Takeoka, Jun, Tanaka, Nagaaki, Tanigaki, Katsuya, Toda, Naohiro, Watanabe, Koin, Komori, Hiromi, Kumuji, Rika, Takesada, Asako, Tanaka, Aya, Maruyama, Shoichi, Hasegawa, Tomonori, Ishiguro, Akiko, Ishimoto, Takuji, Ito, Kazuhiro, Kamimura, Yutaka, Kato, Noritoshi, Kato, Sawako, Kojima, Hiroshi, Kosugi, Tomoki, Maeda, Kayaho, Mizuno, Masasi, Saito, Shoji, Sato, Hitomi, Sato, Yuka, Suzuki, Yasuhiro, Tanaka, Akihito, Yasuda, Yoshinari, Hasegawa, Fujiko, Hayashi, Maiko, Higashi, Shizuka, Shimamura, Kaho, Sumi, Momoko, Tajima, Kazuki, Unekawa, Chimaki, Wakayama, Kana, Wakita, Yukiko, Otani, Takatoshi, Imai, Ayako, Kawashima, Sayaka, Kogure, Eri, Sato, Tomoe, Takezawa, Misato, Yoshida, Shinya, Araki, Hideo, Katsuda, Yuko, Konishi, Masahiro, Matsunaga, Takahiro, Oe, Masashi, Ogane, Kunihiro, Sakai, Masato, Takahashi, Tomoko, Yamano, Takahiro, Yokoyama, Takuya, Ito, Hitomi, Katayama, Masayo, Kuroda, Emi, Ikeda, Toru, Kojo, Takuma, Yoshidome, Etsuo, Mizumachi, Rieko, Yamamoto, Akane, Yamasaki, Narihisa, Yamasaki, Yoshihiko, Wada, Jun, Eguchi, Jun, Higuchi, Chigusa, Katayama, Akihiro, Kinomura, Masaru, Kitagawa, Masashi, Kitamura, Shinji, Miyamoto, Satoshi, Morinaga, Hiroshi, Nakatsuka, Atsuko, Nojima, Ichiro, Shikata, Kenichi, Sugiyama, Hitoshi, Tanabe, Katsuyuki, Tsuji, Kenji, Uchida, Haruhito, Watanabe, Mayu, Hashimoto, Chie, Kato, Takahiro, Yamamoto, Sayaka, Wada, Takehiko, Fukagawa, Masafumi, Hamano, Naoto, Koizumi, Masahiro, Komaba, Hirotaka, Nakagawa, Yosuke, Iwamoto, Michiyo, Masutani, Kosuke, Katanosaka, Akane, Kiyota, Mayu, Uchi, Hikari, Ueda, Yuka, Yamamoto, Sonoka, Nagasu, Hajime, Itano, Seiji, Iwakura, Tsukasa, Kadoya, Hiroyuki, Kanda, Eiichiro, Kashihara, Naoki, Kidokoro, Kengo, Kondo, Megumi, Sasaki, Tamaki, Satoh, Minoru, Tokuyama, Atsuyuki, Umeno, Reina, Wada, Yoshihisa, Yamamoto, Toshiya, Yamanouchi, Yu, Abe, Masumi, Inukai, Yoko, Ogawa, Wataru, Asahara, Shunichiro, Fujii, Hideki, Goto, Shunsuke, Hirota, Yushi, Hosooka, Tetsuya, Kono, Keiji, Nishi, Shinichi, Okada, Yuko, Sakaguchi, Kazuhiko, Sugawara, Kenji, Takahashi, Michiko, Takai, Tomoko, Tamori, Yoshikazu, Watanabe, Kentaro, Kitajima, Miyu, Nishi, Misaki, Wada, Junko, Ito, Yasuhiko, Kamiya, Hideki, Asai, Akimasa, Asai, Nao, Asano, Saeko, Banno, Shogo, Ejima, Yohei, Hase, Hanako, Hayami, Tomohide, Himeno, Tatsuhito, Ishikawa, Takahiro, Ito, Mayumi, Iwagaitsu, Shiho, Kasagi, Rina, Kato, Yoshiro, Kato, Makoto, Kato, Koichi, Katsuno, Takayuki, Kawai, Miyuka, Kinashi, Hiroshi, Kondo, Masaki, Koshino, Masako, Matsuoka, Naoya, Morishita, Yoshiaki, Motegi, Mikio, Nakamura, Jiro, Shimoda, Hiromi, Sugiyama, Hirokazu, Tsunekawa, Shin, Yamaguchi, Makoto, Takahashi, Kazuyo, Watada, Hirotaka, Funayama, Takashi, Furukawa, Yasuhiko, Gohda, Tomohito, Goto, Hiromasa, Kaga, Hideyoshi, Kanaguchi, Yasuhiko, Kanazawa, Akio, Kaneko, Kayo, Kano, Toshiki, Kihara, Masao, Kimura, Shogo, Kobayashi, Takashi, Maiguma, Masayuki, Makita, Yuko, Mano, Satoshi, Mita, Tomoya, Miyatsuka, Takeshi, Murakoshi, Maki, Muto, Masahiro, Nakata, Masami, Nakata, Junichiro, Nishida, Yuya, Nohara, Nao, Ogihara, Takeshi, Sato, Daisuke, Sato, Junko, Sato, Hiroaki, Suzuki, Yusuke, Suzuki, Ruka, Suzuki, Hitoshi, Takagi, Miyuki, Tamura, Yoshifumi, Uchida, Toyoyoshi, Ueda, Seiji, Asawa, Miki, Miyaji, Minako, Nagashima, Eri, Shibata, Yoshie, Yanagisawa, Eri, Yamauchi, Toshimasa, Hirakawa, Yosuke, Nishi, Hiroshi, Shojima, Nobuhiro, Horikawa, Satoko, Nakayama, Yukiko, Yamada, Naoko, Omori, Yuki, Yano, Shintaro, Ioka, Miyabi, Kuwabara, Nahoko, Nagano, Remi, Nozawa, Megumi, Osawa, Yumi, Maegawa, Hiroshi, Kume, Shinji, Araki, Shinichi, Miyazawa, Itsuko, Morino, Katsutaro, Kawai, Ikuko, Sobata, Masumi, Takaoka, Motoko, Iwaita, Yasushi, Udagawa, Takashi, Inamori, Ami, Kawase, Aya, Yamanaka, Aya, Shimano, Hitoshi, Fujita, Akiko, Iwasaki, Hitoshi, Kai, Hirayasu, Osaki, Yoshinori, Saito, Chie, Sekiya, Motohiro, Tsunoda, Ryoya, Yamagata, Kunihiro, Nakamura, Rikako, Yamada, Aiko, Ohsugi, Mitsuru, Awazawa, Motoharu, Bouchi, Ryotaro, Hashimoto, Shota, Hashimoto, Makiko, Hisatake, Tomoko, Ihana, Noriko, Ishizuka, Koko, Izumi, Kazuo, Kajio, Hiroshi, Kobayashi, Michi, Kodani, Noriko, Maruyama, Koji, Matsumoto, Michihiro, Matsushita, Maya, Nakamura, Tomoka, Sugiyama, Takehiro, Tanabe, Akiyo, Terakawa, Aiko, Ueki, Kojiro, Orimo, Yuko, Ozawa, Takako, Takahira, Eriko, Yamasaki, Yoshimitsu, Haneda, Masakazu, Tomita, Tadahiro, Akimoto, Saori, Fujimoto, Akihiro, Ishihara, Kenji, Murakami, Chiho, Nishiyama, Akiyo, Toyonaga, Yukiko, Uozumi, Kana, Yamaji, Yukihiro, Shigehara, Tetsuya, Okajyo, Jun, Shimizu, Yukihiro, Iwasaki, Shingo, Fukao, Yuki, Furusho, Megumi, Nunokawa, Shintaro, Katagiri, Hideki, Izumi, Tomohito, Kaneko, Keizo, Kodama, Shinjiro, Miyazaki, Mariko, Munakata, Yuichiro, Nagasawa, Tasuku, Oe, Yuji, Sugawara, Hiroto, Takahashi, Kei, Hirata, Kazushige, Inomata, Keiko, Otomo, Shoko, Uchida, Taeko, Yamashita, Chigusa, Kiyosue, Arihiro, Tamura, Ryota, Dube, Francoi, Bolduc, Marilene, Talbot, Marie-Christine, Cham, Leslie, Lai, Vesta, Tse, Josephine, Jolly, Shivinder, Duck, Tabbatha, Lyle, Scott, Epp, Rachel, Galloway, Camille, Haskett, Susan, Matvienko, Elizabeta, Paulsen, Liam, Moist, Louise, Lozon, Zabrina, Ramsey, Tina, Whitmore, Brittany, Al-Zeer, Bader, Macleod, Paula, O'Sullivan, Aoife, Sheriff, Zainab, Tholl, Sam, Pandey, Amritanshu, Armstrong, Samantha, Gebeyehu, Bethelihem, Toth, Patrick, Goldenberg, Ronald, Jahangiriesmaili, Mahsa, Sanguila, Shariff, Suresh, Neethi, Talsania, Tanvi, Zalunardo, Nadia, Agharazii, Mohsen, Roussel, Marie-Pier, Saillant, Annie, Samson, France, Bajaj, Harpreet, Bhavsar, Miken, Dhall, Parul, Dhillon, Gagandeep, Grewal, Bhupinder, Nimbkar, Taniya, Madore, Francoi, Marcotte, Guylaine, Steen, Oren, Bullen, Mathura, Raguwaran, Shayani, Valleteau, Andre, Langlois, Marie-France, Brown, Christine, Steele, Andrew, Garrity, Melissa, Ghate, Taneera, Robinson, Holly, Tolibas, Michael, Tailor, Chetna, Elliott, Lauren, McClary-Wright, Christine, Boreky, Fadia, Fikry, Sameh, Ali, Ayesha, Barot, Chintankumar, Basily, Wagdy, Saram, Thisun, Varad, Vinay, Khandwala, Hasnain, Aguilera, Alex, Alvarez, Patricia, Gill, Balwinder, Huda, Nazihah, Navivala, Aamir, Pinto, Daniel, Bevilacqua, Micheli, Fung, Elaine, Hernandez, Geraldine, Mann, Puneet, Saini, Jaskiran, Rabasa-Lhoret, Remi, Bovan, Danijela, Devaux, Marie, Barnini, Cecilia, Leoncini, Giovanna, Manco, Luca, Nobili, Giulia, Piemontese, Matteo, Aucella, Filippo, Grifa, Rachele, Totaro, Francesco, La Manna, Gaetano, Capelli, Irene, Cianciolo, Giuseppe, Lerario, Sarah, Zappulo, Fulvia, Rosati, Alberto, Fani, Filippo, Spatoliatore, Giuseppe, Gesualdo, Loreto, Pesce, Francesco, Russo, Maria, Zippo, Maria, Cafiero, Cesira, Motta, Daria, Bianco, Simona, Bilucaglia, Donatella, Messa, Piergiorgio, Pavone, Laura, Tripodi, Federica, Vettoretti, Simone, Fioretto, Paola, Carraro, Gianni, Farnia, Filippo, Postal, Anna, D'Amelio, Alessandro, Cardone, Antonio, Piccinni, Giovanni, Aloisi, Annalisa, Scolari, Francesco, Alberici, Federico, Guerini, Alice, Saccà, Chiara, Salviani, Chiara, Zani, Roberta, DE NICOLA, Luca, Garofalo, Carlo, Elena Liberti, Maria, Minutolo, Roberto, Pennino, Luigi, Polese, Lucio, Mené, Paolo, Barberi, Simona, Falcone, Clorinda, Russo, Francesco, Caroppo, Maurizio, Santorelli, Gennaro, Rivera, Rodolfo, Santoro, Domenico, Giuffrida, Alfio, Zirino, Fortunata, Calvi, Cristina, Estienne, Luca, Gambaro, Giovanni, Gangemi, Concetta, Ortalda, Vittorio, Pessolano, Giuseppina, Grandaliano, Giuseppe, Baccaro, Rocco, Ferraro, Pietro, Mangiacapra, Roberto, Melandri, Marco, Foligno, Nadia, Quartagno, Rita, Vezzoli, Giuseppe, Brioni, Elena, and Group, EMPA-KIDNEY Collaborative
Subjects: chronic renal disease, empagliflozin, empa-kidney, General Medicine
Abstract: Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; PConclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110. opens in new tab; EudraCT number, 2017-002971-24. opens in new tab.)
Published: 2023

23. Extracellular RNA transfer from non‐malignant human cholangiocytes can promote cholangiocarcinoma growth

Author: Shin Otake, Kenji Takahashi, Mitsuyoshi Okada, Tushar Patel, Yosui Tamaki, Satoshi Fujii, Kazunobu Aso, Masakazu Haneda, Yu Ota, and Irene Yan
Subjects: Stromal cell, Epithelial-Mesenchymal Transition, QH301-705.5, General Biochemistry, Genetics and Molecular Biology, Cholangiocarcinoma, Extracellular Vesicles, Cell Movement, Cell Line, Tumor, microRNA, Tumor Microenvironment, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, Biology (General), Transcription factor, Research Articles, Cell Proliferation, Tumor microenvironment, epithelial‐mesenchymal transition, Cell growth, Chemistry, RNA, Epithelial Cells, Cell biology, secretome, MicroRNAs, Gene Expression Regulation, Extracellular RNA, Research Article, Signal Transduction
Abstract: Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor‐derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, nontransformed cells. We examined the impact of EVs within the cellular secretome from nonmalignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro‐fibrogenic mediator TGF‐β. We identified miR‐195 as a TGF‐β responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion, and migration. The effects of miR‐195 involve modulation of the epithelial–mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV‐mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma., Cholangiocyte cell secretome can include extracellular vesicles (EV) containing tumor‐suppressive noncoding RNA such as miR‐195 and contribute to microenvironmental modulation of cholangiocarcinoma growth. miR‐195 can suppress the epithelial–mesenchymal transition and inhibit tumor invasion, migration, and growth.
Published: 2021

24. Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Author: Kenichi Shikata, Masakazu Haneda, Toshiharu Ninomiya, Daisuke Koya, Yoshiki Suzuki, Daisuke Suzuki, Hitoshi Ishida, Hiroaki Akai, Yasuhiko Tomino, Takashi Uzu, Motonobu Nishimura, Shiro Maeda, Daisuke Ogawa, Satoshi Miyamoto, Hirofumi Makino, and the Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) collaborative group
Subjects: Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Type 2 diabetes, Diabetic nephropathy, 030204 cardiovascular system & hematology, Lower risk, Diseases of the endocrine glands. Clinical endocrinology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Diabetes mellitus, Internal medicine, Early Medical Intervention, Internal Medicine, Medicine, Humans, Diabetic Nephropathies, 030212 general & internal medicine, Prospective Studies, Diabetic kidney disease, education, Creatinine, education.field_of_study, business.industry, Hazard ratio, Remission Induction, General Medicine, Articles, Middle Aged, medicine.disease, RC648-665, Prognosis, Clinical Trial, Diabetic Nephropathy Remission and Regression Team Trial in Japan, Clinical Science and Care, chemistry, Diabetes Mellitus, Type 2, Female, business, Biomarkers, Follow-Up Studies
Abstract: Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P, The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.
Published: 2020

25. Long-Term Safety and Efficacy of Teneligliptin in Elderly Patients with Type 2 Diabetes: Subgroup Analysis of a 3-Year Post-Marketing Surveillance in Japan

Author: Takashi Kadowaki, Hiroshi Ito, Masakazu Haneda, Kazuyo Sasaki, and Yuka Yamada
Subjects: Blood Glucose, Male, 030213 general clinical medicine, medicine.medical_specialty, Postmarketing surveillance, Subgroup analysis, Type 2 diabetes, Dipeptidyl peptidase-4 inhibitor, Teneligliptin, 03 medical and health sciences, 0302 clinical medicine, Japan, Internal medicine, Diabetes mellitus, medicine, Product Surveillance, Postmarketing, Humans, Hypoglycemic Agents, Pharmacology (medical), Original Research, Aged, Aged, 80 and over, Glycated Hemoglobin, Dipeptidyl-Peptidase IV Inhibitors, Type 2 diabetes mellitus, business.industry, Dipeptidyl peptidase 4 inhibitor, Incidence (epidemiology), Diabetes, Post-marketing surveillance, General Medicine, Middle Aged, medicine.disease, Hypoglycemia, Clinical trial, Elderly patients, Real-world, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, Pyrazoles, Thiazolidines, Female, business, medicine.drug
Abstract: Introduction Teneligliptin, a dipeptidyl peptidase 4 inhibitor, was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. However, clinical trials of teneligliptin involved limited numbers of elderly patients. Therefore, we investigated the safety and efficacy of teneligliptin in elderly patients with T2DM. Methods This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. Data were analysed for patients in three age subgroups (, Plain Language Summary Teneligliptin is an oral drug taken once daily to manage blood glucose levels in people with type 2 diabetes. A number of studies of teneligliptin have investigated its safety and efficacy, but these studies included limited numbers of elderly people, aged 75 years or older. Following the approval of teneligliptin in Japan, post-marketing surveillance was started to monitor its safety and efficacy when prescribed by doctors to people in actual clinical practice. We analysed data from the surveillance to check if the safety and efficacy of teneligliptin differ in younger and older people separately. We found that there was no clear difference in the number of adverse drug reactions among three age subgroups
Published: 2020

26. Circulating extracellular vesicle‐encapsulated HULC is a potential biomarker for human pancreatic cancer

Author: Masakazu Haneda, Takayuki Kogure, Yuko Suzuki, Keisuke Yamakita, Hidetaka Iwamoto, Satoshi Fujii, Tushar Patel, Kenji Takahashi, Tsuguhito Ota, Yohei Kitano, and Yu Ota
Subjects: Male, 0301 basic medicine, Cancer Research, endocrine system diseases, Carcinogenesis, Cell, Apoptosis, Mice, 0302 clinical medicine, Cell Movement, Aged, 80 and over, microRNA, Liver Neoplasms, General Medicine, Extracellular vesicle, Middle Aged, Long non-coding RNA, Up-Regulation, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Original Article, Female, RNA, Long Noncoding, Carcinoma, Pancreatic Ductal, Transcriptional Activation, Epithelial-Mesenchymal Transition, HULC, Mice, Nude, Adenocarcinoma, Biology, Exosome, Extracellular Vesicles, 03 medical and health sciences, Cell Line, Tumor, Pancreatic cancer, Biomarkers, Tumor, medicine, exosome, Animals, Humans, Neoplasm Invasiveness, long noncoding RNA, Epithelial–mesenchymal transition, Aged, Cell Proliferation, epithelial‐mesenchymal transition, liquid biopsy, Original Articles, medicine.disease, digestive system diseases, Pancreatic Neoplasms, 030104 developmental biology, Cancer research
Abstract: The role of long noncoding RNAs (lncRNAs) in the epithelial‐mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify an lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA. Expression profiling of lncRNAs revealed that highly upregulated in liver cancer (HULC) was highly expressed, and induced, by transforming growth factor‐β in PDAC cells and their EVs. Knockdown of HULC decreased PDAC cell invasion and migration by inhibiting the EMT. Thus, HULC could be transferred by EVs, and promote EMT, invasion, and migration in recipient PDAC cells. To assess the roles of HULC, PDAC cell xenografts in nude mice were established. Knockdown of HULC in PDAC cells implanted in mice inhibited tumor growth. Moreover, microRNA‐133b suppressed PDAC cell invasion and migration by inhibiting the EMT through targeting HULC. Furthermore, serum samples were obtained from 20 PDAC and 22 intraductal papillary mucinous neoplasm (IPMN) patients, as well as 21 healthy individuals. Analysis of serum EV HULC expression by digital PCR showed that HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. Additionally, HULC showed good predictive performance for discriminating PDAC, suggesting that the analysis of EV‐encapsulated HULC would contribute to the diagnosis for human PDAC. Extracellular vesicle‐transported HULC promotes cell invasion and migration by inducing the EMT, and microRNA‐133b suppresses the EMT by targeting HULC. Extracellular vesicle‐encapsulated HULC could be a potential circulating biomarker for human PDAC., Extracellular vesicle HULC can regulate cell invasion and migration through induction of epithelial‐mesenchymal transition. Extracellular vesicle HULC could compare favorably with CA19‐9 as a novel biomarker in liquid biopsy for human pancreatic ductal adenocarcinoma.
Published: 2019

27. Combined changes in albuminuria and kidney function and subsequent risk for kidney failure in type 2 diabetes

Author: Hirofumi Makino, Tatsumi Moriya, Shinji Kitajima, Takashi Wada, Shigeko Hara, Yoshiki Suzuki, Yasunori Iwata, Akinori Hara, Eiji Kusano, Shin-ichi Araki, Megumi Oshima, Kunitoshi Iseki, Masakazu Haneda, Hiroaki Satoh, Toshiharu Ninomiya, Miho Shimizu, Hiroki Yokoyama, Norihiko Sakai, Tetsuya Babazono, Tadashi Toyama, Hiroyuki Nakamura, Masayuki Iwano, and Kengo Furuichi
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030232 urology & nephrology, Urology, kidney function tests, Renal function, Type 2 diabetes, 030204 cardiovascular system & hematology, Kidney, albuminuria, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, medicine, Humans, Pathophysiology/Complications, Creatinine, function, business.industry, Surrogate endpoint, medicine.disease, RC648-665, chemistry, type 2, Diabetes Mellitus, Type 2, diabetes mellitus, Albuminuria, Kidney Failure, Chronic, medicine.symptom, business, Kidney disease, Cohort study, Glomerular Filtration Rate
Abstract: IntroductionChanges in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD.Research design and methodsUsing data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk.ResultsAmong 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of 2/year): HR 4.19 (95% CI 1.87 to 9.38) and 2.89 (95% CI 1.32 to 6.33) for those with a decline of >5 and 2.5–5 mL/min/1.73 m2/year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m2/year compared with those with a minor change in UACR and eGFR.ConclusionsCombined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.
Published: 2021

28. Clinical practice of diabetic foot, nephropathy, and retinopathy in Japan: cross-sectional study using local and nationwide questionnaire surveys

Author: Yukihiro Fujita and Masakazu Haneda
Subjects: medicine.medical_specialty, Cross-sectional study, business.industry, Endocrinology, Diabetes and Metabolism, Questionnaire surveys, Diabetic nephropathy, medicine.disease, Diabetic foot, Nephropathy, Clinical Practice, Diabetic retinopathy, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Original Article, business, Retinopathy
Abstract: Aims/introduction:It is a reality that there are still many diabetic subjects who suffer from serious complications, but there are few statistics of severe eye complications such as vitrectomy or blindness and diabetic foot including amputations in Japan., Materials and methods:To determine the status of medical examination, consultation, and the actual practice for diabetic foot, retinopathy, and nephropathy, we conducted two surveys on diabetic subjects under treatment by the local physicians in Asahikawa area or in the nationwide diabetes-specialized facilities, respectively., Results:A total of 3649 diabetic subjects responded to the questionnaire from 35 clinics/hospitals in Asahikawa area. Sixty-five percent of the subjects had a routine eye examination at least once a year, but 29% of them interrupted or never attended eye examination. Besides, only 37.2% of subjects had received ankle–brachial index (ABI) test as a useful screening for diabetic foot. The nationwide survey found that 1,273,103 diabetic subjects were undergoing treatment in 472 diabetes-specialized facilities. There, lower extremity amputations accounted for 0.23% and revascularization accounted for 0.64% of the subjects. However, outpatient foot care and dialysis preventive outpatient services were offered only in 77.3% and 66.5% of the facilities, respectively. Furthermore, we found a lower availability of ophthalmologic treatments even in some of the specialized facilities., Conclusion:We considered that interruption and non-attendance of eye examinations were a barrier to prevent severe retinopathy. Our results also suggested that some of the specialized facilities may be inadequate in their efforts to detect and prevent these complications.
Published: 2021

29. 414-P: Apparent Diffusion Coefficient on Diffusion-Weighted Magnetic Resonance Imaging Predicts the Progression of Renal Damage in Diabetic Nephropathy

Author: Hiroya Kitsunai, Naoki Nakagawa, Naoyuki Hasebe, Atsutaka Okizaki, Masakazu Haneda, and Yumi Takiyama
Subjects: medicine.medical_specialty, medicine.diagnostic_test, business.industry, Endocrinology, Diabetes and Metabolism, Urology, Renal function, Magnetic resonance imaging, Urine, Type 2 diabetes, medicine.disease, Diabetic nephropathy, Diabetes mellitus, Internal Medicine, medicine, Effective diffusion coefficient, Renal biopsy, business
Abstract: Renal damage in diabetic nephropathy (DN) is evaluated by biochemical tests such as urine albumin-to-creatinine ratio (UACR) and serum estimated glomerular filtration rate (eGFR). On the other hand, renal biopsy, which is rich in definitive information, is rarely performed because of its complexity and high invasion. To evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) could be a noninvasive approach for distinguishing DN, we performed MRI scanning of the subjects with 6 b-values (b = 0, 50, 100, 350, 400, 700) and analyzed the parameters using the kidney imaging software (Hitachi, Ltd., Tokyo). A total of 40 subjects were enrolled, 25 of whom had type 2 diabetes with or without hypertension (T2D), 9 had nondiabetes but hypertension (HT), and 6 were healthy volunteers (Control). T2D showed lower values of apparent diffusion coefficient (ADC) 0-700 compared with HT (129.0 ± 2.12 x10-5mm2/s in T2D vs. 132.5 ± 1.43 ×10-5mm2/s in HT, p Disclosure H. Kitsunai: None. Y. Takiyama: Other Relationship; Self; Gilead Sciences, Inc., Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Mochida Pharmaceutical Co., Ltd., Roche Diabetes Care, Taisho Pharmaceutical Co., Ltd. N. Nakagawa: None. N. Hasebe: None. A. Okizaki: Research Support; Self; Fuji-Film Toyama Chemical Co., Ltd., Nihon Medhi-physics. M. Haneda: Advisory Panel; Self; Eli Lilly Japan K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc. Funding Japan Society for the Promotion of Science (20K17420)
Published: 2021

30. Secular changes in clinical manifestations of kidney disease among Japanese adults with type 2 diabetes from 1996 to 2014

Author: Yoshihiko Nishio, Satoshi Ugi, Shinji Kume, Daisuke Koya, Hiroshi Maegawa, Masakazu Haneda, Atsunori Kashiwagi, Katsutaro Morino, and Shin-ichi Araki
Subjects: Blood Glucose, Male, Time Factors, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, urologic and male genital diseases, Gastroenterology, Diabetic nephropathy, Cohort Studies, 0302 clinical medicine, Japan, Risk Factors, Prevalence, Diabetic Nephropathies, General Medicine, Articles, Middle Aged, Prognosis, female genital diseases and pregnancy complications, Clinical Science and Care, Disease Progression, Original Article, Female, medicine.symptom, Glomerular Filtration Rate, medicine.medical_specialty, Renal function, 030209 endocrinology & metabolism, albuminuria, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Risk factor, Aged, Glycated Hemoglobin, business.industry, diabetic nephropathy, medicine.disease, RC648-665, diabetic kidney disease, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Albuminuria, Microalbuminuria, business, Biomarkers, Kidney disease, Follow-Up Studies
Abstract: Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (
Published: 2019

31. Prospective study on clinical characteristics of Japanese diabetic patients with chronic limb-threatening ischemia presenting Fontaine stage IV

Author: Takuya Tsujimura, Shota Okuno, Yukihiro Fujita, Osamu Iida, Izumi Nakamura, Mitsuyoshi Takahara, Yosuke Hata, and Masakazu Haneda
Subjects: Gangrene, medicine.medical_specialty, education.field_of_study, business.industry, Endocrinology, Diabetes and Metabolism, Microangiopathy, Population, Ischemia, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, medicine.disease, Confidence interval, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Original Article, Prospective cohort study, Stage iv, education, business
Abstract: The aim of this prospective cross-sectional study was to reveal clinical characteristics of Japanese diabetic patients with chronic limb-threatening ischemia (CLTI) presenting ischemic unhealed ulcer/gangrene (Fontaine stage IV) in the real-world settings. The present study included 132 Japanese diabetic patients who underwent endovascular therapy for CLTI presenting Fontaine stage IV. The prevalence of diabetes-related complications, as well as prior history of ankle-brachial index (ABI) measurement before CLTI onset, was evaluated adopting multiple imputation (50 times). Duration of diabetes was referred to as time from diagnosis. The patients were aged 70 ± 10 years, with duration of diabetes 23 ± 12 years. The diabetes-related complications were so common that only 17% (95% confidence interval: 11–24%) and 25% (17–33%) of the population were free from advanced micro- and macroangiopathies, respectively. The clustering of advanced macroangiopathies was not significantly associated with duration of diabetes (P = 0.62). On the other hand, that of advanced microangiopathies was significantly positively associated with duration of diabetes (P = 0.004). However, even in patients with duration of diabetes
Published: 2019

32. N-Acetyl-seryl-aspartyl-lysyl-proline is a potential biomarker of renal function in normoalbuminuric diabetic patients with eGFR ≥ 30 ml/min/1.73 m2

Author: Yuiko Mizunuma, Munehiro Kitada, Takako Nagai, Keizo Kanasaki, Kyoko Nitta, Daisuke Koya, Masakazu Haneda, Atsushi Nakagawa, Masaru Sakurai, and Masao Toyoda
Subjects: Nephrology, medicine.medical_specialty, Creatinine, Physiology, business.industry, Urinary system, 030232 urology & nephrology, Urology, Renal function, Urine, 030204 cardiovascular system & hematology, medicine.disease, Diabetic nephropathy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Physiology (medical), Internal medicine, Diabetes mellitus, Medicine, Biomarker (medicine), business
Abstract: A biomarker, by which we can predict alterations of renal function in normoalbuminuric diabetic patients, is not available. Here, we report that endogenous anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) represents a potential biomarker to predict alterations in eGFR in normoalbuminuric diabetic patients. We analyzed 21 normoalbuminuric diabetic patients with eGFR ≥ 30 ml/min/1.73 m2 and measured AcSDKP levels in first morning void urine. We divided patients into two groups based on the median values: low or high urinary AcSDKP groups (uAcSDKP/Crlow or uAcSDKP/Crhigh). At baseline, no significant differences in sex, age, HbA1c, BMI, serum creatinine levels, etc., were observed between the two groups. During ~ 4 years, the alteration in eGFR [ΔeGFRop (ΔeGFR observational periods)] was significantly stable in uAcSDKP/Crhigh group compared with uAcSDKP/Crlow group over time (P = 0.003, χ2 = 8.58). We also evaluated urine kidney injury molecule-1 (uKim-1) levels and found that ΔeGFRop was also stable in low uKim-1 group compared with high uKim-1 group over time (P = 0.004, χ2 = 8.38). Patients who fulfilled the criteria for both uAcSDKP/Crhigh and uKim-1low exhibited stable ΔeGFRop (P
Published: 2019

33. Amplified Association Between Blood Pressure and Albuminuria in Overweight Patients With Biopsy-Proven Hypertensive Nephrosclerosis

Author: Yoshifumi Ubara, Hitoshi Yokoyama, Tomoya Nishino, Masakazu Haneda, Takashi Wada, Satoshi Hisano, Koki Mise, Yoshiki Suzuki, Yugo Shibagaki, Seiichi Matsuo, Akinori Hara, Shinichi Nishi, Tadashi Toyama, Yukio Yuzawa, Kengo Furuichi, Noriko Uesugi, Yoshihiko Ueda, Miho Shimizu, Masako Kochi, Daisuke Ogawa, Hirofumi Makino, Kentaro Kohagura, Hiroshi Kitamura, Kenjiro Kimura, Junichi Hoshino, and Hiroshi Sato
Subjects: Male, medicine.medical_specialty, Hypertension, Renal, Biopsy, Kidney Glomerulus, Urology, Renal function, Blood Pressure, Urine, 030204 cardiovascular system & hematology, Overweight, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Internal Medicine, medicine, Albuminuria, Humans, 030212 general & internal medicine, Nephritis, Nephrosclerosis, Proteinuria, business.industry, Middle Aged, Blood pressure, Disease Progression, Female, medicine.symptom, business, Body mass index, Glomerular Filtration Rate
Abstract: BACKGROUND An overweight person is at high risk for hypertensive renal damage. The effect of weight on the association between systolic blood pressure (SBP) and albuminuria remains unknown in patients with histologically diagnosed hypertensive nephrosclerosis. METHODS A total of 97 patients with biopsy-confirmed hypertensive nephrosclerosis were recruited from 13 centers throughout Japan. We examined the relationship between SBP and proteinuria among those who were overweight, which is defined as a body mass index ≥25 kg/m2, and those who were not. We examined the interaction of weight and SBP with albuminuria at baseline and with the changes in estimated glomerular filtration rate (eGFR) during the observational period. RESULTS Our results included mean age (54 years old), blood pressure (138/80), eGFR (53 ml/min/1.73 m2), and urine albumin levels (0.2 g/day). SBP was significantly correlated with log-transformed urine albumin levels (r = 0.4, P = 0.01) in patients who were overweight (n = 38) compared with patients who were not overweight (n = 59). Multiple regression analysis revealed that the interaction between being overweight and SBP with respect to albuminuria was significantly correlated with the log-transformed urine albumin level (β = 0.39, P = 0.047) and was independent of age, sex, and potential confounding factors. The interaction between weight and SBP ≥140 mm Hg was significantly associated with a greater decrease in eGFR in the following 3 years. CONCLUSIONS Being overweight may enhance susceptibility to hypertensive glomerular damage and may eventually lead to renal progression in patients with hypertensive nephrosclerosis.
Published: 2019

34. Establishment of novel specific assay for short‐form glucose‐dependent insulinotropic polypeptide and evaluation of its secretion in nondiabetic subjects

Author: Tsuyoshi Yanagimachi, Nobuhiro Maruyama, Hidemitsu Sakagami, Yukihiro Fujita, Ryoichi Bessho, Jun Honjo, Hiroki Yokoyama, Yasutaka Takeda, and Masakazu Haneda
Subjects: Adult, Blood Glucose, Male, medicine.medical_specialty, endocrine system, Physiology, Alpha (ethology), Enzyme-Linked Immunosorbent Assay, Gastric Inhibitory Polypeptide, 030204 cardiovascular system & hematology, Carbohydrate metabolism, oral glucose tolerance test, cookie meal test, Glucagon, lcsh:Physiology, 03 medical and health sciences, 0302 clinical medicine, In vivo, Physiology (medical), Internal medicine, medicine, Metabolism and Regulation, Animals, Humans, Insulin, Secretion, Rats, Wistar, Original Research, Aged, geography, geography.geographical_feature_category, biology, lcsh:QP1-981, Chemistry, DPP‐4 inhibitor, Glucose Tolerance Test, Middle Aged, Islet, In vitro, Peptide Fragments, GIP (1–30), Endocrinology, biology.protein, ELISA, Female, Endocrine and Metabolic Conditons, Disorders and Treatments, Antibody, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists
Abstract: The short‐form glucose‐dependent insulinotropic polypeptide (GIP) (1–30) is released from islet alpha cells and promotes insulin secretion in a paracrine manner in vitro. However, it is not well elucidated how GIP (1–30) is involved in glucose metabolism in vivo, since a specific assay system for GIP (1–30) has not yet been established. We first developed a sandwich enzyme‐linked immunosorbent assay (ELISA) specific for GIP (1–30) by combining a novel antibody specific to the GIP (1–30) C terminus with the common antibody against GIP N terminus. Then, we explored cross‐reactivities with incretins and glucagon‐related peptides in this ELISA. GIP (1–30) amide, but not GIP (1–42), GLP‐1, or glucagon increased absorbance in a dose‐dependent manner. We next measured plasma GIP (1–30) concentrations in nondiabetic participants (ND) during a 75‐g oral glucose tolerance test or cookie meal test (carbohydrates 75 g, lipids 28.5 g, proteins 8.5 g). Both glucose and cookie load increased GIP (1–30) concentrations in ND, but the increases were much lower than those of GIP (1–42). Furthermore, the DPP‐4 inhibitor significantly increased GIP (1–30) concentrations similarly to GIP (1–42) in ND. In conclusion, we for the first time developed an ELISA specific for GIP (1–30) and revealed its secretion in ND., For the first time, we established a novel ELISA specific for GIP (1–30). GIP (1–30) secretion is promoted by oral glucose and mix meal load in nondiabetics. DPP‐4 inhibitors increased peripheral blood GIP (1–30) levels.
Published: 2020

35. Long-Term, Real-World Safety and Efficacy of Teneligliptin: A Post-Marketing Surveillance of More Than 10,000 Patients with Type 2 Diabetes in Japan

Author: Kazuyo Sasaki, Masakazu Haneda, Hiroshi Ito, Miyuki Matsukawa, Takashi Kadowaki, and Yuka Yamada
Subjects: Blood Glucose, Male, 030213 general clinical medicine, medicine.medical_specialty, medicine.medical_treatment, Postmarketing surveillance, Dipeptidyl peptidase-4 inhibitor, Type 2 diabetes, Teneligliptin, 03 medical and health sciences, 0302 clinical medicine, Japan, Internal medicine, Diabetes mellitus, Product Surveillance, Postmarketing, Medicine, Humans, Hypoglycemic Agents, Pharmacology (medical), Renal impairment, Dialysis, Aged, Original Research, Aged, 80 and over, Glycated Hemoglobin, Dipeptidyl-Peptidase IV Inhibitors, Type 2 diabetes mellitus, business.industry, Dipeptidyl peptidase 4 inhibitor, Incidence (epidemiology), Post-marketing surveillance, General Medicine, Middle Aged, medicine.disease, Clinical trial, Diabetes Mellitus, Type 2, Socioeconomic Factors, Real-world, 030220 oncology & carcinogenesis, Pyrazoles, Thiazolidines, Female, business, medicine.drug, Glomerular Filtration Rate
Abstract: Introduction Teneligliptin is a dipeptidyl peptidase 4 inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. We performed a long-term post-marketing surveillance (RUBY) to obtain real-world evidence regarding the safety and efficacy of teneligliptin in Japan. Methods This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs) and laboratory variables. Data were evaluated in all patients and in patients divided according to baseline renal function across categories of estimated glomerular filtration rate (G1–G5) and dialysis. Safety was assessed as the incidence of ADRs and efficacy was assessed in terms of glycaemic control, for up to 3 years. Results Of 11,677 patients registered, 10,696 and 10,249 were evaluable for safety and efficacy analyses, respectively. The median duration of exposure was 1096 days. ADRs occurred in 412 patients (3.85%) and were serious in 117 patients (1.09%). The most frequent ADR class was gastrointestinal disorders (0.68%), which included constipation. There were no new ADRs warranting attention beyond those already described in teneligliptin’s package insert. ADRs and serious ADRs in renal function subgroups occurred in 3.24–7.14% and 0.65–5.36% in G1–G5, and 4.49% and 1.92% in patients on dialysis, respectively. Reduction in HbA1c was sustained for 3 years after starting teneligliptin (− 0.70% ± 1.36%, p
Published: 2019

36. Increment of plasma glucose by exogenous glucagon is associated with present and future renal function in type 2 diabetes a retrospective study from glucagon stimulation test

Author: Yumi Takiyama, Hidemitsu Sakagami, Yukihiro Fujita, Tsuguhito Ota, Mao Sato, Tsuyoshi Yanagimachi, Masakazu Haneda, Atsuko Abiko, Yasutaka Takeda, Tomoe Abe, and Ryoichi Bessho
Subjects: Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Renal function, 030209 endocrinology & metabolism, Type 2 diabetes, Kidney Function Tests, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Glucagon, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Japan, Internal medicine, Diabetes mellitus, medicine, Humans, Diabetic Nephropathies, Retrospective Studies, Creatinine, Kidney, Free fatty acid, lcsh:RC648-665, business.industry, Incidence, Gluconeogenesis, ΔGlucose, General Medicine, Middle Aged, Prognosis, medicine.disease, Hormones, Cross-Sectional Studies, medicine.anatomical_structure, Endocrinology, Diabetes Mellitus, Type 2, chemistry, 030220 oncology & carcinogenesis, Female, Liver function, business, Biomarkers, Follow-Up Studies, Glomerular Filtration Rate, Research Article, Kidney disease
Abstract: BackgroundGlucagon stimulation test (GST) is often employed to assess the insulin reserve of the pancreatic beta cells in diabetic subjects. The clinical significance of the increment of plasma glucose (Δglucose) by exogenous glucagon during GST has not been elucidated. We investigated the relationship between Δglucose and clinical parameters including the liver and renal function in type 2 diabetic subjects, since we hypothesized that Δglucose is associated with the liver and renal function reflecting the capacity for gluconeogenesis in the organs.MethodsA total of 209 subjects with type 2 diabetes who underwent GST during admission were included in this cross-sectional study. We defined the difference between plasma glucose at fasting and 6 min after intravenous injection of 1 mg glucagon as Δglucose. We assessed correlations between Δglucose and clinical parameters such as diabetic duration, BMI, HbA1c, beta cell function, serum free fatty acids (FFA) which is known to stimulate gluconeogenesis, liver function, the indices of liver function, renal function, and urinary albumin excretion (UAE).ResultsIn correlation analysis, Δglucose positively correlated to FFA and estimated glomerular filtration rate (eGFR), but inversely to serum creatinine and cystatin C, although Δglucose showed no correlation with both liver function and the indices of residual liver function. Multiple regression analysis revealed that Δglucose was an independent determinant for the eGFR after 1 year, equally BMI, HbA1c, serum lipids, and UAE, which are known as the predictors for the development of chronic kidney disease.ConclusionOur results suggest that Δglucose during GST might be related to gluconeogenesis in the kidney and could be the determinant of future renal function in type 2 diabetes.
Published: 2019

37. Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial

Author: Yuki Miyamoto, Christopher Lee, Jyothis T. George, Fernando Solimando, Keiko Suzaki, Kosuke Shiki, Jisoo Lee, Ryuzo Kawamori, Masakazu Haneda, and Gang Cheng
Subjects: linagliptin, Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Fixed-dose combination, empagliflozin, Placebo-controlled study, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Linagliptin, law.invention, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Double-Blind Method, Glucosides, Randomized controlled trial, law, Internal medicine, randomized trial, Internal Medicine, Empagliflozin, medicine, Humans, Hypoglycemic Agents, Benzhydryl Compounds, Aged, Glycated Hemoglobin, business.industry, Body Weight, Original Articles, Middle Aged, medicine.disease, phase III study, Safety profile, glycaemic control, Treatment Outcome, Diabetes Mellitus, Type 2, Original Article, Drug Therapy, Combination, Female, type 2 diabetes, business, medicine.drug
Abstract: Aims This double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients. Methods The trial (40 sites; May 2015‐March 2017) involved screening 433 adults (≥20 years) who were treatment‐naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%‐10.0% after ≥16 weeks of using Lina (pre‐enrolment or during a 16‐week, open‐label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once‐daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up‐titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks. Results Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, −0.93% vs 0.21%; adjusted mean difference, −1.14%) and Week 52 (−1.16% vs 0.06%; adjusted mean difference, −1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin‐associated events (eg, increased urination, increased blood ketones). There were no adjudication‐confirmed diabetic ketoacidosis events or lower limb amputations. Conclusions These results support the notion that empagliflozin‐linagliptin in fixed‐dose combination is a therapeutic option for Japanese patients with type 2 diabetes.
Published: 2018

38. 糖尿病診療ガイドライン2016

Author: Masakazu Haneda
Subjects: General Medicine
Published: 2018

39. Relationship of Eating Patterns and Metabolic Parameters, and Teneligliptin Treatment: Interim Results from Post-marketing Surveillance in Japanese Type 2 Diabetes Patients

Author: Hiroshi Ito, Takashi Kadowaki, Kazuyo Sasaki, Sonoe Hiraide, Masakazu Haneda, Makoto Ueno, and Miyuki Matsukawa
Subjects: Blood Glucose, Male, medicine.medical_specialty, HbA1c, Eating pattern, Postmarketing surveillance, 030209 endocrinology & metabolism, Type 2 diabetes, Dipeptidyl peptidase-4 inhibitor, Teneligliptin, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Japan, Internal medicine, medicine, Humans, Hypoglycemic Agents, Pharmacology (medical), Original Research, Aged, Glycated Hemoglobin, Dipeptidyl-Peptidase IV Inhibitors, business.industry, digestive, oral, and skin physiology, Post-marketing surveillance, General Medicine, Middle Aged, medicine.disease, Interim analysis, Combined Modality Therapy, Hypoglycemia, Postprandial, chemistry, Diabetes Mellitus, Type 2, Hyperglycemia, Pyrazoles, Thiazolidines, Female, Glycated hemoglobin, Diet, Healthy, business, Body mass index, medicine.drug
Abstract: Introduction Healthy eating is a critical aspect of the prevention and management of type 2 diabetes (T2DM). Disrupted eating patterns can result in poor glucose control and increase the likelihood of diabetic complications. Teneligliptin inhibits dipeptidyl peptidase-4 activity for 24 h and suppresses postprandial hyperglycemia after all three daily meals. This interim analysis of data from the large-scale post-marketing surveillance of teneligliptin (RUBY) in Japan examined eating patterns and their relationship with metabolic parameters and diabetic complications. We also examined whether eating patterns affected safety and efficacy of teneligliptin. Methods We analyzed baseline data from survey forms collected in RUBY between May 2013 and June 2017, including patient characteristics, metabolic parameters, and eating patterns (eating three meals per day or not; timing of evening meal) before teneligliptin treatment was initiated. Safety and efficacy of 12 months’ teneligliptin (20–40 mg/day) treatment was assessed. Results Data from 10,532 patients were available for analysis. Most patients who did not eat three meals per day (n =757) or who ate their evening meal after 10 PM (n =206) were 64 years old or younger. At baseline, glycated hemoglobin (HbA1c), fasting blood glucose, triglycerides, total and low-density lipoprotein cholesterol, body mass index, alanine aminotransferase, and aspartate aminotransferase levels were higher in those patients who did not eat three meals per day (p
Published: 2018

40. Safety and Efficacy of Teneligliptin in Patients with Type 2 Diabetes Mellitus and Impaired Renal Function: Interim Report from Post-marketing Surveillance

Author: Sonoe Hiraide, Masakazu Haneda, Manabu Ishii, Miyuki Matsukawa, Kazuyo Sasaki, Takashi Kadowaki, Makoto Ueno, and Hiroshi Ito
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Postmarketing surveillance, 030209 endocrinology & metabolism, Teneligliptin, Dipeptidyl peptidase-4 inhibitor, Type 2 diabetes, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Type 2 diabetes mellitus, Internal Medicine, medicine, Renal impairment, Dialysis, Original Research, business.industry, Post-marketing surveillance, medicine.disease, Interim analysis, business, medicine.drug, Kidney disease
Abstract: Introduction Teneligliptin is a novel oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Safety and efficacy of teneligliptin have been demonstrated in clinical studies; however, data supporting its use in patients with moderate or severe renal impairment are limited. This interim analysis of a post-marketing surveillance of teneligliptin, exploRing the long-term efficacy and safety included cardiovascUlar events in patients with type 2 diaBetes treated bY teneligliptin in the real-world (RUBY), aims to verify the long-term safety and efficacy of teneligliptin in Japanese patients with T2DM and impaired renal function. Methods For this analysis, we used the data from case report forms of the RUBY surveillance between May 2013 and June 2017. The patients were classified into G1–G5 stages of chronic kidney disease according to estimated glomerular filtration rate (eGFR) at initiation of teneligliptin treatment. Safety and efficacy were evaluated in these subgroups. Patients on dialysis were also assessed. Safety was assessed from adverse drug reactions (ADRs). Glycemic control was evaluated up to 2 years after teneligliptin initiation. Results A total of 11,677 patients were enrolled in the surveillance and 11,425 patient case-report forms were collected for the interim analysis. The incidence of ADRs in each subgroup was 2.98–6.98% of patients, with no differences in the ADR profile (including hypoglycemia and renal function ADRs) between subgroups. At 1 and 2 years after starting teneligliptin, the least-squares mean change in HbA1c adjusted to the baseline was − 0.68 to − 0.85% and − 0.71 to − 0.85% across the eGFR groups, respectively. Treatment with teneligliptin in patients on dialysis reduced or tended to reduce glycated albumin levels [− 2.29%, (p
Published: 2018

41. Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment

Author: Masakazu Haneda, Yutaka Seino, Takashi Sasaki, Atsushi Fukatsu, Yusuke Kubo, Yoshishige Samukawa, Soichi Sakai, and Yuri Sato
Subjects: luseogliflozin, renal impairment, Adult, Blood Glucose, Male, medicine.medical_specialty, T2DM patients, Urinary system, Urology, Pharmaceutical Science, Renal function, 030209 endocrinology & metabolism, Original Manuscript, Type 2 diabetes, 030204 cardiovascular system & hematology, Diabetes Complications, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pharmacokinetics, Asian People, pharmacodynamics, Medicine, Humans, Sorbitol, Pharmacology (medical), Renal Insufficiency, Adverse effect, Sodium-Glucose Transporter 2 Inhibitors, Aged, business.industry, Type 2 Diabetes Mellitus, Articles, Middle Aged, medicine.disease, Diabetes Mellitus, Type 2, Pharmacodynamics, Female, SGLT2 Inhibitor, business, pharmacokinetics, Glomerular Filtration Rate
Abstract: This open‐label, parallel‐group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5‐mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60–89, 45–59, 30–44, 15–29 mL/min/1.73 m2, respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment.
Published: 2018

42. Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition

Author: Masakazu Haneda, Yu Ota, Yosui Tamaki, Kenji Takahashi, Kazunobu Aso, Mitsuyoshi Okada, Tsuguhito Ota, Shin Otake, Satoshi Fujii, and Yuichi Makino
Subjects: 0301 basic medicine, Cell, Exosome, microRNA (miRNA), 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, microRNA, medicine, exosome, Epithelial–mesenchymal transition, Transcription factor, Chemistry, fungi, Extracellular vesicle, epithelial-mesenchymal transition (EMT), 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, cholangiocarcinoma, extracellular vesicles, Intracellular, Research Paper, Transforming growth factor
Abstract: Creative Commons Attribution 3.0 License, Early-staged cholangiocarcinoma (CCA) is difficult to diagnose due to its high potential for invasion and metastasis. Epithelial-mesenchymal transition (EMT) is induced by transforming growth factor-β (TGF-β) in a process thought to be important for invasion and metastasis in several cancers, including CCA. Although microRNAs (miRNAs) have been implicated in the pathogenesis of several malignancies, their roles to CCA are not clearly understood. Some miRNAs were reported to be included in extracellular vesicles (EVs) and transferred from their donor cells to other cells, modulating recipient cell behaviors. In this study, the involvement and functional roles of EV-contained miRNAs during EMT in human CCA were determined. Expression profiling identified a subset of miRNAs that were reduced by TGF-β in CCA cells. Among these, miR-30e was highly downregulated by TGF-β and predicted to target Snail, which is an EMT-inducible transcription factor. MiR-30e overexpression suppressed cell invasion and migration via inhibiting EMT, whereas miR-30e inhibition promoted EMT, cell invasion and migration. Moreover, miR-30e was enriched in EVs derived from CCA cells after miR-30e overexpression, and miR-30e intercellular transfer through EVs suppressed EMT, cell invasion and migration in recipient CCA cells. Together, our results suggest that EV-mediated miR-30e transfer could inhibit EMT via directly targeting Snail, which subsequently suppresses CCA cell invasion and migration. These findings provide several new insights into regulatory mechanisms of tumor invasion and metastasis in human CCA.
Published: 2018

43. Japanese Clinical Practice Guideline for Diabetes 2016

Author: Mitsuhiko Noda, Atsushi Goto, Masakazu Haneda, Daisuke Yabe, Tatsuya Kondo, Hiroshi Noto, Hideki Origasa, Eiichi Araki, and Yukihiro Fujita
Subjects: medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Diabetes, Correction, Diabetology, 030209 endocrinology & metabolism, Guideline, General Medicine, medicine.disease, Clinical Practice, Treatment, 03 medical and health sciences, 0302 clinical medicine, Special Reports, Diabetes mellitus, Family medicine, Diagnosis, medicine, Internal Medicine, 030212 general & internal medicine, business, Corrigendum, Special Report
Abstract: This article is based on the "Japanese Clinical Practice Guideline for Diabetes 2016" (ISBN978-4-524-25857-4), which was published in Japanese by Nankodo Co., Ltd. (© The Japan Diabetes Society (JDS), 2016) and has been jointly published in Journal of Diabetes Investigation (the official journal of the Asian Association for the Study of Diabetes: https://doi.org/10.1111/jdi.12810 ) and Diabetology International (the official English journal of JDS).
Published: 2018

44. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial

Author: Frank C. Brosius, Ravindra L. Mehta, Fabio P. Nunes, William L. Macias, Katherine R. Tuttle, Sharon G. Adler, Jonathan Janes, Kevin L. Duffin, James A. Tumlin, Maria E Silk, Joseph V. Haas, Jiajun Liu, Matthias Kretzler, Yoshiya Tanaka, Masakazu Haneda, and Tracy Cardillo
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, estimated glomerular filtration rate, Renal function, Type 2 diabetes, JAK inhibition, 030204 cardiovascular system & hematology, Placebo, Gastroenterology, albuminuria, Gene Expression Regulation, Enzymologic, Diabetic nephropathy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Clinical Research, Interquartile range, Diabetes mellitus, Internal medicine, medicine, Humans, Diabetic Nephropathies, Protein Kinase Inhibitors, Sulfonamides, Transplantation, Creatinine, business.industry, diabetic nephropathy, biomarkers, Janus Kinase 1, Janus Kinase 2, Middle Aged, Prognosis, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 2, chemistry, Purines, Nephrology, Albuminuria, Azetidines, Pyrazoles, Female, ORIGINAL ARTICLES, medicine.symptom, business, Glomerular Filtration Rate
Abstract: Background Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD. Methods In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4–8 weeks of washout. Results Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin–creatinine ratio (UACR) of 820 (407–1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38–0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4–8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C–X–C motif chemokine 10 and urine C–C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo. Conclusions Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.
Published: 2018

45. Safety and efficacy of long-term treatment with teneligliptin: Interim analysis of a post-marketing surveillance of more than 10,000 Japanese patients with type 2 diabetes mellitus

Author: Makoto Ueno, Hiroshi Ito, Takashi Kadowaki, Miyuki Matsukawa, Kazuyo Sasaki, Hiroaki Iijima, Tomoko Yamakura, Masakazu Haneda, and Mayumi Kimura
Subjects: Blood Glucose, Male, medicine.medical_specialty, Long term treatment, Postmarketing surveillance, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Japan, Surveys and Questionnaires, Interim, Product Surveillance, Postmarketing, medicine, Humans, Hypoglycemic Agents, Pharmacology (medical), Teneligliptin, Intensive care medicine, health care economics and organizations, Aged, Glycated Hemoglobin, Pharmacology, business.industry, DPP-4 Inhibitors, Type 2 Diabetes Mellitus, General Medicine, Middle Aged, Interim analysis, Hypoglycemia, Diabetes Mellitus, Type 2, Pyrazoles, Thiazolidines, Female, Chemical and Drug Induced Liver Injury, business, Constipation, medicine.drug
Abstract: This post-marketing surveillance examined the safety and efficacy of long-term teneligliptin therapy in Japanese patients.We report interim results (cut-off date: 28 June 2017) of a 3-year PMS undertaken in subjects with type 2 diabetes mellitus (T2DM). Survey items included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. A subgroup analysis was also performed across three age groups (65 years; 65 to75 years; ≥75 years). Main outcome measures were incidence of ADRs, laboratory variables, and change in glycated hemoglobin (HbA1c) from baseline over time.Of 11,677 patients registered, data from 10,532 patients (6,338 males/4,194 females) were analyzed for the safety analysis set; the median administration period was 731 days. Overall, ADRs and serious ADRs were reported in 364 (3.46%) and 91 patients (0.86%), respectively. The most common ADRs were all hypoglycemia (0.32%), constipation (0.27%), and hepatic function abnormal (0.24%). No change in mean body weight occurred, and a reduction in mean HbA1c was observed until 2 years. The safety and efficacy profiles did not differ markedly among the three age groups.These interim results show that teneligliptin was well tolerated and improved hyperglycemia in Japanese patients with T2DM in clinical practice.
Published: 2018

46. Association between all-cause mortality and severity of depressive symptoms in patients with type 2 diabetes: Analysis from the Japan Diabetes Complications Study (JDCS)

Author: Satoshi Matsunaga, Yasuo Akanuma, Hirohito Sone, Masafumi Kitaoka, Hitoshi Shimano, Shiro Tanaka, Kazuya Fujihara, Jiro Nakamura, Masakazu Haneda, Asako Sato, Chika Horikawa, Yasuo Ohashi, and Satoshi Iimuro
Subjects: Adult, Male, medicine.medical_specialty, endocrine system diseases, Population, Type 2 diabetes, Hypoglycemia, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Japan, Risk Factors, Internal medicine, Humans, Medicine, 030212 general & internal medicine, Psychiatry, education, Depression (differential diagnoses), Aged, education.field_of_study, Depression, business.industry, Proportional hazards model, Hazard ratio, nutritional and metabolic diseases, Middle Aged, Center for Epidemiologic Studies Depression Scale, medicine.disease, Survival Analysis, Psychiatry and Mental health, Clinical Psychology, Diabetes Mellitus, Type 2, Relative risk, Female, business, 030217 neurology & neurosurgery
Abstract: Objective The aims of this study are to confirm whether the excess mortality caused by depressive symptoms is independent of severe hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and to evaluate the association between all-cause mortality and degrees of severity of depressive symptoms in Japanese patients with T2DM. Methods A total of 1160 Japanese patients with T2DM were eligible for this analysis. Participants were followed prospectively for 3 years and their depressive states were evaluated at baseline by the Center for Epidemiologic Studies Depression Scale (CES-D). Cox proportional hazards model was used to evaluate the relative risk of all-cause mortality and was adjusted by possible confounding factors, including severe hypoglycemia, all of which are known as risk factors for both depression and mortality. Results After adjustment for severe hypoglycemia, each 5-point increase in the CES-D score was significantly associated with excess all-cause mortality (hazard ratio 1.69 [95% CI 1.26–2.17]). The spline curve of HRs for mortality according to total CES-D scores showed that mortality risk was slightly increased at lower scores but was sharply elevated at higher scores. Conclusion A high score on the CES-D at baseline was significantly associated with all-cause mortality in patients with T2DM after adjusting for confounders including severe hypoglycemia. However, only a small effect on mortality risk was found at relatively lower levels of depressive symptoms in this population. Further research is needed to confirm this relationship between the severity of depressive symptoms and mortality in patients with T2DM.
Published: 2017

47. Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001-2010: Report of the Committee on Causes of Death in Diabetes Mellitus

Author: Jiro Nakamura, Hideki Kamiya, Masakazu Haneda, Nobuya Inagaki, Yukio Tanizawa, Eiichi Araki, Kohjiro Ueki, and Takeo Nakayama
Subjects: Adult, Male, Adolescent, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Diabetes Complications, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Asian People, Japan, Cause of Death, Surveys and Questionnaires, Diabetes Mellitus, Internal Medicine, Humans, Average age at the time of death, Child, Special Report, Aged, Infant, Newborn, Infant, General Medicine, Middle Aged, Causes of death in Japanese diabetics, Child, Preschool, Malignant neoplasia, Female, Diabetic Angiopathies
Abstract: The principal causes of death among 45,708 patients with diabetes (29,801 men and 15,907 women) who died in 241 hospitals throughout Japan during 2001–2010 were determined based on a survey of the hospital records. Autopsy had been conducted in 978 of the 45,708 cases. The most frequent cause of death was malignant neoplasia (38.3%), followed by, in order of descending frequency: infections (17.0%); and then vascular diseases (14.9%), including renal failure (3.5%), ischemic heart diseases (4.8%) and cerebrovascular diseases (6.6%). Diabetic coma associated with hyperglycemia with or without ketoacidosis accounted for only 0.6% of the deaths. In regard to the relationship between the age and cause of death in patients with diabetes, the incidence of death due to vascular diseases was higher in patients over the age of 30 or 40 years, and the 97.0% of the total death due to vascular diseases was observed in patients over the age of 50 years. The incidence of death due to infectious diseases, especially pneumonia, increased in an age‐dependent fashion, and the 80.7% of the total death due to pneumonia was observed in patients over the age of 70 years. ’Poorer’ glycemic control was associated with the reduced lifespan of patients with diabetes, especially of those with nephropathy. The average age at death in the survey population was 72.6 years. The lifespan was 1.6 years shorter in patients with ‘poorer’ glycemic control than in those with ‘better’ glycemic control. In patients with diabetes of less than 10 years’ duration, the incidence of death due to macroangiopathy was higher than that due to nephropathy. Of the 45,708 patients with diabetes, 33.9% were on oral medication, 41.9% received insulin therapy and 18.8% were treated by diet alone. Among the patients in whom the cause of death was diabetic nephropathy, a high percentage, 53.7%, was on insulin therapy. The average age at death of the 45,708 patients with diabetes was 71.4 years in men and 75.1 years in women. However, the report of the Ministry of Health and Welfare of Japan in 2010 set the average lifespan of the Japanese at 79.6 years for men and 86.3 years for women. Thus, the average lifespan of patients with diabetes still appears to be shorter than that of the general population in Japan. However, the differences in lifespan between patients with diabetes and the general population were shorter than those in the former surveys.
Published: 2017

48. Nationwide multicentre kidney biopsy study of Japanese patients with type 2 diabetes

Author: Tomoya Nishino, Tadashi Toyama, Takashi Wada, Kenjiro Kimura, Yugo Shibagaki, Hirofumi Makino, Kengo Furuichi, Hiroshi Sato, Daisuke Ogawa, Miho Shimizu, Kentaro Kohagura, Masakazu Haneda, Yoshihiko Ueda, Akinori Hara, Hitoshi Yokoyama, Noriko Uesugi, Yoshifumi Ubara, Hiroshi Kitamura, Seiichi Matsuo, Koki Mise, Yoshiki Suzuki, Satoshi Hisano, Shinichi Nishi, and Yukio Yuzawa
Subjects: Adult, Male, medicine.medical_specialty, Biopsy, medicine.medical_treatment, Kidney biopsy, 030232 urology & nephrology, Renal function, 030209 endocrinology & metabolism, Diabetic nephropathy, Type 2 diabetes, Kidney, Gastroenterology, Nephropathy, CKD heat map, 03 medical and health sciences, Diabetes mellitus, 0302 clinical medicine, Japan, Risk Factors, Internal medicine, medicine, Humans, Diabetic Nephropathies, Aged, Retrospective Studies, Transplantation, business.industry, Hazard ratio, Middle Aged, Nodular lesion, medicine.disease, Survival Rate, Diabetes Mellitus, Type 2, Nephrology, Creatinine, Female, Hemodialysis, business, Glomerular Filtration Rate, Kidney disease
Abstract: 金沢大学医薬保健研究域医学系, Background. The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are diverse, but large-scale pathologic studies with long-termobservations are limited. Methods. Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results. During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions. This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients. © The Author 2017., Embargo Period 12 months
Published: 2017

49. Dipeptidyl peptidase-4 inhibitor treatment induces a greater increase in plasma levels of bioactive GIP than GLP-1 in non-diabetic subjects

Author: Yasutaka Takeda, Yukihiro Fujita, Atsuko Abiko, Timothy J. Kieffer, Hiroya Kitsunai, Yumi Takiyama, Tsuyoshi Yanagimachi, Masakazu Haneda, Jun Honjo, Hidemitsu Sakagami, and Yuichi Makino
Subjects: Adult, Blood Glucose, Male, Glucagon-like peptide-1, 0301 basic medicine, Gene isoform, lcsh:Internal medicine, endocrine system, medicine.medical_specialty, Receptor-mediated incretin bioassays, Glucose-dependent insulinotropic polypeptide, Dipeptidyl Peptidase 4, Incretin, 030209 endocrinology & metabolism, Gastric Inhibitory Polypeptide, Dipeptidyl peptidase-4 inhibitor, Biology, Brief Communication, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Glucagon-Like Peptide 1, Internal medicine, medicine, Humans, Insulin, Protein Isoforms, Dipeptidyl peptidase-4, Bioassay, lcsh:RC31-1245, Molecular Biology, chemistry.chemical_classification, Dipeptidyl-Peptidase IV Inhibitors, digestive, oral, and skin physiology, Biological activity, Cell Biology, Glucose Tolerance Test, Glucagon, Peptide Fragments, 030104 developmental biology, Enzyme, Endocrinology, chemistry, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract: Objective Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) possess multiple bioactive isoforms that are rendered non-insulinotropic by the enzyme dipeptidyl peptidase-4 (DPP-4). Recently, some ELISA kits have been developed to specifically measure “active” GIP and GLP-1, but it is unclear if these kits can accurately quantify all bioactive forms. Therefore, it remains uncertain to what extent treatment with a DPP-4 inhibitor boosts levels of biologically active GIP and GLP-1. Thus, we evaluated our novel receptor-mediated incretin bioassays in comparison to commercially available ELISA kits using plasma samples from healthy subjects before and after DPP-4 inhibitor administration. Methods We utilized cell lines stably co-transfected with human GIP or GLP-1 receptors and a cAMP-inducible luciferase expression construct for the bioassays and commercially available ELISA kits. Assays were tested with synthetic GIP and GLP-1 receptor agonists and plasma samples collected from subjects during a 75 g oral glucose tolerance test (OGTT) performed before or following 3-day administration of a DPP-4 inhibitor. Results A GIP isoform GIP(1–30)NH2 increased luciferase activity similarly to GIP(1–42) in the GIP bioassay but was not detectable by either a total or active GIP ELISA kit. During an OGTT, total GIP levels measured by ELISA rapidly increased from 0 min to 15 min, subsequently reaching a peak of 59.2 ± 8.3 pmol/l at 120 min. In contrast, active GIP levels measured by the bioassay peaked at 15 min (43.4 ± 6.4 pmol/l) and then progressively diminished at all subsequent time points. Strikingly, at 15 min, active GIP levels as determined by the bioassay reached levels approximately 20-fold higher after the DPP-4 inhibitor treatment, while total and active GIP levels determined by ELISA were increased just 1.5 and 2.1-fold, respectively. In the absence of DPP-4 inhibition, total GLP-1 levels measured by ELISA gradually increased up to 90 min, reaching 23.5 ± 2.4 pmol/l, and active GLP-1 levels determined by the bioassay did not show any apparent peak. Following administration of a DPP-4 inhibitor there was an observable peak of active GLP-1 levels as determined by the bioassay at 15 min after oral glucose load, reaching 11.0 ± 0.62 pmol/l, 1.4-fold greater than levels obtained without DPP-4 inhibitor treatment. In contrast, total GLP-1 levels determined by ELISA were decreased after DPP-4 inhibitor treatment. Conclusion Our results using bioassays indicate that there is a greater increase in plasma levels of bioactive GIP than GLP-1 in subjects treated with DPP-4 inhibitors, which may be unappreciated using conventional ELISAs., Highlights • Receptor-mediated bioassays were used to measure GIP and GLP-1 in humans. • The GIP bioassay, but not two ELISAs, detected both GIP(1–42) and GIP(1–30)NH2. • Active GIP levels were increased more than GLP-1 after DPP-4 inhibitor treatment.
Published: 2017

50. MicroRNA148b-3p inhibits mTORC1-dependent apoptosis in diabetes by repressing TNFR2 in proximal tubular cells

Author: Hisazumi Araki, Daisuke Koya, Shogo Kuwagata, Takeshi Sugaya, Masami Chin-Kanasaki, Shinji Kume, Masakazu Haneda, Jun Nakazawa, Takashi Uzu, Shin-ichi Araki, and Hiroshi Maegawa
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Palmitic Acid, Apoptosis, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Article, Diabetes Mellitus, Experimental, Kidney Tubules, Proximal, Diabetic nephropathy, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, microRNA, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, Hypoxia, Cells, Cultured, TOR Serine-Threonine Kinases, Insulin, JNK Mitogen-Activated Protein Kinases, Lipid metabolism, Hypoxia (medical), Lipid Metabolism, medicine.disease, Rats, Cell biology, MicroRNAs, Glucose, 030104 developmental biology, Endocrinology, Nephrology, Multiprotein Complexes, 030220 oncology & carcinogenesis, biological phenomena, cell phenomena, and immunity, medicine.symptom, Signal Transduction
Abstract: Hypoxia causes proximal tubular cell damage in diabetes, even though proximal tubular cells have an adaptive system to combat hypoxia involving induction of hypoxia factor-1 (HIF-1) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). Here, we examined the interference effect of altered glucose and lipid metabolism on the hypoxia responses in proximal tubular cells. In culture, hypoxia alone induced HIF-1 and inhibited mTORC1, preventing death in proximal tubular cells. However, hypoxia with high glucose and palmitate increased mTORC1 activity and promoted apoptosis in proximal tubular cells, which was inhibited by pharmacological and genetic inactivation of mTORC1. Since inhibition of all mTORC1's physiological functions regulated by growth factors including insulin causes various adverse effects, we screened for a microRNA that can inhibit only pro-apoptotic effects of mTORC1 to discover a safe therapeutic target. This screen found microRNA-148b-3p was able to specifically inhibit mTORC1-dependent apoptosis in hypoxic proximal tubular cells exposed to high glucose and palmitate, without affecting insulin-dependent mTORC1 activation. Furthermore, tumor necrosis factor receptor (TNFR) 2 was the target of microRNA-148b-3p and its suppression inhibited apoptosis. Finally, enhanced apoptosis with TNFR2 overexpression was found in hypoxic and mTORC1-activated proximal tubular cells in diabetic rats. Thus, diabetes activated mTORC1 even in hypoxic proximal tubular cells, leading to apoptosis by reducing microRNA-148b-3p expression. Modulating this pathogenic pathway may be a novel therapy for proximal tubular cell damage in diabetes.
Published: 2016

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