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1. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes – 2nd edition (English version)

Author: Ryotaro Bouchi, Tatsuya Kondo, Yasuharu Ohta, Atsushi Goto, Daisuke Tanaka, Hiroaki Satoh, Daisuke Yabe, Rimei Nishimura, Norio Harada, Hideki Kamiya, Ryo Suzuki, Toshimasa Yamauchi, and JDS Committee on Consensus Statement Development
Subjects: Algorithm, Pharmacotherapy, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2024
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2. Simplified electrophysiological approach combining a point‐of‐care nerve conduction device and an electrocardiogram produces an accurate diagnosis of diabetic polyneuropathy

Author: Yusuke Hayashi, Tatsuhito Himeno, Yuka Shibata, Nobuhiro Hirai, Yuriko Asada‐Yamada, Sachiko Sasajima, Emi Asano‐Hayami, Mikio Motegi, Saeko Asano, Makoto Kato, Hiromi Nakai‐Shimoda, Hiroya Tani, Emiri Miura‐Yura, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Takayuki Nakayama, Jiro Nakamura, and Hideki Kamiya
Subjects: Coefficient of variation of R‐R intervals, Diabetic polyneuropathies, DPNCheck, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction This study aimed to investigate the diagnostic potential of two simplified tests, a point‐of‐care nerve conduction device (DPNCheck™) and a coefficient of variation of R‐R intervals (CVR‐R), as an alternative to traditional nerve conduction studies for the diagnosis of diabetic polyneuropathy (DPN) in patients with diabetes. Materials and Methods Inpatients with type 1 or type 2 diabetes (n = 167) were enrolled. The study population consisted of 101 men, with a mean age of 60.8 ± 14.8 years. DPN severity was assessed using traditional nerve conduction studies, and differentiated based on Baba's classification (BC). To examine the explanatory potential of variables in DPNCheck™ and CVR‐R regarding the severity of DPN according to BC, a multiple regression analysis was carried out, followed by a receiver operating characteristic analysis. Results Based on BC, 61 participants (36.5% of the total) were categorized as having DPN severity of stage 2 or more. The multiple regression analysis yielded a predictive formula with high predictive power for DPN diagnosis (estimated severity of DPN in BC = 2.258 – 0.026 × nerve conduction velocity [m/s] – 0.594 × ln[sensory nerve action potential amplitude (μV)] + 0.528In[age(years)] – 0.178 × ln[CVR‐R], r = 0.657). The area under the curve in receiver operating characteristic analysis was 0.880. Using the optimal cutoff value for DPN with severer than stage 2, the predictive formula showed good diagnostic efficacy: sensitivity of 83.6%, specificity of 79.2%, positive predictive value of 51.7% and negative predictive value of 76.1%. Conclusions These findings suggest that DPN diagnosis using DPNCheck™ and CVR‐R could improve diagnostic efficiency and accessibility for DPN assessment in patients with diabetes.
Published: 2024
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3. Hyperglycaemia Aggravates Oxidised Low-Density Lipoprotein-Induced Schwann Cell Death via Hyperactivation of Toll-like Receptor 4

Author: Wataru Nihei, Ayako Kato, Tatsuhito Himeno, Masaki Kondo, Jiro Nakamura, Hideki Kamiya, Kazunori Sango, and Koichi Kato
Subjects: diabetic neuropathy, TLR4, OxLDL, apoptosis, Medicine, Internal medicine, RC31-1245, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Increased low-density lipoprotein levels are risk factors for diabetic neuropathy. Diabetes mellitus is associated with elevated metabolic stress, leading to oxidised low-density lipoprotein formation. Therefore, it is important to investigate the mechanisms underlying the pathogenesis of diabetic neuropathy in diabetes complicated by dyslipidaemia with increased levels of oxidised low-density lipoprotein. Here, we examined the effects of hyperglycaemia and oxidised low-density lipoprotein treatment on Schwann cell death and its underlying mechanisms. Immortalised mouse Schwann cells were treated with oxidised low-density lipoprotein under normo- or hyperglycaemic conditions. We observed that oxidised low-density lipoprotein-induced cell death increased under hyperglycaemic conditions compared with normoglycaemic conditions. Moreover, hyperglycaemia and oxidised low-density lipoprotein treatment synergistically upregulated the gene and protein expression of toll-like receptor 4. Pre-treatment with TAK-242, a selective toll-like receptor 4 signalling inhibitor, attenuated hyperglycaemia- and oxidised low-density lipoprotein-induced cell death and apoptotic caspase-3 pathway. Our findings suggest that the hyperactivation of toll-like receptor 4 signalling by hyperglycaemia and elevated oxidised low-density lipoprotein levels synergistically exacerbated diabetic neuropathy; thus, it can be a potential therapeutic target for diabetic neuropathy.
Published: 2024
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4. Prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy in Japanese patients with type 2 diabetes: The Japan Diabetes Complication and its Prevention Prospective study (JDCP study 10)

Author: Hideki Kamiya, Tatsuhito Himeno, Atsuko Watarai, Masayuki Baba, Rimei Nishimura, Naoko Tajima, and Jiro Nakamura
Subjects: Diabetic symmetric sensorimotor polyneuropathy, JDCP study, The Simple Diagnostic Criteria for Diabetic Polyneuropathy, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract This study aimed to investigate the prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes registered in the Japan Diabetes Complication and its Prevention Prospective study. In the study, 6,338 patients with diabetes who had been treated by diabetes specialists were registered in 2007–2009. Of these, patients with type 2 diabetes who could be evaluated for DSPN were analyzed using the t‐test, χ2‐test and logistic regression analyses. DSPN was diagnosed using the Simple Diagnostic Criteria for Diabetic Polyneuropathy proposed by the Diabetic Neuropathy Study Group in Japan. Of the total participants, 5,451 patients (mean age 61.4 years, duration of diabetes 10.8 years) were analyzed. Based on the criteria, 35.8% of patients were diagnosed with DSPN. The prevalence of sensory symptoms was 25.8%. The following factors increased the risk for DSPN: age (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.42–1.73), duration of diabetes (OR 1.32, 95% CI 1.21–1.43), body mass index (OR 1.19, 95% CI 1.09–1.30), systolic blood pressure (OR 1.06, 95% CI 1.01–1.10), hemoglobin A1c (OR 1.15, 95% CI 1.09–1.22), biguanides (OR 1.22, 95% CI 1.06–1.39) and insulin therapy (OR 1.59, 95% CI 1.36–1.84). The following factors decreased the risk for DSPN: total cholesterol (OR 0.98, 95% CI 0.96–1.00) and exercise therapy (OR 0.85, 95% CI 0.73–0.98). The baseline survey clarified the prevalence and characteristics of DSPN in Japanese patients with type 2 diabetes. The survey also showed the risk factors of DSPN.
Published: 2024
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5. Dipeptidyl Peptidase (DPP)-4 Inhibitors and Pituitary Adenylate Cyclase-Activating Polypeptide, a DPP-4 Substrate, Extend Neurite Outgrowth of Mouse Dorsal Root Ganglia Neurons: A Promising Approach in Diabetic Polyneuropathy Treatment

Author: Masahiro Yamaguchi, Saeko Noda-Asano, Rieko Inoue, Tatsuhito Himeno, Mikio Motegi, Tomohide Hayami, Hiromi Nakai-Shimoda, Ayumi Kono, Sachiko Sasajima, Emiri Miura-Yura, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Koichi Kato, Keiko Naruse, Jiro Nakamura, and Hideki Kamiya
Subjects: diabetic polyneuropathy, dipeptidylpeptidase-4, pituitary adenylate cyclase-activating polypeptide, neurite outgrowth of dorsal root ganglia neurons, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a—known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.
Published: 2024
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6. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes

Author: Ryotaro Bouchi, Tatsuya Kondo, Yasuharu Ohta, Atsushi Goto, Daisuke Tanaka, Hiroaki Satoh, Daisuke Yabe, Rimei Nishimura, Norio Harada, Hideki Kamiya, Ryo Suzuki, Toshimasa Yamauchi, and JDS Committee on Consensus Statement Development
Subjects: Algorithm, Pharmacotherapy, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2023
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7. Thermal gradient ring reveals thermosensory changes in diabetic peripheral neuropathy in mice

Author: Sachiko Sasajima, Masaki Kondo, Nobuhiko Ohno, Tomoyo Ujisawa, Mikio Motegi, Tomohide Hayami, Saeko Asano, Emi Asano-Hayami, Hiromi Nakai-Shimoda, Rieko Inoue, Yuichiro Yamada, Emiri Miura-Yura, Yoshiaki Morishita, Tatsuhito Himeno, Shin Tsunekawa, Yoshiro Kato, Jiro Nakamura, Hideki Kamiya, and Makoto Tominaga
Subjects: Medicine, Science
Abstract: Abstract Diabetic peripheral neuropathy (DPN) includes symptoms of thermosensory impairment, which are reported to involve changes in the expression or function, or both, of nociceptive TRPV1 and TRPA1 channels in rodents. In the present study, we did not find changes in the expression or function of TRPV1 or TRPA1 in DPN mice caused by STZ, although thermal hypoalgesia was observed in a murine model of DPN or TRPV1 −/− mice with a Plantar test, which specifically detects temperature avoidance. With a Thermal Gradient Ring in which mice can move freely in a temperature gradient, temperature preference can be analyzed, and we clearly discriminated the temperature-dependent phenotype between DPN and TRPV1 −/− mice. Accordingly, we propose approaches with multiple behavioral methods to analyze the progression of DPN by response to thermal stimuli. Attention to both thermal avoidance and preference may provide insight into the symptoms of DPN.
Published: 2022
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8. Protocol to image and analyze the morphology of mouse peripheral nerves using transmission electron microscopy

Author: Hiromi Nakai-Shimoda, Tatsuhito Himeno, Mikio Motegi, Norio Ozeki, Rieko Inoue, Tomohide Hayami, Emiri Miura-Yura, Yuichiro Yamada, Yoshiaki Morishita, Shin Tsunekawa, Yoshiro Kato, Yusuke Seino, Masaki Kondo, Keiko Naruse, Koichi Kato, Hiroki Mizukami, Jiro Nakamura, and Hideki Kamiya
Subjects: Metabolism, Microscopy, Neuroscience, Science (General), Q1-390
Abstract: Summary: Morphological analysis of peripheral nerves in mouse models can be used to characterize the pathophysiology of peripheral nerve disease, but obtaining high-quality electron micrographs can be challenging. Here, we present a protocol to obtain electron micrographs of mouse peripheral nerves. We detail the procedures of sampling, fixation, and embedding of peripheral nerves. We then outline the steps for ultrathin sectioning and transmission electron microscopy imaging. Finally, we describe morphological evaluation of nerve fibers in these images using ImageJ and AxonSeg.For complete details on the use and execution of this protocol, please refer to Nakai-Shimoda et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Published: 2022
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9. Not out of the woods yet: 'Diabetic neuropathy' or 'neuropathy associated with diabetes'?

Author: Tatsuhito Himeno, Hideki Kamiya, and Jiro Nakamura
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2022
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10. Alterations of retinal thickness measured by optical coherence tomography correlate with neurophysiological measures in diabetic polyneuropathy

Author: Yuichiro Yamada, Tatsuhito Himeno, Kotaro Tsuboi, Yuka Shibata, Miyuka Kawai, Yuriko Asada‐Yamada, Yusuke Hayashi, Emi Asano‐Hayami, Tomohide Hayami, Yuichiro Ishida, Yohei Ejima, Mikio Motegi, Saeko Asano, Makoto Kato, Eriko Nagao, Hiromi Nakai‐Shimoda, Takahiro Ishikawa, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Takayuki Nakayama, Motohiro Kamei, Jiro Nakamura, and Hideki Kamiya
Subjects: Diabetic polyneuropathies, Neuroretina, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Diabetic polyneuropathy (DPN) and diabetic retinopathy (DR) are traditionally regarded as microvascular complications. However, these complications may share similar neurodegenerative pathologies. Here we evaluate the correlations in the severity of DPN and changes in the thickness of neuroretinal layers to elucidate whether these complications exist at similar stages of progression. Materials and Methods A total of 43 patients with type 2 diabetes underwent a nerve conduction study (NCS), a macular optical coherence tomography, and a carotid artery ultrasound scan. Diabetic polyneuropathy was classified according to Baba’s classification using NCS. The retina was automatically segmented into four layers; ganglion cell complex (GCC), inner nuclear layer/outer plexiform layer (INL/OPL), outer nuclear layer/photoreceptor inner and outer segments, and retinal pigment epithelium (RPE). The thickness of each retinal layer was separately analyzed for the fovea and the parafovea. Results Fourteen patients were classified as having moderate to severe diabetic polyneuropathy. The thicknesses of the foveal and parafoveal INL/OPL increased in patients with diabetic polyneuropathy compared with patients without. The thickness of the parafoveal retinal pigment epithelium decreased in patients with diabetic polyneuropathy. The thinning of parafoveal ganglion cell complex and foveal and parafoveal retinal pigment epithelium were positively correlated with deterioration of nerve functions in the nerve conduction study, but the thickening of INL/OPL was positively correlated with the nerve function deterioration. The thinning of parafoveal ganglion cell complex and foveal retinal pigment epithelium were positively correlated with the thickening of the carotid intima‐media. Conclusions Depending on the progression of diabetic polyneuropathy, the ganglion cell complex and retinal pigment epithelium became thinner and the INL/OPL became thicker. These retinal changes might be noteworthy for pathological investigations and for the assessment of diabetic polyneuropathy and diabetic retinopathy.
Published: 2021
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11. Neuroretinal dysfunction revealed by a flicker electroretinogram correlated with peripheral nerve dysfunction and parameters of atherosclerosis in patients with diabetes

Author: Miyuka Kawai, Tatsuhito Himeno, Yuka Shibata, Nobuhiro Hirai, Yuriko Asada‐Yamada, Emi Asano‐Hayami, Yohei Ejima, Rina Kasagi, Eriko Nagao, Yukako Sugiura‐Roth, Hiromi Nakai‐Shimoda, Takayuki Nakayama, Yuichiro Yamada, Takahiro Ishikawa, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Jiro Nakamura, and Hideki Kamiya
Subjects: Diabetic neuropathies, Electroretinography, Point‐of‐care testing, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Diabetic polyneuropathy (DPN) develops in the early stage of diabetes. However, no common diagnostic protocol has yet been established. Here, to verify that the flicker electroretinogram using a hand‐held device can detect the early dysfunction of the peripheral nervous system in patients with diabetes, we investigated the correlation between the progression of DPN and neuroretinal dysfunction. Materials and Methods In total, 184 participants with type 1 or 2 diabetes underwent a flicker electroretinogram (ERG) using a hand‐held device RETeval™ and nerve conduction study. Participants were also evaluated for intima‐media thickness, ankle‐brachial index, toe brachial index and brachial‐ankle pulse wave velocity. Parameters of the nerve conduction study were used to diagnose the severity according to Baba’s classification. A multiple regression analysis was used to examine the associations of ERG parameters with the severity of DPN categorized by Baba’s classification. Diagnostic properties of the device in DPN were evaluated using a receiver operating characteristic curve. Results A multiple regression model to predict the severity of DPN was generated using ERG. In the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.692, sensitivity 56.5%, specificity 78.3%, positive predictive value 70.6%, negative predictive value 66.1%, positive likelihood ratio 2.60, negative likelihood ratio 0.56). In the patients without diabetic retinopathy, the implicit time and amplitude in ERG significantly correlated with the parameters of the nerve conduction study, brachial‐ankle pulse wave velocity and intima‐media thickness. Conclusions Electroretinogram parameters obtained by the hand‐held device successfully predict the severity of DPN. The device might be useful to evaluate DPN.
Published: 2021
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12. Point‐of‐care nerve conduction device predicts the severity of diabetic polyneuropathy: A quantitative, but easy‐to‐use, prediction model

Author: Hideki Kamiya, Yuka Shibata, Tatsuhito Himeno, Hiroya Tani, Takayuki Nakayama, Kenta Murotani, Nobuhiro Hirai, Miyuka Kawai, Yuriko Asada‐Yamada, Emi Asano‐Hayami, Hiromi Nakai‐Shimoda, Yuichiro Yamada, Takahiro Ishikawa, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Masayuki Baba, and Jiro Nakamura
Subjects: Diabetic neuropathies, Electromyography, Point‐of‐care testing, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction A gold standard in the diagnosis of diabetic polyneuropathy (DPN) is a nerve conduction study. However, as a nerve conduction study requires expensive equipment and well‐trained technicians, it is largely avoided when diagnosing DPN in clinical settings. Here, we validated a novel diagnostic method for DPN using a point‐of‐care nerve conduction device as an alternative way of diagnosis using a standard electromyography system. Materials and Methods We used a multiple regression analysis to examine associations of nerve conduction parameters obtained from the device, DPNCheck™, with the severity of DPN categorized by the Baba classification among 375 participants with type 2 diabetes. A nerve conduction study using a conventional electromyography system was implemented to differentiate the severity in the Baba classification. The diagnostic properties of the device were evaluated using a receiver operating characteristic curve. Results A multiple regression model to predict the severity of DPN was generated using sural nerve conduction data obtained from the device as follows: the severity of DPN = 2.046 + 0.509 × ln(age [years]) − 0.033 × (nerve conduction velocity [m/s]) − 0.622 × ln(amplitude of sensory nerve action potential [µV]), r = 0.649. Using a cut‐off value of 1.3065 in the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.871, sensitivity 70.1%, specificity 87.7%, positive predictive value 83.0%, negative predictive value 77.3%, positive likelihood ratio 5.67, negative likelihood ratio 0.34). Conclusions Nerve conduction parameters in the sural nerve acquired by the handheld device successfully predict the severity of DPN.
Published: 2021
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13. Tumor‐like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin‐induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat

Author: Tomohide Hayami, Norihide Yokoi, Takuro Yamaguchi, Kohei Honda, Naoya Murao, Harumi Takahashi, Shujie Wang, Yusuke Seino, Hideki Kamiya, Daisuke Yabe, Ian R Sweet, Akira Mizoguchi, Jiro Nakamura, and Susumu Seino
Subjects: Enlarged islets, Incretin, Tumor cells, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non‐large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin‐induced insulin secretion (IIIS) in these islets. Materials and Methods Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks‐of‐age were isolated. The islets of fa/fa rats at 12 weeks‐of‐age were separated into non‐large islets (≤200 μm in diameter) and enlarged islets (>300 μm in diameter). Morphological analyses, insulin secretion experiments, transcriptome analysis, metabolome analysis and oxygen consumption analysis were carried out on these islets. Results The number of enlarged islets was increased with age in fatty rats, and IIIS was significantly reduced in the enlarged islets. Markers for β‐cell differentiation were markedly decreased in the enlarged islets, but those for cell proliferation were increased. Glycolysis was enhanced in the enlarged islets, whereas the tricarboxylic acid cycle was suppressed. The oxygen consumption rate under glucose stimulation was reduced in the enlarged islets. Production of glutamate, a key signal for IIIS, was decreased in the enlarged islets. Conclusions The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for IIIS, show tumor cell‐like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age‐dependent increase in such islets could contribute to the pathophysiology of obese diabetes.
Published: 2020
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14. Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: the role of angiogenic and neurotrophic factors

Author: Masaki Hata, Maiko Omi, Yasuko Kobayashi, Nobuhisa Nakamura, Megumi Miyabe, Mizuho Ito, Eriko Makino, Saki Kanada, Tomokazu Saiki, Tasuku Ohno, Yuka Imanishi, Tatsuhito Himeno, Hideki Kamiya, Jiro Nakamura, Shogo Ozawa, Ken Miyazawa, Kenichi Kurita, Shigemi Goto, Jun Takebe, Tatsuaki Matsubara, and Keiko Naruse
Subjects: Human dental pulp stem cells (hDPSCs), Diabetic polyneuropathy, Cell therapy, Regenerative medicine, Diabetes, NGF, Medicine (General), R5-920, Biochemistry, QD415-436
Abstract: Abstract Background Dental pulp stem cells (DPSCs) have high proliferation and multi-differentiation capabilities that maintain their functionality after cryopreservation. In our previous study, we demonstrated that cryopreserved rat DPSCs improved diabetic polyneuropathy and that the efficacy of cryopreserved rat DPSCs was equivalent to that of freshly isolated rat DPSCs. The present study was conducted to evaluate whether transplantation of cryopreserved human DPSCs (hDPSCs) is also effective for the treatment of diabetic polyneuropathy. Methods hDPSCs were isolated from human impacted third molars being extracted for orthodontic reasons. Eight weeks after the induction of diabetes in nude mice, hDPSCs (1 × 105/limb) were unilaterally transplanted into the hindlimb skeletal muscle, and vehicle (saline) was injected into the opposite side as a control. The effects of hDPSCs were analyzed at 4 weeks after transplantation. Results hDPSC transplantation significantly ameliorated reduced sensory perception thresholds, delayed nerve conduction velocity, and decreased the blood flow to the sciatic nerve in diabetic mice 4 weeks post-transplantation. Cultured hDPSCs secreted the vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) proteins. A subset of the transplanted hDPSCs was localized around the muscle bundles and expressed the human VEGF and NGF genes at the transplanted site. The capillary/muscle bundle ratio was significantly increased on the hDPSC-transplanted side of the gastrocnemius muscles in diabetic mice. Neutralizing antibodies against VEGF and NGF negated the effects of hDPSC transplantation on the nerve conduction velocity in diabetic mice, suggesting that VEGF and NGF may play roles in the effects of hDPSC transplantation on diabetic polyneuropathy. Conclusions These results suggest that stem cell transplantation with hDPSCs may be efficacious in treating diabetic polyneuropathy via the angiogenic and neurotrophic mechanisms of hDPSC-secreted factors.
Published: 2020
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15. Secreted factors from cultured dental pulp stem cells promoted neurite outgrowth of dorsal root ganglion neurons and ameliorated neural functions in streptozotocin‐induced diabetic mice

Author: Emiri Miura‐Yura, Shin Tsunekawa, Keiko Naruse, Nobuhisa Nakamura, Mikio Motegi, Hiromi Nakai‐Shimoda, Saeko Asano, Makoto Kato, Yuichiro Yamada, Takako Izumoto‐Akita, Akihito Yamamoto, Tatsuhito Himeno, Masaki Kondo, Yoshiro Kato, Jiro Nakamura, and Hideki Kamiya
Subjects: Conditioned medium, Diabetic polyneuropathy, Stem cells from human exfoliated deciduous teeth, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Transplantation of stem cells promotes axonal regeneration and angiogenesis in a paracrine manner. In the present study, we examined whether the secreted factors in conditioned medium of stem cells from human exfoliated deciduous teeth (SHED‐CM) had beneficial effects on diabetic polyneuropathy in mice. Materials and Methods Conditioned medium of stem cells from human exfoliated deciduous teeth was collected 48 h after culturing in serum‐free Dulbecco's modified Eagle's medium (DMEM), and separated into four fractions according to molecular weight. Dorsal root ganglion neurons from C57BL/6J mice were cultured with SHED‐CM or DMEM to evaluate the effect on neurite outgrowth. Streptozotocin‐induced diabetic mice were injected with 100 μL of SHED‐CM or DMEM into the unilateral hindlimb muscles twice a week over a period of 4 weeks. Peripheral nerve functions were evaluated by the plantar test, and motor and sensory nerve conduction velocities. Intraepidermal nerve fiber densities, capillary number‐to‐muscle fiber ratio, capillary blood flow and morphometry of sural nerves were also evaluated. Results Conditioned medium of stem cells from human exfoliated deciduous teeth significantly promoted neurite outgrowth of dorsal root ganglion neurons compared with DMEM. Among four fractions of SHED‐CM, the only fraction of
Published: 2020
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16. Lumos for the long trail: Strategies for clinical diagnosis and severity staging for diabetic polyneuropathy and future directions

Author: Tatsuhito Himeno, Hideki Kamiya, and Jiro Nakamura
Subjects: Baba’s classification, Diabetic polyneuropathy, DPNCheck, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Diabetic polyneuropathy, which is a chronic symmetrical length‐dependent sensorimotor polyneuropathy, is the most common form of diabetic neuropathy. Although diabetic polyneuropathy is the most important risk factor in cases of diabetic foot, given its poor prognosis, the criteria for diagnosis and staging of diabetic polyneuropathy has not been established; consequently, no disease‐modifying treatment is available. Most criteria and scoring systems that were previously proposed consist of clinical signs, symptoms and quantitative examinations, including sensory function tests and nerve conduction study. However, in diabetic polyneuropathy, clinical symptoms, including numbness, pain and allodynia, show no significant correlation with the development of pathophysiological changes in the peripheral nervous system. Therefore, these proposed criteria and scoring systems have failed to become a universal clinical end‐point for large‐scale clinical trials evaluating the prognosis in diabetes patients. We should use quantitative examinations of which validity has been proven. Nerve conduction study, for example, has been proven effective to evaluate dysfunctions of large nerve fibers. Baba’s classification, which uses a nerve conduction study, is one of the most promising diagnostic methods. Loss of small nerve fibers can be determined using corneal confocal microscopy and intra‐epidermal nerve fiber density. However, no staging criteria have been proposed using these quantitative evaluations for small fiber neuropathy. To establish a novel diagnostic and staging criteria of diabetic polyneuropathy, we propose three principles to be considered: (i) include only generalizable objective quantitative tests; (ii) exclude clinical symptoms and signs; and (iii) do not restrictively exclude other causes of polyneuropathy.
Published: 2020
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17. Kir6.2-deficient mice develop somatosensory dysfunction and axonal loss in the peripheral nerves

Author: Hiromi Nakai-Shimoda, Tatsuhito Himeno, Tetsuji Okawa, Emiri Miura-Yura, Sachiko Sasajima, Makoto Kato, Yuichiro Yamada, Yoshiaki Morishita, Shin Tsunekawa, Yoshiro Kato, Yusuke Seino, Rieko Inoue, Masaki Kondo, Susumu Seino, Keiko Naruse, Koichi Kato, Hiroki Mizukami, Jiro Nakamura, and Hideki Kamiya
Subjects: Molecular neuroscience, Cellular neuroscience, Sensory neuroscience, Science
Abstract: Summary: Glucose-responsive ATP-sensitive potassium channels (KATP) are expressed in a variety of tissues including nervous systems. The depolarization of the membrane potential induced by glucose may lead to hyperexcitability of neurons and induce excitotoxicity. However, the roles of KATP in the peripheral nervous system (PNS) are poorly understood. Here, we determine the roles of KATP in the PNS using KATP-deficient (Kir6.2-deficient) mice. We demonstrate that neurite outgrowth of dorsal root ganglion (DRG) neurons was reduced by channel closers sulfonylureas. However, a channel opener diazoxide elongated the neurite. KATP subunits were expressed in mouse DRG, and expression of certain subunits including Kir6.2 was increased in diabetic mice. In Kir6.2-deficient mice, the current perception threshold, thermal perception threshold, and sensory nerve conduction velocity were impaired. Electron microscopy revealed a reduction of unmyelinated and small myelinated fibers in the sural nerves. In conclusion, KATP may contribute to the development of peripheral neuropathy.
Published: 2022
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18. Diabetic polyneuropathy: Progress in diagnostic strategy and novel target discovery, but stagnation in drug development

Author: Tatsuhito Himeno, Hideki Kamiya, and Jiro Nakamura
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2020
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19. Validity and reliability of a point‐of‐care nerve conduction device in diabetes patients

Author: Yuka Shibata, Tatsuhito Himeno, Taeko Kamiya, Hiroya Tani, Takayuki Nakayama, Chika Kojima, Yukako Sugiura‐Roth, Ena Naito, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Jiro Nakamura, and Hideki Kamiya
Subjects: Diabetic polyneuropathy, Nerve conduction study, Point‐of‐care device, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Although nerve conduction study (NCS) using a standard electromyography system (EMGS) is considered to be the gold standard in evaluating diabetic polyneuropathy, this examination requires expensive equipment and well‐trained technicians. We aimed to validate a point‐of‐care device, NC‐stat/DPNCheck™, that has been developed for widespread use of NCS in diabetic polyneuropathy. Materials and Methods Diabetes patients underwent two kinds of NCS: DPNCheck™ and electromyography system. Inter‐/intrarater reliability of DPNCheck™ were also determined by the intraclass correlation coefficient. Results A total of 57 patients were evaluated. The parameters of NCS between the two methods correlated well (r = 0.7734 for the sural nerve conduction velocity, r = 0.6155 for the amplitude of sural nerve action potential). The intraclass correlation coefficients were excellent (intrarater: the velocity 0.767, the amplitude 0.811; interrater: the velocity 0.974, the amplitude 0.834). Conclusions The point‐of‐care device has excellent reproducibility and good agreement with standard electromyography system. The device might be useful to evaluate diabetic polyneuropathy.
Published: 2019
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20. Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti‐inflammatory, neuroprotective and angiogenic actions: Cell‐free regenerative medicine for diabetic polyneuropathy

Author: Eriko Makino, Nobuhisa Nakamura, Megumi Miyabe, Mizuho Ito, Saki Kanada, Masaki Hata, Tomokazu Saiki, Kazunori Sango, Hideki Kamiya, Jiro Nakamura, Ken Miyazawa, Shigemi Goto, Tatsuaki Matsubara, and Keiko Naruse
Subjects: Dental pulp stem cell, Diabetic neuropathy, Regenerative medicine, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC‐conditioned media (DPSC‐CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats. Eight weeks after the induction of diabetes, DPSC‐CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC‐CM on diabetic polyneuropathy were assessed 4 weeks after DPSC‐CM injection. To confirm the angiogenic effect of DPSC‐CM, the effect of DPSC‐CM on cultured human umbilical vascular endothelial cell proliferation was investigated. Results The administration of DPSC‐CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC‐CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro‐inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC‐CM significantly increased the proliferation of umbilical vascular endothelial cells. Conclusions We showed that DPSC‐CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti‐inflammatory actions. DPSC‐CM could be a novel cell‐free regenerative medicine treatment for diabetic polyneuropathy.
Published: 2019
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21. Omega‐3 polyunsaturated fatty acids exert anti‐oxidant effects through the nuclear factor (erythroid‐derived 2)‐related factor 2 pathway in immortalized mouse Schwann cells

Author: Yasuaki Tatsumi, Ayako Kato, Kazunori Sango, Tatsuhito Himeno, Masaki Kondo, Yoshiro Kato, Hideki Kamiya, Jiro Nakamura, and Koichi Kato
Subjects: Diabetic neuropathy, Omega‐3 polyunsaturated fatty acids, Oxidative stress, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Recent studies advocate that omega‐3 polyunsaturated fatty acids (ω‐3 PUFAs) have direct anti‐oxidative and anti‐inflammatory effects in the vasculature; however, the role of ω‐3 PUFAs in Schwann cells remains undetermined. Materials and methods Immortalized mouse Schwann (IMS32) cells were incubated with the ω‐3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The messenger ribonucleic acid levels of several anti‐oxidant enzymes (heme oxygenase‐1 [Ho‐1], nicotinamide adenine dinucleotide [phosphate] H quinone oxidoreductase 1, catalase, superoxide dismutase and glutathione peroxidase) were identified using real‐time reverse transcription polymerase chain reaction. Ho‐1 and nicotinamide adenine dinucleotide [phosphate] H quinone oxidoreductase 1 protein levels were evaluated using Western blotting. Nuclear factor (erythroid‐derived 2)‐related factor 2 (Nrf2) of the nuclear fraction was also quantified using western blotting. Catalase activity and glutathione content were determined by colorimetric assay kits. Nrf2 promoter‐luciferase activity was evaluated by a dual luciferase assay system. Results Treatment with tert‐butyl hydroperoxide decreased cell viability dose‐dependently. DHA or EPA pretreatment significantly alleviated tert‐butyl hydroperoxide‐induced cytotoxicity. DHA or EPA increased the messenger ribonucleic acid levels of Ho‐1, nicotinamide adenine dinucleotide (phosphate) H quinone oxidoreductase 1 and catalase dose‐dependently. Ho‐1 protein level, catalase activity, Nrf2 promoter‐luciferase activity and intracellular glutathione content were significantly increased by DHA and EPA. Conclusions These findings show that DHA and EPA can induce Ho‐1 and catalase through Nrf2, thus protecting Schwann cells against oxidative stress. ω‐3 PUFAs appear to exert their neuroprotective effect by increasing defense mechanisms against oxidative stress in diabetic neuropathies.
Published: 2019
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22. Small Fibre Neuropathy Is Associated With Impaired Vascular Endothelial Function in Patients With Type 2 Diabetes

Author: Akihiko Ando, Michiaki Miyamoto, Naoko Saito, Kazuhiko Kotani, Hideki Kamiya, Shun Ishibashi, and Mitra Tavakoli
Subjects: diabetic polyneuropathy (DPN), small fibre neuropathy, corneal confocal microscopy, RH-PAT, endothelial dysfunction, macroangiopathy, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Diabetic polyneuropathy (DPN) and endothelial dysfunction are prevalent complications of diabetes mellitus. Currently, there are two non-invasive markers for endothelial dysfunction: flow-mediated dilation and reactive hyperaemia peripheral arterial tonometry (RH-PAT). However, the relationship between diabetic small fibre neuropathy and macroangiopathy remains obscure thus far. Corneal confocal microscopy (CCM) has emerged as a new diagnostic modality to assess DPN, especially of small fibre. To clarify the relationship between diabetic small fibre neuropathy and vascular dysfunction, we aimed to determine the functions of peripheral nerves and blood vessels through clinical tests such as nerve conduction study, coefficient of variation in the R-R interval, CCM, and RH-PAT in 82 patients with type 2 diabetes. Forty healthy control subjects were also included to study corneal nerve parameters. Correlational and multiple linear regression analyses were performed to determine the associations between neuropathy indices and markers for vascular functions. The results revealed that patients with type 2 diabetes had significantly lower values for most variables of CCM than healthy control subjects. RH-PAT solely remained as an explanatory variable significant in multiple regression analysis for several CCM parameters and vice versa. Other vascular markers had no significant multiple regression with any CCM parameters. In conclusion, endothelial dysfunction as revealed by impaired RH-PAT was significantly associated with CCM parameters in patients with type 2 diabetes. This association may indicate that small fibre neuropathy results from impaired endothelial dysfunction in type 2 diabetes. CCM parameters may be considered surrogate markers of autonomic nerve damage, which is related to diabetic endothelial dysfunction. This study is the first to report the relationship between corneal nerve parameter as small fibre neuropathy in patients with type 2 diabetes and RH-PAT as a marker of endothelial dysfunction.
Published: 2021
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23. Docosahexaenoic Acid Suppresses Oxidative Stress-Induced Autophagy and Cell Death via the AMPK-Dependent Signaling Pathway in Immortalized Fischer Rat Schwann Cells 1

Author: Yasuaki Tatsumi, Ayako Kato, Naoko Niimi, Hideji Yako, Tatsuhito Himeno, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Hideki Kamiya, Jiro Nakamura, Koji Higai, Kazunori Sango, and Koichi Kato
Subjects: DHA, oxidative stress, autophagy, AMPK, Schwann cells, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Autophagy is the process by which intracellular components are degraded by lysosomes. It is also activated by oxidative stress; hence, autophagy is thought to be closely related to oxidative stress, one of the major causes of diabetic neuropathy. We previously reported that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) induced antioxidant enzymes and protected Schwann cells from oxidative stress. However, the relationship between autophagy and oxidative stress-induced cell death in diabetic neuropathy has not been elucidated. Treatment with tert-butyl hydroperoxide (tBHP) decreased the cell survival rate, as measured by an MTT assay in immortalized Fischer rat Schwann cells 1 (IFRS1). A DHA pretreatment significantly prevented tBHP-induced cytotoxicity. tBHP increased autophagy, which was revealed by the ratio of the initiation markers, AMP-activated protein kinase, and UNC51-like kinase phosphorylation. Conversely, the DHA pretreatment suppressed excessive tBHP-induced autophagy signaling. Autophagosomes induced by tBHP in IFRS1 cells were decreased to control levels by the DHA pretreatment whereas autolysosomes were only partially decreased. These results suggest that DHA attenuated excessive autophagy induced by oxidative stress in Schwann cells and may be useful to prevent or reduce cell death in vitro. However, its potentiality to treat diabetic neuropathy must be validated in in vivo studies.
Published: 2022
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24. The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice

Author: Yoji Hamada, Moritaka Goto, Go Nishimura, Hiroshi Nagasaki, Yusuke Seino, Hideki Kamiya, and Jiro Nakamura
Subjects: Physiology, QP1-981, Biochemistry, QD415-436
Abstract: Purpose: Bile acids (BAs) have been shown to contribute to glucose and energy homeostasis. We have recently reported that miglitol, an alpha-glucosidase inhibitor, increases fecal BA excretion and ameliorate insulin resistance and obesity in mice. The aim of this study was to clarify the mechanisms by which miglitol affects BA metabolism. The expression of genes regulating BA metabolism, gut microbiome and short-chain fatty acids (SCFA) were examined. Procedures: NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet with or without miglitol for 4 weeks. The expression of BA-related genes in the liver and the lower intestine were measured. Alterations in fecal microbiome, fecal SCFA along with plasma lipid levels were also evaluated. Major findings: Miglitol significantly increased fecal BA secretion and markedly upregulated the mRNA expression, protein levels and enzyme activity of hepatic cholesterol 7α-hydroxylase, a rate-limiting enzyme of BA synthesis. In the intestine, miglitol treatment significantly suppressed the mRNA expression of apical sodium-dependent bile acid transporter and ATP-binding cassette transporter G5 and G8. In fecal microbiome, the prevalence of prevotella was remarkably reduced and that of clostridium subcluster XIVa was increased by miglitol. Miglitol elevated formic and n-butyric acids along with total SCFA concentration in feces, while succinic acid was decreased. There was no change in plasma total cholesterol levels. Conclusions: Collectively, miglitol may affect BA metabolism via enhanced CYP7A1 activity resulting from at least in part the alterations in gut microbiome and SCFA production in obese diabetic mice. Keywords: Alpha-glucosidase inhibitors, Bile acids, Cholesterol 7α-hydroxylase, Gut microbiome, Short-chain fatty acids, Miglitol
Published: 2020
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25. High Protein Diet Feeding Aggravates Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

Author: Shinji Ueno, Yusuke Seino, Shihomi Hidaka, Ryuya Maekawa, Yuko Takano, Michiyo Yamamoto, Mika Hori, Kana Yokota, Atsushi Masuda, Tatsuhito Himeno, Shin Tsunekawa, Hideki Kamiya, Jiro Nakamura, Hitoshi Kuwata, Haruki Fujisawa, Megumi Shibata, Takeshi Takayanagi, Yoshihisa Sugimura, Daisuke Yabe, Yoshitaka Hayashi, and Atsushi Suzuki
Subjects: protein diet, glucagon, hyperaminoacidemia, food intake, hypoglycemia, Nutrition. Foods and food supply, TX341-641
Abstract: (1) Background: Protein stimulates the secretion of glucagon (GCG), which can affect glucose metabolism. This study aimed to analyze the metabolic effect of a high-protein diet (HPD) in the presence or absence of proglucagon-derived peptides, including GCG and GLP-1. (2) Methods: The response to HPD feeding for 7 days was analyzed in mice deficient in proglucagon-derived peptides (GCGKO). (3) Results: In both control and GCGKO mice, food intake and body weight decreased with HPD and intestinal expression of Pepck increased. HPD also decreased plasma FGF21 levels, regardless of the presence of proglucagon-derived peptides. In control mice, HPD increased the hepatic expression of enzymes involved in amino acid metabolism without the elevation of plasma amino acid levels, except branched-chain amino acids. On the other hand, HPD-induced changes in the hepatic gene expression were attenuated in GCGKO mice, resulting in marked hyperaminoacidemia with lower blood glucose levels; the plasma concentration of glutamine exceeded that of glucose in HPD-fed GCGKO mice. (4) Conclusions: Increased plasma amino acid levels are a common feature in animal models with blocked GCG activity, and our results underscore that GCG plays essential roles in the homeostasis of amino acid metabolism in response to altered protein intake.
Published: 2022
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26. Different trends in causes of death in patients with diabetes between Japan and the USA

Author: Shin Tsunekawa, Hideki Kamiya, and Jiro Nakamura
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2019
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27. Transplantation of dental pulp stem cells improves long-term diabetic polyneuropathy together with improvement of nerve morphometrical evaluation

Author: Maiko Omi, Masaki Hata, Nobuhisa Nakamura, Megumi Miyabe, Shogo Ozawa, Hitoshi Nukada, Masami Tsukamoto, Kazunori Sango, Tatsuhito Himeno, Hideki Kamiya, Jiro Nakamura, Jun Takebe, Tatsuaki Matsubara, and Keiko Naruse
Subjects: Dental pulp stem cells, Diabetic polyneuropathy, Cell transplantation, Nerve repair, Medicine (General), R5-920, Biochemistry, QD415-436
Abstract: Abstract Background Although previous reports have revealed the therapeutic potential of stem cell transplantation in diabetic polyneuropathy, the effects of cell transplantation on long-term diabetic polyneuropathy have not been investigated. In this study, we investigated whether the transplantation of dental pulp stem cells (DPSCs) ameliorated long-term diabetic polyneuropathy in streptozotocin (STZ)-induced diabetic rats. Methods Forty-eight weeks after STZ injection, we transplanted DPSCs into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation (i.e., 52 weeks after STZ injection) the effects of DPSC transplantation on diabetic polyneuropathy were assessed. Results STZ-induced diabetic rats showed significant reductions in the sciatic motor/sensory nerve conduction velocity, increases in the current perception threshold, and decreases in capillary density in skeletal muscles and intra-epidermal nerve fiber density compared with normal rats, all of which were ameliorated by DPSC transplantation. Furthermore, sural nerve morphometrical analysis revealed that the transplantation of DPSCs significantly increased the myelin thickness and area. DPSC-conditioned media promoted the neurite outgrowth of dorsal root ganglion neurons and increased the viability and myelin-related protein expression of Schwann cells. Conclusions These results indicated that the transplantation of DPSCs contributed to the neurophysiological and neuropathological recovery from a long duration of diabetic polyneuropathy.
Published: 2017
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28. Sustainable Effects of Human Dental Pulp Stem Cell Transplantation on Diabetic Polyneuropathy in Streptozotocine-Induced Type 1 Diabetes Model Mice

Author: Masaki Hata, Maiko Omi, Yasuko Kobayashi, Nobuhisa Nakamura, Megumi Miyabe, Mizuho Ito, Tasuku Ohno, Yuka Imanishi, Tatsuhito Himeno, Hideki Kamiya, Jiro Nakamura, Hitoshi Miyachi, Shogo Ozawa, Ken Miyazawa, Akio Mitani, Toru Nagao, Shigemi Goto, Jun Takebe, Tatsuaki Matsubara, and Keiko Naruse
Subjects: human dental pulp stem cells (hDPSCs), diabetic polyneuropathy, hDPSC-conditioned medium (hDPSC-CM), regenerative medicine, Cytology, QH573-671
Abstract: Dental pulp stem cells (DPSCs) are suitable for use in regenerative medicine. Cryopreserved human DPSCs (hDPSCs) ameliorate diabetic polyneuropathy, and the effects of hDPSC transplantation are related to VEGF and NGF secretion. This study evaluated the long-term effects of a single transplantation of hDPSCs on diabetic polyneuropathy. hDPSCs were obtained from human third molars extracted for orthodontic treatment, which were then transplanted into the unilateral hindlimb skeletal muscles 8 weeks after streptozotocin injection in nude mice. The effects of hDPSC transplantation were analyzed at 16 weeks post-transplantation. DPSC transplantation significantly improved delayed nerve conduction velocity, decreased blood flow, and increased sensory perception thresholds. Furthermore, the hDPSC-conditioned medium promoted the neurite outgrowth of dorsal root ganglion neurons. In conclusion, the therapeutic effects of hDPSC transplantation with a single injection last for prolonged periods and may be beneficial in treating long-term diabetic polyneuropathy.
Published: 2021
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29. Ranirestat Improved Nerve Conduction Velocities, Sensory Perception, and Intraepidermal Nerve Fiber Density in Rats with Overt Diabetic Polyneuropathy

Author: Saeko Asano, Tatsuhito Himeno, Tomohide Hayami, Mikio Motegi, Rieko Inoue, Hiromi Nakai-Shimoda, Emiri Miura-Yura, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Koichi Kato, Keiko Naruse, Jiro Nakamura, and Hideki Kamiya
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Distal sensory-motor polyneuropathy is one of the most frequent diabetic complications. However, few therapies address the etiology of neurodegeneration in the peripheral nervous systems of diabetic patients. Several metabolic mechanisms have been proposed as etiologies of this polyneuropathy. In this study, we revisited one of those mechanisms, the polyol pathway, and investigated the curative effects of a novel strong aldose reductase inhibitor, ranirestat, in streptozotocin-induced diabetic rats with preexisting polyneuropathy. Twelve weeks after the onset of diabetes, rats which had an established polyneuropathy were treated once daily with a placebo, ranirestat, or epalrestat, over 6 weeks. Before and after the treatment, nerve conduction velocities and thermal perception threshold of hindlimbs were examined. After the treatment, intraepidermal fiber density was evaluated. As an ex vivo assay, murine dorsal root ganglion cells were dispersed and cultured with or without 1 μmol/l ranirestat for 48 hours. After the culture, neurite outgrowth was quantified using immunological staining. Sensory nerve conduction velocity increased in diabetic rats treated with ranirestat (43.3±3.6 m/s) compared with rats treated with placebo (39.8±2.3). Motor nerve conduction velocity also increased in the ranirestat group (45.6±3.9) compared with the placebo group (38.9±3.5). The foot withdrawal latency to noxious heating was improved in the ranirestat group (17.7±0.6 seconds) compared with the placebo group (20.6±0.6). The decrease in the intraepidermal fiber density was significant in the diabetic placebo group (21.6±1.7/mm) but not significant in the diabetic ranirestat group (26.2±1.2) compared with the nondiabetic placebo group (30.3±1.5). Neurite outgrowth was promoted in the neurons supplemented with ranirestat (control 1446±147 μm/neuron, ranirestat 2175±149). Ranirestat improved the peripheral nervous dysfunctions in rats with advanced diabetic polyneuropathy. Ranirestat could have potential for regeneration in the peripheral nervous system of diabetic rats.
Published: 2019
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30. Glucagon-Like Peptide-1 Receptor Agonist Protects Dorsal Root Ganglion Neurons against Oxidative Insult

Author: Mohammad Sarif Mohiuddin, Tatsuhito Himeno, Rieko Inoue, Emiri Miura-Yura, Yuichiro Yamada, Hiromi Nakai-Shimoda, Saeko Asano, Makoto Kato, Mikio Motegi, Masaki Kondo, Yusuke Seino, Shin Tsunekawa, Yoshiro Kato, Atsushi Suzuki, Keiko Naruse, Koichi Kato, Jiro Nakamura, and Hideki Kamiya
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Objective. Diabetic polyneuropathy (DPN) is one of the most prevalent diabetic complications. We previously demonstrated that exendin-4 (Ex4), a glucagon-like peptide-1 receptor agonist (GLP-1RA), has beneficial effects in animal models of DPN. We hypothesized that GLP-1 signaling would protect neurons of the peripheral nervous system from oxidative insult in DPN. Here, the therapeutic potential of GLP-1RAs on DPN was investigated in depth using the cellular oxidative insult model applied to the dorsal root ganglion (DRG) neuronal cell line. Research Design and Methods. Immortalized DRG neuronal 50B11 cells were cultured with and without hydrogen peroxide in the presence or absence of Ex4 or GLP-1(7-37). Cytotoxicity and viability were determined using a lactate dehydrogenase assay and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt), respectively. Antioxidant enzyme activity was evaluated using a superoxide dismutase assay. Alteration of neuronal characteristics of 50B11 cells induced by GLP-1RAs was evaluated with immunocytochemistry utilizing antibodies for transient receptor potential vanilloid subfamily member 1, substance P, and calcitonin gene-related peptide. Cell proliferation and apoptosis were also examined by ethynyl deoxyuridine incorporation assay and APOPercentage dye, respectively. The neurite projection ratio induced by treatment with GLP-1RAs was counted. Intracellular activation of adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling was also quantified after treatment with GLP-1RAs. Results. Neither Ex4 nor GLP-1(7-37) demonstrated cytotoxicity in the cells. An MTS assay revealed that GLP-1RAs amended impaired cell viability induced by oxidative insult in 50B11 cells. GLP-1RAs activated superoxide dismutase. GLP-1RAs induced no alteration of the distribution pattern in neuronal markers. Ex4 rescued the cells from oxidative insult-induced apoptosis. GLP-1RAs suppressed proliferation and promoted neurite projections. No GLP-1RAs induced an accumulation of cAMP. Conclusions. Our findings indicate that GLP-1RAs have neuroprotective potential which is achieved by their direct actions on DRG neurons. Beneficial effects of GLP-1RAs on DPN could be related to these direct actions on DRG neurons.
Published: 2019
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31. Glucagon Prevents Cytotoxicity Induced by Methylglyoxal in a Rat Neuronal Cell Line Model

Author: Mohammad Sarif Mohiuddin, Tatsuhito Himeno, Yuichiro Yamada, Yoshiaki Morishita, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Jiro Nakamura, and Hideki Kamiya
Subjects: diabetic polyneuropathy, glucagon, methylglyoxal, peripheral neuronal cell, 50B11, apoptosis, Microbiology, QR1-502
Abstract: Although diabetic polyneuropathy (DPN) is a frequent diabetic complication, no effective therapeutic approach has been established. Glucagon is a crucial hormone for glucose homeostasis but has pleiotropic effects, including neuroprotective effects in the central nervous system. However, the importance of glucagon in the peripheral nervous system (PNS) has not been clarified. Here, we hypothesized that glucagon might have a neuroprotective function in the PNS. The immortalized rat dorsal root ganglion (DRG) neuronal cell line 50B11 was treated with methylglyoxal (MG) to mimic an in vitro DPN model. The cells were cultured with or without glucagon or MG. Neurotoxicity, survival, apoptosis, neurite projection, cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) were examined. Glucagon had no cytotoxicity and rescued the cells from neurotoxicity. Cell survival was increased by glucagon. The ratio of apoptotic cells, which was increased by MG, was reduced by glucagon. Neurite outgrowth was accelerated in glucagon-treated cells. Cyclic AMP and PKA accumulated in the cells after glucagon stimulation. In conclusion, glucagon protected the DRG neuronal cells from MG-induced cellular stress. The cAMP/PKA pathway may have significant roles in those protective effects of glucagon. Glucagon may be a potential target for the treatment of DPN.
Published: 2021
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32. Secreted Factors from Stem Cells of Human Exfoliated Deciduous Teeth Directly Activate Endothelial Cells to Promote All Processes of Angiogenesis

Author: Makoto Kato, Shin Tsunekawa, Nobuhisa Nakamura, Emiri Miura-Yura, Yuichiro Yamada, Yusuke Hayashi, Hiromi Nakai-Shimoda, Saeko Asano, Tomohide Hayami, Mikio Motegi, Emi Asano-Hayami, Sachiko Sasajima, Yoshiaki Morishita, Tatsuhito Himeno, Masaki Kondo, Yoshiro Kato, Takako Izumoto-Akita, Akihito Yamamoto, Keiko Naruse, Jiro Nakamura, and Hideki Kamiya
Subjects: angiogenesis, endothelial cell, SHED, conditioned medium, Cytology, QH573-671
Abstract: Diabetes is a major risk factor for atherosclerosis and ischemic vascular diseases. Recently, regenerative medicine is expected to be a novel therapy for ischemic diseases. Our previous studies have reported that transplantation of stem cells promoted therapeutic angiogenesis for diabetic neuropathy and ischemic vascular disease in a paracrine manner, but the precise mechanism is unclear. Therefore, we examined whether secreted factors from stem cells had direct beneficial effects on endothelial cells to promote angiogenesis. The soluble factors were collected as conditioned medium (CM) 48 h after culturing stem cells from human exfoliated deciduous teeth (SHED) in serum-free DMEM. SHED-CM significantly increased cell viability of human umbilical vein endothelial cells (HUVECs) in MTT assays and accelerated HUVECs migration in wound healing and Boyden chamber assays. In a Matrigel plug assay of mice, the migrated number of primary endothelial cells was markedly increased in the plug containing SHED-CM or SHED suspension. SHED-CM induced complex tubular structures of HUVECs in a tube formation assay. Furthermore, SHED-CM significantly increased neovascularization from the primary rat aorta, indicating that SHED-CM stimulated primary endothelial cells to promote comprehensive angiogenesis processes. The angiogenic effects of SHED-CM were the same or greater than the effective concentration of VEGF. In conclusion, SHED-CM directly stimulates vascular endothelial cells to promote angiogenesis and is promising for future clinical application.
Published: 2020
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33. Angioblast Derived from ES Cells Construct Blood Vessels and Ameliorate Diabetic Polyneuropathy in Mice

Author: Tatsuhito Himeno, Hideki Kamiya, Keiko Naruse, Zhao Cheng, Sachiko Ito, Taiga Shibata, Masaki Kondo, Jiro Kato, Tetsuji Okawa, Atsushi Fujiya, Hirohiko Suzuki, Tetsutaro Kito, Yoji Hamada, Yutaka Oiso, Kenichi Isobe, and Jiro Nakamura
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Background. Although numerous reports addressing pathological involvements of diabetic polyneuropathy have been conducted, a universally effective treatment of diabetic polyneuropathy has not yet been established. Recently, regenerative medicine studies in diabetic polyneuropathy using somatic stem/progenitor cell have been reported. However, the effectiveness of these cell transplantations was restricted because of their functional and numerical impairment in diabetic objects. Here, we investigated the efficacy of treatment for diabetic polyneuropathy using angioblast-like cells derived from mouse embryonic stem cells. Methods and Results. Angioblast-like cells were obtained from mouse embryonic stem cells and transplantation of these cells improved several physiological impairments in diabetic polyneuropathy: hypoalgesia, delayed nerve conduction velocities, and reduced blood flow in sciatic nerve and plantar skin. Furthermore, pathologically, the capillary number to muscle fiber ratios were increased in skeletal muscles of transplanted hindlimbs, and intraepidermal nerve fiber densities were ameliorated in transplanted plantar skin. Transplanted cells maintained their viabilities and differentiated to endothelial cells and smooth muscle cells around the injection sites. Moreover, several transplanted cells constructed chimeric blood vessels with recipient cells. Conclusions. These results suggest that transplantation of angioblast like cells induced from embryonic stem cells appears to be a novel therapeutic strategy for diabetic polyneuropathy.
Published: 2015
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34. Transplantation of Neural Crest-Like Cells Derived from Induced Pluripotent Stem Cells Improves Diabetic Polyneuropathy in Mice

Author: Tetsuji Okawa, Hideki Kamiya, Tatsuhito Himeno, Jiro Kato, Yusuke Seino, Atsushi Fujiya, Masaki Kondo, Shin Tsunekawa, Keiko Naruse, Yoji Hamada, Nobuaki Ozaki, Zhao Cheng, Tetsutaro Kito, Hirohiko Suzuki, Sachiko Ito, Yutaka Oiso, Jiro Nakamura, and Ken-Ichi Isobe
Subjects: Medicine
Abstract: Impaired vascularity and nerve degeneration are the most important pathophysiological abnormalities of diabetic polyneuropathy (DPN). Therefore, regeneration of both the vascular and nervous systems is required for the treatment of DPN. The neural crest (NC) is a transient embryonic structure in vertebrates that differentiates into a vast range of cells, including peripheral neurons, Schwann cells, and vascular smooth muscle cells. In this study, we investigated the ability of transplantation of NC-like (NCL) cells derived from aged mouse induced pluripotent stem (iPS) cells in the treatment of DPN. iPS cells were induced to differentiate into neural cells by stromal cell-derived inducing activity (SDIA) and subsequently supplemented with bone morphogenetic protein 4 to promote differentiation of NC lineage. After the induction, p75 neurotrophin receptor-positive NCL cells were purified using magnetic-activated cell sorting. Sorted NCL cells differentiated to peripheral neurons, glial cells, and smooth muscle cells by additional SDIA. NCL cells were transplanted into hind limb skeletal muscles of 16-week streptozotocin-diabetic mice. Nerve conduction velocity, current perception threshold, intraepidermal nerve fiber density, sensitivity to thermal stimuli, sciatic nerve blood flow, plantar skin blood flow, and capillary number-to-muscle fiber ratio were evaluated. Four weeks after transplantation, the engrafted cells produced growth factors: nerve growth factor, neurotrophin 3, vascular endothelial growth factor, and basic fibroblast growth factor. It was also confirmed that some engrafted cells differentiated into vascular smooth muscle cells or Schwann cell-like cells at each intrinsic site. The transplantation improved the impaired nerve and vascular functions. These results suggest that transplantation of NCL cells derived from iPS cells could have therapeutic effects on DPN through paracrine actions of growth factors and differentiation into Schwann cell-like cells and vascular smooth muscle cells.
Published: 2013
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35. Transplantation of bone marrow-derived mononuclear cells improves mechanical hyperalgesia, cold allodynia and nerve function in diabetic neuropathy.

Author: Keiko Naruse, Jun Sato, Megumi Funakubo, Masaki Hata, Nobuhisa Nakamura, Yasuko Kobayashi, Hideki Kamiya, Taiga Shibata, Masaki Kondo, Tatsuhito Himeno, Tatsuaki Matsubara, Yutaka Oiso, and Jiro Nakamura
Subjects: Medicine, Science
Abstract: Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.
Published: 2011
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36. A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes

Author: Ryotaro Bouchi, Tatsuya Kondo, Yasuharu Ohta, Atsushi Goto, Daisuke Tanaka, Hiroaki Satoh, Daisuke Yabe, Rimei Nishimura, Norio Harada, Hideki Kamiya, Ryo Suzuki, and Toshimasa Yamauchi
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Published: 2022

37. Clinical parameters correlated with the psoas muscle index in Japanese individuals with type 2 diabetes mellitus

Author: Emi Asano-Hayami, Yoshiaki Morishita, Tomohide Hayami, Yuka Shibata, Toshiki Kiyose, Sachiko Sasajima, Yusuke Hayashi, Mikio Motegi, Makoto Kato, Saeko Asano, Hiromi Nakai-Shimoda, Yuichiro Yamada, Emiri Miura-Yura, Tatsuhito Himeno, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Jiro Nakamura, and Hideki Kamiya
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Published: 2022

38. Gianotti-Crosti syndrome with granulomatous changes in an infant, possibly induced by multiple hepatitis B virus vaccinations.

Author: Tomoyuki HIOKI, Hideki KAMIYA, Tetsuya YAMADA, Kengo MATSUNAGA, and Yasuo KITAJIMA
Published: 2024
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39. 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 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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 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Forsyth, Rowan McDougall, Tanaji Dasgupta, Louisa Davies, Maggie Ryder, Philip Grimmer, Clare Macdonald, Mary Webster, Newcastle Newcastle, Timothy Ellam, Edwin Wong, Christine Meshykhi, Andrea Webster, Peter Wilson, Enric Vilar, Jocelyn Berdeprado, Eunice Doctolero, Lily Wilkinson, Frank McCarroll, Hesham Ammar, Ying Kuan, Conor Moran, Girish Shivashankar, Ryan Campbell, Deborah Glowski, Paula McDermott, Amar Ali, Zuber Patel, Christine Bond, Gillian Whalley, Haitao Zhang, Liu Yang, Lihua Zhang, Tingting Kan, Ling Zhu, Jinghong Zhao, Weiping Hou, Jing Wu, Hong Cheng, Weijing Bian, Zhirui Zhao, Fengmin Shao, Huixia Cao, Xiaojing Jiao, Peiyuan Niu, Jianying Niu, Yu Chen, Lihong Zhang, Shenglang Zhu, Haiyan Lin, Shaopeng Yao, Jiehui Chen, Ying Jiang, Ying Hu, Huaying Xiao, Fuye Yang, Xinzhou Zhang, Baochun Guo, Qiu Jin, Lixia Liu, Xiangcheng Xiao, Yanyun Xie, Ting Meng, Chuanwen Xu, Jie Huang, Yanmei Xu, Weixin Kong, Xiaoliang Wang, Qianpan Liu, Xueying Wang, Ming Gao, Xiumei Hu, Ying Lu, Li Wang, Kun Peng, Wei Wang, Qiuhong Gong, Jianfang Cai, Xiaojue Li, Xuejiao Liu, Shuhan Zhou, Hong Liu, Yao Weng, Shuai Tang, Yao Yao, Shi Zhao, Chen Cheng, Wei Wei, Na Li, Sadanah Aqashiah Mazlan, Alia Zubaidah Bahtar, Elliyyin Katiman, Noraini Othman, Lily Mushahar, Nurdiana Mazlan, Nur Sharafina Safiee, Sarasa Ramasamy, Hin Seng Wong, Hajar Ahmad Rosdi, Esther Zhao Zhi Tan, Ju Fan Tay, Kok Seng Teng, Hasnah Yahaya, Wen Jiun Liu, Lik Wee Ee, Kenneth Kay Leong Khoo, Yuana Mohd Yusoff, Fariz Safhan Mohamad Nor, Mohd Kamil Ahmad, Mohd Ramli Seman, Clare Hui Hong Tan, Laura Lui Sian Ngu, Jaime Yoke May Chan, Javelin Peji, Chek Loong Loh, Yee Yan Lee, Sridhar Ramanaidu, Kah Mean Thong, Yik Hong Wong, Suria Junus, Chen Hua Ching, Mohammad Faisal Asmee, Ku Ruziana Ku Md Razi, Chun Leong Low, Christopher Sze Bing Sim, Zhang Duan Tham, Noor Kamila Abdullah, Tai Meng Chen, Yong Chieh Chan, Eason Chang, Huan Yean Kang, Kai Quan Lee, Sue Ann Lee, Aik Kheng Lee, Jeevika Vinathan, Rizna Abdul Cader, Ruslinda Mustafar, Lydia Kamaruzaman, Rozita Mohd, Rahimah Ismail, Chong Men Leong, Chee Koon Low, Liang Wei Wong, Norlezah Adnan, Sabariah Ibrahim, Mohamad Zaimi Abdul Wahab, Sunita Bavanandan, Yik Shen Lim, Wan Hazlina Wan Mohamad, Siti Munirah Jaafar, Nur Ashykeen Mohd Fauzi, Aziee Sudin, Soo Kun Lim, Chye Chung Gan, Albert Hing, Wan Ahmad Faizal Alaidin Razali, Yew Fong Liew, Chelsia Bao Tyng Chan, Mei Chih Cheng, Yu Chen Ong, Loke Meng Ong, Farah Amalina Mohamed Affandi, Korina Rahmat, Ban Chai Peng, Masayu Amat, Nuzaimin Hadafi Ahmad, Doo Yee Mah, Yi Loon Tye, Zaid Azhari, Siti Nabilah Mohamad Zaini, Mohd Aidil Musa, Norazinizah Ahmad Miswan, Rafizanur Ramli, Nor Aziah Ahmad, Bak Leong Goh, Nurul Izah Ahmad, Fairol Huda Ibrahim, Tze Jian Ng, Malini Shanmuganathan, Li Lian Tay, Zaiha Harun, Salmi Ramli, Nurul 'Ain Yusof, Rossenizal Abd Rahman, Muhammad Iqbal Abdul Hafidz, Nur Hidayati Mohd Sharif, Irda Yasmoon Awang, Eitaro Nakashima, Rui Imamine, Makiko Minatoguchi, Yukari Miura, Miduki Nakaoka, Yoshiki Suzuki, Hitomi Yoshikawa, Koki Shin, Kanae Fujita, Misuzu Iwasa, Haruka Sasajima, Airi Sato, Yoshiyuki Hamamoto, Yuki Fujita, Takuya Haraguchi, Takanori Hyo, Kiyohiro Izumi, Toshiyuki Komiya, Sodai Kubota, Takeshi Kurose, Hitoshi Kuwata, Susumu Nakatani, Kaori Oishi, Saki Okamoto, Kaori Okamura, Jun Takeoka, Nagaaki Tanaka, Katsuya Tanigaki, Naohiro Toda, Koin Watanabe, Hiromi Komori, Rika Kumuji, Asako Takesada, Aya Tanaka, Shoichi Maruyama, Tomonori Hasegawa, Akiko Ishiguro, Takuji Ishimoto, Kazuhiro Ito, Yutaka Kamimura, Noritoshi Kato, Sawako Kato, Hiroshi Kojima, Tomoki Kosugi, Kayaho Maeda, Masasi Mizuno, Shoji Saito, Hitomi Sato, Yuka Sato, Yasuhiro Suzuki, Akihito Tanaka, Yoshinari Yasuda, Fujiko Hasegawa, Maiko Hayashi, Shizuka Higashi, Kaho Shimamura, Momoko Sumi, Kazuki Tajima, Chimaki Unekawa, Kana Wakayama, Yukiko Wakita, Takatoshi Otani, Ayako Imai, Sayaka Kawashima, Eri Kogure, Tomoe Sato, Misato Takezawa, Shinya Yoshida, Hideo Araki, Yuko Katsuda, Masahiro Konishi, Takahiro Matsunaga, Masashi Oe, Kunihiro Ogane, Masato Sakai, Tomoko Takahashi, Takahiro Yamano, Takuya Yokoyama, Hitomi Ito, Masayo Katayama, Emi Kuroda, Toru Ikeda, Takuma Kojo, Etsuo Yoshidome, Rieko Mizumachi, Akane Yamamoto, Narihisa Yamasaki, Yoshihiko Yamasaki, Jun Wada, Jun Eguchi, Chigusa Higuchi, Akihiro Katayama, Masaru Kinomura, Masashi Kitagawa, Shinji Kitamura, Satoshi Miyamoto, Hiroshi Morinaga, Atsuko Nakatsuka, Ichiro Nojima, Kenichi Shikata, Hitoshi Sugiyama, Katsuyuki Tanabe, Kenji Tsuji, Haruhito Uchida, Mayu Watanabe, Chie Hashimoto, Takahiro Kato, Sayaka Yamamoto, Takehiko Wada, Masafumi Fukagawa, Naoto Hamano, Masahiro Koizumi, Hirotaka Komaba, Yosuke Nakagawa, Michiyo Iwamoto, Kosuke Masutani, Akane Katanosaka, Mayu Kiyota, Hikari Uchi, Yuka Ueda, Sonoka Yamamoto, Hajime Nagasu, Seiji Itano, Tsukasa Iwakura, Hiroyuki Kadoya, Eiichiro Kanda, Naoki Kashihara, Kengo Kidokoro, Megumi Kondo, Tamaki Sasaki, Minoru Satoh, Atsuyuki Tokuyama, Reina Umeno, Yoshihisa Wada, Toshiya Yamamoto, Yu Yamanouchi, Masumi Abe, Yoko Inukai, Wataru Ogawa, Shunichiro Asahara, Hideki Fujii, Shunsuke Goto, Yushi Hirota, Tetsuya Hosooka, Keiji Kono, Shinichi Nishi, Yuko Okada, Kazuhiko Sakaguchi, Kenji Sugawara, Michiko Takahashi, Tomoko Takai, Yoshikazu Tamori, Kentaro Watanabe, Miyu Kitajima, Misaki Nishi, Junko Wada, Yasuhiko Ito, Hideki Kamiya, Akimasa Asai, Nao Asai, Saeko Asano, Shogo Banno, Yohei Ejima, Hanako Hase, Tomohide Hayami, Tatsuhito Himeno, Takahiro Ishikawa, Mayumi Ito, Shiho Iwagaitsu, Rina Kasagi, Yoshiro Kato, Makoto Kato, Koichi Kato, Takayuki Katsuno, Miyuka Kawai, Hiroshi Kinashi, Masaki Kondo, Masako Koshino, Naoya Matsuoka, Yoshiaki Morishita, Mikio Motegi, Jiro Nakamura, Hiromi Shimoda, Hirokazu Sugiyama, Shin Tsunekawa, Makoto Yamaguchi, Kazuyo Takahashi, Hirotaka Watada, Takashi Funayama, Yasuhiko Furukawa, Tomohito Gohda, Hiromasa Goto, Hideyoshi Kaga, Yasuhiko Kanaguchi, Akio Kanazawa, Kayo Kaneko, Toshiki Kano, Masao Kihara, Shogo Kimura, Takashi Kobayashi, Masayuki Maiguma, Yuko Makita, Satoshi Mano, Tomoya Mita, Takeshi Miyatsuka, Maki Murakoshi, Masahiro Muto, Masami Nakata, Junichiro Nakata, Yuya Nishida, Nao Nohara, Takeshi Ogihara, Daisuke Sato, Junko Sato, Hiroaki Sato, Yusuke Suzuki, Ruka Suzuki, Hitoshi Suzuki, Miyuki Takagi, Yoshifumi Tamura, Toyoyoshi Uchida, Seiji Ueda, Miki Asawa, Minako Miyaji, Eri Nagashima, Yoshie Shibata, Eri Yanagisawa, Toshimasa Yamauchi, Yosuke Hirakawa, Hiroshi Nishi, Nobuhiro Shojima, Satoko Horikawa, Yukiko Nakayama, Naoko Yamada, Yuki Omori, Shintaro Yano, Miyabi Ioka, Nahoko Kuwabara, Remi Nagano, Megumi Nozawa, Yumi Osawa, Hiroshi Maegawa, Shinji Kume, Shinichi Araki, Itsuko Miyazawa, Katsutaro Morino, Ikuko Kawai, Masumi Sobata, Motoko Takaoka, Yasushi Iwaita, Takashi Udagawa, Ami Inamori, Aya Kawase, Aya Yamanaka, Hitoshi Shimano, Akiko Fujita, Hitoshi Iwasaki, Hirayasu Kai, Yoshinori Osaki, Chie Saito, Motohiro Sekiya, Ryoya Tsunoda, Kunihiro Yamagata, Rikako Nakamura, Aiko Yamada, Mitsuru Ohsugi, Motoharu Awazawa, Ryotaro Bouchi, Shota Hashimoto, Makiko Hashimoto, Tomoko Hisatake, Noriko Ihana, Koko Ishizuka, Kazuo Izumi, Hiroshi Kajio, Michi Kobayashi, Noriko Kodani, Koji Maruyama, Michihiro Matsumoto, Maya Matsushita, Tomoka Nakamura, Takehiro Sugiyama, Akiyo Tanabe, Aiko Terakawa, Kojiro Ueki, Yuko Orimo, Takako Ozawa, Eriko Takahira, Yoshimitsu Yamasaki, Masakazu Haneda, Tadahiro Tomita, Saori Akimoto, Akihiro Fujimoto, Kenji Ishihara, Chiho Murakami, Akiyo Nishiyama, Yukiko Toyonaga, Kana Uozumi, Yukihiro Yamaji, Tetsuya Shigehara, Jun Okajyo, Yukihiro Shimizu, Shingo Iwasaki, Yuki Fukao, Megumi Furusho, Shintaro Nunokawa, Hideki Katagiri, Tomohito Izumi, Keizo Kaneko, Shinjiro Kodama, Mariko Miyazaki, Yuichiro Munakata, Tasuku Nagasawa, Yuji Oe, Hiroto Sugawara, Kei Takahashi, Kazushige Hirata, Keiko Inomata, Shoko Otomo, Taeko Uchida, Chigusa Yamashita, Arihiro Kiyosue, Ryota Tamura, Francois Dube, Marilene Bolduc, Marie-Christine Talbot, Leslie Cham, Vesta Lai, Josephine Tse, Shivinder Jolly, Tabbatha Duck, Scott Lyle, Rachel Epp, Camille Galloway, Susan Haskett, Elizabeta Matvienko, Liam Paulsen, Louise Moist, Zabrina Lozon, Tina Ramsey, Brittany Whitmore, Bader Al-Zeer, Paula Macleod, Aoife O'Sullivan, Zainab Sheriff, Sam Tholl, Amritanshu Pandey, Samantha Armstrong, Bethelihem Gebeyehu, Patrick Toth, Ronald Goldenberg, Mahsa Jahangiriesmaili, Shariff Sanguila, Neethi Suresh, Tanvi Talsania, Nadia Zalunardo, Mohsen Agharazii, Marie-Pier Roussel, Annie Saillant, France Samson, Harpreet Bajaj, Miken Bhavsar, Parul Dhall, Gagandeep Dhillon, Bhupinder Grewal, Taniya Nimbkar, Francois Madore, Guylaine Marcotte, Oren Steen, Mathura Bullen, Shayani Raguwaran, Andre Valleteau, Marie-France Langlois, Christine Brown, Andrew Steele, Melissa Garrity, Taneera Ghate, Holly Robinson, Michael Tolibas, Chetna Tailor, Lauren Elliott, Christine McClary-Wright, Fadia Boreky, Sameh Fikry, Ayesha Ali, Chintankumar Barot, Wagdy Basily, Thisun Saram, Vinay Varad, Hasnain Khandwala, Alex Aguilera, Patricia Alvarez, Balwinder Gill, Nazihah Huda, Aamir Navivala, Daniel Pinto, Micheli Bevilacqua, Elaine Fung, Geraldine Hernandez, Puneet Mann, Jaskiran Saini, Remi Rabasa-Lhoret, Danijela Bovan, Marie Devaux, Cecilia Barnini, Giovanna Leoncini, Luca Manco, Giulia Nobili, Matteo Piemontese, Filippo Aucella, Rachele Grifa, Francesco Totaro, Gaetano La Manna, Irene Capelli, Giuseppe Cianciolo, Sarah Lerario, Fulvia Zappulo, Alberto Rosati, Filippo Fani, Giuseppe Spatoliatore, Loreto Gesualdo, Francesco Pesce, Maria Russo, Maria Zippo, Cesira Cafiero, Daria Motta, Simona Bianco, Donatella Bilucaglia, Piergiorgio Messa, Laura Pavone, Federica Tripodi, Simone Vettoretti, Paola Fioretto, Gianni Carraro, Filippo Farnia, Anna Postal, Alessandro D'Amelio, Antonio Cardone, Giovanni Piccinni, Annalisa Aloisi, Francesco Scolari, Federico Alberici, Alice Guerini, Chiara Saccà, Chiara Salviani, Roberta Zani, Luca De Nicola, Carlo Garofalo, Maria Elena Liberti, Roberto Minutolo, Luigi Pennino, Lucio Polese, Paolo Mené, Simona Barberi, Clorinda Falcone, Francesco Russo, Maurizio Caroppo, Gennaro Santorelli, Rodolfo Rivera, Domenico Santoro, Alfio Giuffrida, Fortunata Zirino, Cristina Calvi, Luca Estienne, Giovanni Gambaro, Concetta Gangemi, Vittorio Ortalda, Giuseppina Pessolano, Giuseppe Grandaliano, Rocco Baccaro, Pietro Ferraro, Roberto Mangiacapra, Marco Melandri, Nadia Foligno, Rita Quartagno, Giuseppe Vezzoli, Elena Brioni, William G, Herrington, Natalie, Staplin, Christoph, Wanner, Jennifer B, Green, Sibylle J, Hauske, Jonathan R, Emberson, David, Prei, Parminder, Judge, Kaitlin J, Mayne, Sarah Y A, Ng, Emily, Sammon, Doreen, Zhu, Michael, Hill, Will, Steven, Karl, Wallendszu, Susanne, Brenner, Alfred K, Cheung, Zhi-Hong, Liu, Jing, Li, Lai Seong, Hooi, Wen, Liu, Takashi, Kadowaki, Masaomi, Nangaku, Adeera, Levin, David, Cherney, Aldo P, Maggioni, Roberto, Pontremoli, Rajat, Deo, Shinya, Goto, Xavier, Rossello, Katherine R, Tuttle, Dominik, Steubl, Michaela, Petrini, Dan, Massey, Jens, Eilbracht, Martina, Brueckmann, Martin J, Landray, Colin, Baigent, Richard, Hayne, EMPA-KIDNEY Collaborative Group: Colin Baigent, The, J Landray, Martin, Wanner, Christoph, G Herrington, William, Haynes, Richard, B Green, Jennifer, J Hauske, Sibylle, Brueckmann, Martina, Hopley, Mark, von-Eynatten, Maximillian, George, Jyothi, Brenner, Susanne, K Cheung, Alfred, Preiss, David, Liu, Zhi-Hong, Li, Jing, Hooi, Laiseong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Pontremoli, Roberto, P Maggioni, Aldo, Staplin, Natalie, Emberson, Jonathan, Hantel, Stefan, Goto, Shinya, Deo, Rajat, R Tuttle, Katherine, Hill, Michael, Judge, Parminder, J Mayne, Kaitlin, A Ng, Sarah Y, Rossello, Xavier, Sammons, Emily, Zhu, Doreen, Sandercock, Peter, Bilous, Rudolf, Herzog, Charle, Whelton, Paul, Wittes, Janet, Bennett, Derrick, Achiri, Patricia, Ambrose, 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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, 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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, 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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

40. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes

Author: Ryotaro, Bouchi, Tatsuya, Kondo, Yasuharu, Ohta, Atsushi, Goto, Daisuke, Tanaka, Hiroaki, Satoh, Daisuke, Yabe, Rimei, Nishimura, Norio, Harada, Hideki, Kamiya, Ryo, Suzuki, and Toshimasa, Yamauchi
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine, General Medicine
Published: 2022

41. 3D-aggregated dermal stem cells with partial-pluripotency.

Author: Masaki Kondo, Hideki Kamiya, Tetsuji Okawa, Sachiko Ito, Naomi Nishio, Tatsuhito Himeno, Yutaka Oiso, Jiro Nakamura, and Ken-ichi Isobe
Published: 2012
Full Text: View/download PDF

42. Home Appliance Control Using Heterogeneous Sensor Networks.

Author: Yuichiro Kato, Takahiro Ito, Hideki Kamiya, Masatoshi Ogura, Hiroshi Mineno, Norihiro Ishikawa, and Tadanori Mizuno
Published: 2009
Full Text: View/download PDF

43. Composite Event Detection in Heterogeneous Sensor Networks.

Author: Hideki Kamiya, Hiroshi Mineno, Norihiro Ishikawa, Tomoyuki Osano, and Tadanori Mizuno
Published: 2008
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44. Multifocal Neuroarthropathy of the Knee and Foot Induced by Physical Training of the Lower Extremities in a Patient With Latent Autoimmune Diabetes in Adults

Author: Chika Kojima, Tatsuhito Himeno, Machiko Akao, Hideki Kamiya, and Jiro Nakamura
Subjects: General Engineering
Published: 2022

45. 463-P: Effects of Imeglimin, a New Oral Hyperglycemic Agent, on High Glucose and Low Glucose–Induced Cell Death and Mitochondrial Dysfunction in Schwann Cells

Author: AYAKO KATO, YASUAKI TATSUMI, WATARU NIHEI, HIDEJI YAKO, TATSUHITO HIMENO, MASAKI KONDO, YOSHIRO KATO, JIRO NAKAMURA, HIDEKI KAMIYA, KAZUNORI SANGO, and KOICHI KATO
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: It is known that hyperglycemia-induced oxidative stress is a major cause of the pathogenesis of diabetic neuropathy, and hyperglycemia-induced mitochondrial ROS production is considered as one pivotal mechanism of increased oxidative stress. On the other hand, imeglimin is a new class of oral hypoglycemic agents called “glymines” containing tetrahydrotriazines, which targets mitochondrial dysfunction. We investigated the effects of imeglimin on cell death and mitochondrial dysfunction induced by high glucose and low glucose in Schwann cells. Immortalized adult mouse Schwann (IMS32) cells were cultured for 1 hour in the medium with normal glucose concentration of 5.5 mM, low glucose of 2.5 mM, and high glucose of 25 mM. Compared to normal glucose, not only high glucose but also low glucose decreased cell viability of IMS32 cells and increased mitochondrial oxidative stress. Mitochondrial membrane potential was also decreased either by high glucose or low glucose. In addition, mitochondrial oxygen consumption rate (OCR) was increased by low glucose as well as high glucose. Mitochondria isolated from IMS32 cells exposed to high glucose and low glucose for 1 hour exhibited increased activity of complex I. The expression of complex I protein was unchanged by high glucose for 1 hour. Imeglimin ameliorated the decrease in cell viability and improved the mitochondrial dysfunctions via inhibiting the increase of mitochondrial oxidative stress, OCR and the activity of complex I caused by high glucose and low glucose. These results indicate that hyperglycemia and hypoglycemia induce mitochondrial dysfunction in nerves, and that imeglimin may prevent against diabetic neuropathy by attenuation mitochondrial dysfunction and cell death in Schwann cells. Disclosure T. Himeno: None. J. Nakamura: None. H. Kamiya: Research Support; Abbott Japan Co., Ltd., Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Terumo Corporation. Speaker's Bureau; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. K. Sango: None. K. Kato: None.
Published: 2022

46. 624-P: Effects of Semaglutide Treatment on Dietary Behavior in Japanese Patients with Type 2 Diabetes Mellitus

Author: SHIORI T. SATO, TAKAHIRO TOSAKI, AOI KOTORII, MASAKI KONDO, EMIRI MIURA-YURA, SHIN TSUNEKAWA, TATSUHITO HIMENO, YOSHIRO KATO, JIRO NAKAMURA, and HIDEKI KAMIYA
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Objective and Methods: Eating behavior questionnaire issued by the Japan Society for the Study of Obesity was administered to 41 patients who received semaglutide injection (SI) and 52 patients who received oral semaglutide (OS) in our outpatient clinic. Changes in HbA1c levels, body weight, eating behavior, and their correlations after 3 months of treatment were examined. Results: The mean dose after 3 months of treatment was 0.50 ± 0.17 mg/week in the SI group and 6.35 ± 2.29 mg/day in the OS group. Mean HbA1c significantly decreased from 7.34 ± 0.97% to 6.85 ± 0.72% in the SI group and from 7.65 ± 0.94% to 7.± 0.91% in the OS group (p Conclusion: These results suggest that semaglutide improves glycemic control and eating behavior in Japanese patients with type 2 diabetes. Disclosure S.T.Sato: None. H.Kamiya: Research Support; Abbott Japan Co., Ltd., Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Terumo Corporation, Speaker's Bureau; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T.Tosaki: Other Relationship; Eli Lilly and Company, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd. A.Kotorii: None. M.Kondo: n/a. E.Miura-yura: None. S.Tsunekawa: n/a. T.Himeno: None. Y.Kato: None. J.Nakamura: None.
Published: 2022

47. Neuroretinal dysfunction revealed by a flicker electroretinogram correlated with peripheral nerve dysfunction and parameters of atherosclerosis in patients with diabetes

Author: Eriko Nagao, Emi Asano-Hayami, Hiromi Nakai-Shimoda, Yukako Sugiura-Roth, Shin Tsunekawa, Jiro Nakamura, Rina Kasagi, Yuka Shibata, Yoshiro Kato, Hideki Kamiya, Nobuhiro Hirai, Masaki Kondo, Yoshiaki Morishita, Yohei Ejima, Takayuki Nakayama, Yuriko Asada-Yamada, Takahiro Ishikawa, Miyuka Kawai, Yuichiro Yamada, and Tatsuhito Himeno
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Neural Conduction, 030209 endocrinology & metabolism, Pulse Wave Analysis, Carotid Intima-Media Thickness, Severity of Illness Index, Likelihood ratios in diagnostic testing, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Diabetes mellitus, Internal medicine, Electroretinography, Internal Medicine, medicine, Humans, Ankle Brachial Index, Peripheral Nerves, Pulse wave velocity, Aged, Diabetic Retinopathy, Receiver operating characteristic, medicine.diagnostic_test, business.industry, Articles, General Medicine, Diabetic retinopathy, Middle Aged, Atherosclerosis, RC648-665, medicine.disease, Diabetes Mellitus, Type 1, Clinical Science and Care, Diabetes Mellitus, Type 2, ROC Curve, 030221 ophthalmology & optometry, Nerve conduction study, Cardiology, Female, Original Article, business, Erg, Point‐of‐care testing, Diabetic neuropathies
Abstract: Aims/Introduction Diabetic polyneuropathy (DPN) develops in the early stage of diabetes. However, no common diagnostic protocol has yet been established. Here, to verify that the flicker electroretinogram using a hand‐held device can detect the early dysfunction of the peripheral nervous system in patients with diabetes, we investigated the correlation between the progression of DPN and neuroretinal dysfunction. Materials and Methods In total, 184 participants with type 1 or 2 diabetes underwent a flicker electroretinogram (ERG) using a hand‐held device RETeval™ and nerve conduction study. Participants were also evaluated for intima‐media thickness, ankle‐brachial index, toe brachial index and brachial‐ankle pulse wave velocity. Parameters of the nerve conduction study were used to diagnose the severity according to Baba’s classification. A multiple regression analysis was used to examine the associations of ERG parameters with the severity of DPN categorized by Baba’s classification. Diagnostic properties of the device in DPN were evaluated using a receiver operating characteristic curve. Results A multiple regression model to predict the severity of DPN was generated using ERG. In the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.692, sensitivity 56.5%, specificity 78.3%, positive predictive value 70.6%, negative predictive value 66.1%, positive likelihood ratio 2.60, negative likelihood ratio 0.56). In the patients without diabetic retinopathy, the implicit time and amplitude in ERG significantly correlated with the parameters of the nerve conduction study, brachial‐ankle pulse wave velocity and intima‐media thickness. Conclusions Electroretinogram parameters obtained by the hand‐held device successfully predict the severity of DPN. The device might be useful to evaluate DPN., The progression of diabetic retinopathy and the dysfunction of neuroretina evaluated using the mydriasis‐free flicker electroretinogram showed a significant correlation. In patients without apparent diabetic retinopathy, the electroretinogram data correlated with parameters indicating vascular dysfunction, and with parameters indicating diabetic polyneuropathy, such as data of a nerve conduction study. Therefore, the electroretinogram data might reflect the neural and vascular impairments of the retina in patients with diabetes. The electroretinogram data were able to be used to predict the severity of diabetic polyneuropathy.
Published: 2020

48. Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice

Author: Saeko Asano, Yoshiaki Morishita, Hideki Kamiya, Yusuke Seino, Jiro Nakamura, Tatsuhito Himeno, Yoshiro Kato, Emiri Miura-Yura, Shin Tsunekawa, Mikio Motegi, Hiromi Nakai-Shimoda, Keiko Naruse, Masaki Kondo, Norio Ozeki, Sachiko Sasajima, Yusuke Hayashi, Emi Asano-Hayami, Yoshitaka Hayashi, Koichi Kato, Rieko Inoue, Makoto Kato, and Mohammad Sarif Mohiuddin
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Neurite, Neuronal Outgrowth, Glucagon-Like Peptides, Neural Conduction, Biophysics, Nerve fiber, Nerve Fibers, Myelinated, Biochemistry, Glucagon, Neuroprotection, Mice, 03 medical and health sciences, 0302 clinical medicine, Diabetic Neuropathies, Glucagon-Like Peptide 1, Ganglia, Spinal, Internal medicine, Receptors, Glucagon, Animals, Medicine, RNA, Messenger, Molecular Biology, Pathological, Mice, Knockout, Hypoalgesia, business.industry, Cell Biology, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Peripheral neuropathy, medicine.anatomical_structure, Endocrinology, Hyperalgesia, 030220 oncology & carcinogenesis, Peripheral nervous system, business
Abstract: Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg−/−) mice were examined. The gcg−/− mice showed tactile allodynia and thermal hyperalgesia at 12–18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg−/− mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.
Published: 2020

49. Point‐of‐care nerve conduction device predicts the severity of diabetic polyneuropathy: A quantitative, but easy‐to‐use, prediction model

Author: Emi Asano-Hayami, Yoshiro Kato, Shin Tsunekawa, Miyuka Kawai, Yuichiro Yamada, Kenta Murotani, Hiromi Nakai-Shimoda, Masaki Kondo, Hiroya Tani, Jiro Nakamura, Takahiro Ishikawa, Tatsuhito Himeno, Takayuki Nakayama, Yuriko Asada-Yamada, Hideki Kamiya, Nobuhiro Hirai, Yoshiaki Morishita, Yuka Shibata, and Masayuki Baba
Subjects: Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Neural Conduction, 030209 endocrinology & metabolism, Sural nerve, Electromyography, Severity of Illness Index, Likelihood ratios in diagnostic testing, Diseases of the endocrine glands. Clinical endocrinology, Nerve conduction velocity, 03 medical and health sciences, 0302 clinical medicine, Diabetic Neuropathies, Internal medicine, Linear regression, Internal Medicine, medicine, Humans, Aged, Aged, 80 and over, Models, Statistical, Receiver operating characteristic, medicine.diagnostic_test, business.industry, Articles, General Medicine, Gold standard (test), Middle Aged, RC648-665, Clinical Science and Care, Point-of-Care Testing, Nerve conduction study, Cardiology, Original Article, Female, business, Point‐of‐care testing, 030217 neurology & neurosurgery
Abstract: Aims/Introduction A gold standard in the diagnosis of diabetic polyneuropathy (DPN) is a nerve conduction study. However, as a nerve conduction study requires expensive equipment and well‐trained technicians, it is largely avoided when diagnosing DPN in clinical settings. Here, we validated a novel diagnostic method for DPN using a point‐of‐care nerve conduction device as an alternative way of diagnosis using a standard electromyography system. Materials and Methods We used a multiple regression analysis to examine associations of nerve conduction parameters obtained from the device, DPNCheck™, with the severity of DPN categorized by the Baba classification among 375 participants with type 2 diabetes. A nerve conduction study using a conventional electromyography system was implemented to differentiate the severity in the Baba classification. The diagnostic properties of the device were evaluated using a receiver operating characteristic curve. Results A multiple regression model to predict the severity of DPN was generated using sural nerve conduction data obtained from the device as follows: the severity of DPN = 2.046 + 0.509 × ln(age [years]) − 0.033 × (nerve conduction velocity [m/s]) − 0.622 × ln(amplitude of sensory nerve action potential [µV]), r = 0.649. Using a cut‐off value of 1.3065 in the model, moderate‐to‐severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.871, sensitivity 70.1%, specificity 87.7%, positive predictive value 83.0%, negative predictive value 77.3%, positive likelihood ratio 5.67, negative likelihood ratio 0.34). Conclusions Nerve conduction parameters in the sural nerve acquired by the handheld device successfully predict the severity of DPN., Currently, most diagnostic criteria for diabetic polyneuropathy consist of physical examinations; for example, Achilles tendon reflex or vibration sensation with a tuning fork. Therefore, the low diagnostic sensitivity of these criteria should be improved. Although the gold standard for quantitative evaluation of diabetic polyneuropathy is an electromyography system, these have not become widely used due to their high cost and necessity of an advanced examination technique. The current work verified the efficacy of a handheld nerve conduction device. If clinicians recognize the validity and reliability of the device, this simplified nerve conduction study could be carried out in various clinical settings, including clinics or hospitals in developing or developed countries. The worldwide utilization of the device would improve diagnostic sensitivity for diabetic polyneuropathy in the future.
Published: 2020

50. Tumor‐like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin‐induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat

Author: Naoya Murao, Akira Mizoguchi, Daisuke Yabe, Harumi Takahashi, Kohei Honda, Susumu Seino, Jiro Nakamura, Norihide Yokoi, Takuro Yamaguchi, Ian R. Sweet, Shujie Wang, Yusuke Seino, Tomohide Hayami, and Hideki Kamiya
Subjects: Male, 0301 basic medicine, Basic Science and Research, endocrine system, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Incretin, Enlarged islets, Tumor cells, Incretins, Diseases of the endocrine glands. Clinical endocrinology, Islets of Langerhans, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Insulin Secretion, Internal Medicine, medicine, Animals, Glycolysis, Obesity, geography, geography.geographical_feature_category, business.industry, Gene Expression Profiling, Pancreatic islets, Glutamate receptor, Articles, General Medicine, RC648-665, medicine.disease, Islet, Rats, Rats, Zucker, Pancreatic Neoplasms, Citric acid cycle, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Anaerobic glycolysis, 030220 oncology & carcinogenesis, Metabolome, Original Article, business
Abstract: Aims/Introduction Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non‐large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin‐induced insulin secretion (IIIS) in these islets. Materials and Methods Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks‐of‐age were isolated. The islets of fa/fa rats at 12 weeks‐of‐age were separated into non‐large islets (≤200 μm in diameter) and enlarged islets (>300 μm in diameter). Morphological analyses, insulin secretion experiments, transcriptome analysis, metabolome analysis and oxygen consumption analysis were carried out on these islets. Results The number of enlarged islets was increased with age in fatty rats, and IIIS was significantly reduced in the enlarged islets. Markers for β‐cell differentiation were markedly decreased in the enlarged islets, but those for cell proliferation were increased. Glycolysis was enhanced in the enlarged islets, whereas the tricarboxylic acid cycle was suppressed. The oxygen consumption rate under glucose stimulation was reduced in the enlarged islets. Production of glutamate, a key signal for IIIS, was decreased in the enlarged islets. Conclusions The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for IIIS, show tumor cell‐like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age‐dependent increase in such islets could contribute to the pathophysiology of obese diabetes., The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for incretin‐induced insulin secretion, show tumor cell‐like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age‐dependent increase in such islets could contribute to the pathophysiology of obese diabetes.
Published: 2020

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