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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. The criteria for diagnosis and staging of diabetic polyneuropathy has not been established; consequently, no disease‐modifying treatment is available. 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) no restrictive exclusion diagnosis for other causes of polyneuropathy.

Electrochemical sodium deposition/dissolution behaviors in propylene carbonate-based electrolyte solution were observed by means of in situ light microscopy. First, granular sodium was deposited at pits in a sodium electrode in the cathodic process. Then, the sodium particles grew linearly from the electrode surface, becoming needle-like in shape. In the subsequent anodic process, the sodium dissolved near the base of the needles on the sodium electrode and the so-called “ dead sodium ” broke away from the electrode. The mechanisms of electrochemical sodium deposition and dissolution on a copper electrode were similar to those on the sodium electrode.

We propose key performance indicators (KPIs) based on the Gross Social Feel-Good Index to evaluate a smart sustainable city and report the results of a field trial in a city located almost at the center of the Tokyo Metropolitan Area. We developed KPIs based on the following concepts: (1). The triple bottom line is the basic evaluation criteria; (2). The same unit is used for every evaluation criterion; (3). The KPIs can be used to assess a diverse range of smart sustainable cities with different goals. With the proposed KPIs of smart sustainable cities, indicators are divided into four layers for simplicity: the triple bottom line and “satisfaction” lie in the first layer. Since the notion of “society” is broad, it is further split into “safety”, “health”, and “comfort”, which are positioned in the second layer. The third layer includes indicators such as “information security” and “ubiquitous society” from the perspective of information communication technology (ICT). We conducted a trial evaluation by applying the proposed KPIs to individual ICT solutions of “Internet Protocol announcements”, “Wi-Fi around the station” and “information transmission and control” which have already been installed in a smart sustainable city.

Aims/Introduction Imeglimin, a novel oral antidiabetic drug, enhances glucose‐stimulated insulin secretion, improves insulin sensitivity, and reduces mitochondrial reactive oxygen species (ROS) generation. Diabetic neuropathy is driven by oxidative stress caused by hyperglycemia, with mitochondrial ROS overproduction playing a central role. Hypoglycemia also contributes to oxidative stress. This study evaluates the effects of imeglimin on Schwann cells under high‐ and low‐glucose conditions. Materials and Methods We used IMS32 cells, an immortalized mouse Schwann cell line, to investigate cell survival and mitochondrial function under normal, high‐, and low‐glucose conditions. Assessments included mitochondrial oxidative stress, cytochrome c release, mitochondrial membrane potential, oxygen consumption rate (OCR), Complex I activity, and ATP synthesis. Results High‐ and low‐glucose conditions caused cell death, elevated mitochondrial ROS, triggered cytochrome c release, disrupted mitochondrial membrane potential, and increased OCR and Complex I activity, while suppressing ATP synthesis. Imeglimin treatment mitigated cell death, reduced oxidative stress, restored mitochondrial membrane potential, normalized OCR and Complex I activity, and improved ATP synthesis under both glucose conditions. Conclusions Fluctuations in glucose levels impair mitochondrial function in Schwann cells, contributing to peripheral nerve damage in diabetic neuropathy. Imeglimin demonstrated protective effects by alleviating mitochondrial dysfunction and preventing apoptosis signaling. These findings suggest the potential application of imeglimin in preventing and treating diabetic neuropathy; however, the clinical implications require further investigation. Imeglimin reduces Schwann cell death by suppressing Complex I and oxidative stress, which may prevent diabetic neuropathy by protecting mitochondrial functions.

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. We demonstrated that both DHA and EPA could prevent cell death by inducing numerous antioxidants in IMS32 cells. Our findings suggest that enhancements of antioxidative defenses might have therapeutic value in the treatment of diabetic neuropathy.

Aims/Introduction Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68‐positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC‐conditioned media on lipopolysaccharide‐stimulated murine macrophage RAW264.7 cells were investigated. Results Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68‐positive monocytes/macrophages and the gene expressions of M1 macrophage‐expressed cytokines, tumor necrosis factor‐α and interleukin‐1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor‐α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC‐conditioned media significantly increased the gene expressions of interleukin‐10 and CD206 in lipopolysaccharide‐stimulated RAW264.7 cells. Conclusions These results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy. Effects of DPSC transplantation on the inflammatory mRNA expressions in sciatic nerves. Transplantation of DPSCs significantly decreased TNF‐α gene expression and increased the CD206 gene expression in the sciatic nerves compared with the vehicle‐injected side in diabetic rats.

The principal aim of this investigation was to assess the utility of a novel DR score for the early detection of diabetic polyneuropathy (DPN). This score, currently integrated into the RETeval™ electroretinogram (ERG) system, is derived from parameters such as ERG wave characteristics, patient age, and pupillary response. Traditional nerve conduction studies (NCS), though valuable, have notable limitations, including the necessity for costly equipment and specialized personnel. Consequently, it was postulated that the DR score-initially devised for predicting diabetic retinopathy-might serve as a practical alternative for diagnosing DPN. This study sought to test the hypothesis that the DR score could offer a reliable means of both diagnosing DPN and estimating its severity. The study retrospectively analyzed 82 diabetic patients admitted to Aichi Medical University Hospital between November 2016 and January 2019. ERG was performed using the RETeval™ device, and NCS was conducted to classify DPN stages according to the Baba's Differentiation Classification (BDC) system. Multiple regression analysis and receiver operating characteristics (ROC) analysis were employed to assess the relationship between the DR score and DPN stages. Among 82 participants, 24.4% (n = 20) had no DPN (stage 0), and 75.6% (n = 62) had stage 1 or higher DPN. The DR score was significantly correlated with various clinical parameters, including nerve conduction velocities and the severity of DPN as classified by BDC stages. The regression model showed that both the DR score and age were significant predictors of DPN severity. The ROC analysis demonstrated that the DR score had a moderate ability to discriminate between no DPN and stage 1 or more of DPN, with an area under the ROC curve of 0.738. In conclusion, this study involving 82 patients suggests that the DR score may be a valuable tool for the early detection and staging of DPN, potentially offering a more accessible and cost-effective alternative to traditional NCS, with significant implications for improving diabetic care.

The principal causes of death among 45,708 patients with diabetes (29,801 men and 15,907 women) who died in 241 hospitals throughout Japan during 2001–2010 were determined based on a survey of the hospital records. Autopsy had been conducted in 978 of the 45,708 cases. The most frequent cause of death was malignant neoplasia (38.3%), followed by, in order of descending frequency: infections (17.0%); and then vascular diseases (14.9%), including renal failure (3.5%), ischemic heart diseases (4.8%) and cerebrovascular diseases (6.6%). Diabetic coma associated with hyperglycemia with or without ketoacidosis accounted for only 0.6% of the deaths. In regard to the relationship between the age and cause of death in patients with diabetes, the incidence of death due to vascular diseases was higher in patients over the age of 30 or 40 years, and the 97.0% of the total death due to vascular diseases was observed in patients over the age of 50 years. The incidence of death due to infectious diseases, especially pneumonia, increased in an age‐dependent fashion, and the 80.7% of the total death due to pneumonia was observed in patients over the age of 70 years. ’Poorer’ glycemic control was associated with the reduced lifespan of patients with diabetes, especially of those with nephropathy. The average age at death in the survey population was 72.6 years. The lifespan was 1.6 years shorter in patients with ‘poorer’ glycemic control than in those with ‘better’ glycemic control. In patients with diabetes of less than 10 years’ duration, the incidence of death due to macroangiopathy was higher than that due to nephropathy. Of the 45,708 patients with diabetes, 33.9% were on oral medication, 41.9% received insulin therapy and 18.8% were treated by diet alone. Among the patients in whom the cause of death was diabetic nephropathy, a high percentage, 53.7%, was on insulin therapy. The average age at death of the 45,708 patients with diabetes was 71.4 years in men and 75.1 years in women. However, the report of the Ministry of Health and Welfare of Japan in 2010 set the average lifespan of the Japanese at 79.6 years for men and 86.3 years for women. Thus, the average lifespan of patients with diabetes still appears to be shorter than that of the general population in Japan. However, the differences in lifespan between patients with diabetes and the general population were shorter than those in the former surveys. The principal causes of death among 45,708 patients with diabetes (29,801 men and 15,907 women) who died in 241 hospitals throughout Japan during 2001–2010 were determined based on a survey of the hospital records. The most frequent cause of death was malignant neoplasia, followed, in order of descending frequency, by infections and then vascular diseases, including renal failure, ischemic heart diseases and cerebrovascular diseases.

Aims/Introduction The etiology and treatment of type 2 diabetes might differ between specific populations. This post‐hoc exploratory analysis assessed the efficacy and safety of once‐weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long‐term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. Materials and Methods This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post‐hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end‐point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end‐point was change from baseline to end of study in bodyweight (kg). Results Change from baseline to end of study in glycated hemoglobin with once‐weekly semaglutide ranged from −1.32 to −1.85% points in the overall populations, and −1.69 to −2.49% points in Japanese participants. With once‐weekly semaglutide, relative bodyweight was reduced from baseline to end of study by 4.0–7.3% in the overall populations, and 2.7–10.4% in Japanese participants. In the Japanese subpopulation, no new safety concerns were identified with once‐weekly semaglutide, and there were no adverse events leading to death or severe hypoglycemic episodes. Conclusions In this post‐hoc analysis, participants with type 2 diabetes initiating once‐weekly semaglutide experienced improvements in glycated hemoglobin and bodyweight in both the overall and Japanese population, and no new safety concerns were identified among Japanese participants, supporting the efficacy of once‐weekly semaglutide in this population. Etiology and treatment of type 2 diabetes may differ between specific populations. This post hoc exploratory analysis of four phase 3 studies in the SUSTAIN clinical development program found that the efficacy and safety of once‐weekly subcutaneous semaglutide in subjects with type 2 diabetes were comparable in both Japanese subjects and the total study populations.

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. We showed the therapeutic efficacy of dental pulp stem cell‐conditioned media (DPSC‐CM) injection into hindlimb skeletal muscles for diabetic polyneuropathy by neuroprotective, angiogenic and anti‐inflammatory actions. As the use of DPSC‐CM will lead to a reduction of the medical costs, maintenance of DPSC‐CM quality by using selected DPSCs with high viability, and freedom from immune incompatibility and tumorigenicity, DPSC‐CM injection could be a novel therapy for diabetic polyneuropathy.