Versican maintains the homeostasis of adipose tissues and regulates energy metabolism.

Versican is a large chondroitin sulfate proteoglycan in the extracellular matrix. It plays a pivotal role in the formation of the provisional matrix. S100a4, previously known as fibroblast-specific protein, functions as a calcium channel-binding protein. To investigate the role of versican expressed in fibroblasts, we generated conditional knockout mice in which versican expression is deleted in cells expressing S100a4. We found that S100a4 is expressed in adipose tissues, and these mice exhibit obesity under a normal diet, which becomes apparent as early as five months. The white adipose tissues of these mice exhibited decreased expression levels of S100a4 and versican and hypertrophy of adipocytes. qRT-PCR showed a reduced level of UCP1 in their white adipose tissues, indicating that the basic energy metabolism is diminished. These results suggest that versican in adipose tissues maintains the homeostasis of adipose tissues and regulates energy metabolism.

Docosahexaenoic Acid Suppresses Oxidative Stress-Induced Autophagy and Cell Death via the AMPK-Dependent Signaling Pathway in Immortalized Fischer Rat Schwann Cells 1.

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.

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

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.

Is Regenerative Medicine Ready for Prime Time in Diabetic Polyneuropathy?

PURPOSE OF REVIEW: After a prolonged warm-up period of basic research, several modalities of cell replacement therapies are under development for diseases with no available cure. Diabetic polyneuropathy (DPN) is one of the most prevalent chronic diabetes complications that causes sensorimotor dysfunction, subsequent high risks for lower limb amputations, and high mortality. Currently, no disease modifying therapy exists for DPN. RECENT FINDINGS: Several types of well-documented stem/progenitor cells have been utilized for cell transplantation therapies in DPN model rodents: mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and cells with similar characteristics of MSCs or EPCs derived from embryonic stem cells or induced pluripotent stem cells. Some recent experimental studies reported that these immature cells may have beneficial effects on DPN. Although the role of nerve regeneration in the pathology of DPN has not been sufficiently elucidated, many intervention studies attempting regenerative therapy of DPN have been reported. Further studies are needed to better evaluate the potential of regeneration in reversing the pathology of DPN.

Renal function evaluation in patients with cancer who were scheduled to receive carboplatin or S-1.

BACKGROUND: Accurate glomerular filtration rate (GFR) evaluation is significant for drug dosing of carboplatin, anticancer drug excreted mainly from kidney. Serum cystatin-C (sCys-C) is a GFR marker with little affected by body muscle mass volume. And GFR equations based on serum creatinine (eGFRcreat) and sCys-C (eGFRcys) were developed; however, accuracy of eGFRcys has not been elucidated fully among patients with cancer. Therefore, we analyzed the performance of GFR equations among patients with cancer whose GFR values were measured by inulin clearance (Cin). METHODS: Study design was a cross-sectional study. Subjects were 41 patients with cancer whose GFR values were measured by Cin for drug dosing studies of carboplatin or S-1 in Nagoya University Hospital from 2007 to 2010 and 29 non-cancer patients. Correlation with Cin and slope of regression line were evaluated in eGFRcreat and eGFRcys. Single and multiple regression analyses were analyzed to identify associating factors with eGFRcreat/Cin or eGFRcys/Cin. RESULTS: Age, body weight, body mass index (BMI) and sCr were different between cancer patients and non-cancer patients, but sCys-C and Cin were consistent in 2 groups. The slope of the regression line for Cin vs. eGFRcys with zero intercept in cancer patients was 1.10 (95 % CI: 1.02-1.17), which was significantly different from 1.0. In multiple regression analysis revealed that BMI and urinary creatinine excretion were significantly associated with eGFRcreat/Cin, and cancer was only associating factor with eGFRcys/Cin. CONCLUSION: eGFRcys should not be used for evaluation of renal function in patients with cancer because it underestimates GFR.

[Diabetic neuropathy].

Diagnostic criteria of diabetic neuropathy that can be easily used at bedsides and have international consensus have not been established. The most important therapeutic strategy is to maintain strict glycemic control. In addition, treatment with an aldose reductase inhibitor that is innovated from the viewpoint of the pathogenesis of diabetic neuropathy would be useful for preventing the progression of diabetic neuropathy. For painful diabetic neuropathy, pregabalin and duloxetine effectively relieve the pain, and contribute to the improvement of the quality of life.

[Diabetic neuropathy].

Diabetic neuropathy is one of the major three diabetic complications, together with diabetic retinopathy and nephropathy. It develops early and with a high incidence after the onset of diabetes mellitus and influences the QOL and prognosis of patients with diabetes mellitus. Although the exact mechanism by which hyperglycemia causes nerve damage remains a subject of debate, metabolic and vascular disturbances due to hyperglycemia are assumed to cause nerve damage. The treatments of diabetic neuropathy aim at both the inhibition of its onset and progression (causative treatment) and the care for symptoms due to neuropathy such as pain(symptomatic treatment). In this paper, we describe the outlines of these two kinds of treatment for diabetic neuropathy.

Spironolactone inhibits production of proinflammatory mediators in response to lipopolysaccharide via inactivation of nuclear factor-κB.

The effect of spironolactone (SPIR) on lipopolysaccharide (LPS)-induced production of proinflammatory mediators was examined using RAW 264.7 macrophage-like cells and mouse peritoneal macrophages. SPIR significantly inhibited LPS-induced production of nitric oxide (NO), tumor necrosis factor-α and prostaglandin E2. The inhibition was not mediated by cell death. SPIR reduced the expression of an inducible NO synthase mRNA in response to LPS. SPIR significantly inhibited phosphorylation of p65 nuclear factor (NF)-κB in response to LPS. Furthermore, SPIR inhibited phosphorylation of IκB kinase (IKK) as an upstream molecule of NF-κB in response to LPS. LPS did not induce the production of aldosterone in RAW 264.7 cells. Taken together, SPIR is suggested to inhibit LPS-induced proinflammatory mediators via inactivation of IKK/NF-κB in LPS signaling.

Hyperglycaemia Aggravates Oxidised Low-Density Lipoprotein-Induced Schwann Cell Death via Hyperactivation of Toll-like Receptor 4.

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.

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).

Aim/introduction: This study aims 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 (JDCP) study. Materials and methods: In the study, 6338 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 t test, chi-square 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. Results: Of the total participants, 5451 patients (mean age 61.4 years old and 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 risk for DSPN: age [odds ratio (OR) 1.57, 95% confidence intervals (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 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). Conclusions: The baseline survey clarified the prevalence and characteristics of DSPN in Japanese patients with type 2 diabetes. The survey also revealed the risk factors of DSPN.

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).

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.

Simplified electrophysiological approach combining a point-of-care nerve conduction device and an electrocardiogram produces an accurate diagnosis of diabetic polyneuropathy.

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.

The efficacy of switching basal-bolus insulin therapy to basal insulin-supported oral therapy with a glinide and an α-glucosidase inhibitor in patients with type 2 diabetes depends on insulin secretory capacity, but not on blood glucose profiles and insulin dosages prior to the switching.

Aims: We aimed to identify patients who would benefit from basal insulin-supported oral therapy (BOT) with a glinide and an α-glucosidase inhibitor (a fixed-dose combination tablet of mitiglinide 10 mg and voglibose 0.2 mg) in Japanese type 2 diabetic patients. Methods: Patients who were hospitalized to improve hyperglycemia received basal-bolus insulin therapy. After the reduction of glucose toxicity, a 75 g oral glucose tolerance test and a glucagon test were performed. Thereafter, the basal-bolus insulin therapy was switched to BOT with mitiglinide, followed by further addition of voglibose. Interstitial glucose levels were continuously monitored throughout the study period. Diurnal glucose profile was recorded and analyzed. Patients were divided into two groups according to whether their percentage of time in range (TIR, 70-180 mg/dL) under BOT with mitiglinide/voglibose was higher than 70% or not, and the differences in clinical characteristics between the groups were analyzed. Results: Twenty patients were enrolled, and 19 of them completed the study. BOT with mitiglinide/voglibose achieved ≥ 70% of TIR in thirteen patients. The area under the curve of serum C-peptide levels during the oral glucose tolerance test was significantly higher in the patients with ≥ 70% of TIR. The daily insulin dosages and blood glucose profiles were comparable between the two groups. Conclusions: The efficacy of BOT with mitiglinide/voglibose depended on residual insulin secretory abilities. This therapy would be a useful therapeutic option for patients with type 2 diabetes.

Correction: A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-022-00605-x.].

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

Aims: Muscle atrophy is a diabetic complication, which results in a deterioration in glycemic control in type 2 diabetes mellitus (T2DM) individuals. The psoas muscle mass index (PMI) is a reliable indicator for estimating whole-body muscle mass. We aimed to examine the relationship between clinical parameters and the PMI to clarify the mechanism underlying muscle atrophy in diabetes. Methods: This retrospective, cross-sectional study examined 51 patients (31 men and 20 women) with T2DM and a mean HbA1c value of 9.9 ± 1.7%. These patients were admitted to Aichi Medical University Hospital and underwent abdominal computed tomography imaging from July 2020 to April 2021. Multiple clinical parameters were assessed with the PMI. Results: In a multiple regression analysis adjusted for age and sex, the PMI was correlated with body weight, body mass index, serum concentrations of corrected calcium, aspartate aminotransferase, alanine aminotransferase, creatine kinase, thyroid-stimulating hormone (TSH), urinary C-peptide concentrations, the free triiodothyronine/free thyroxine (FT3/FT4) ratio, and the young adult mean score at the femur neck. Receiver operating characteristic curves were created using TSH concentrations and the FT3/FT4 ratio for diagnosing a low PMI. The area under the curve was 0.593 and 0.699, respectively. The cut-off value with maximum accuracy for TSH concentrations was 1.491 µIU/mL, sensitivity was 56.1%, and specificity was 80.0%. Corresponding values for the FT3/FT4 ratio were 1.723, 78.0, and 66.7%, respectively. Conclusion: TSH concentrations and the FT3/FT4 ratio are correlated with the PMI, and their thresholds may help prevent muscle mass loss in Japanese individuals with T2DM.

[Radiation-induced skin injuries].

Early radiation dermatitis develops after large doses of X-radiation. Inflammatory erythema develops within about a week. This may heal with desquamation and pigmentation. If the dose was high enough, painful blisters may develop at the site of erythema. In that case, healing usually takes place with atrophy, teleangiectasia, and irregular hyperpigmentation. Subsequent to very large doses, ulceration occurs, generally within 2 months. Such an ulcer may heal ultimately with severe atrophic scarring. Chronic radiation dermatitis occurs from a few months to many years. The skin shows atrophy, teleangiectasia, and irregular hyper- and hypopigmentation. Ulceration may be seen within the areas of atrophy. Radiation ulcerations should be studied by biopsy if they have been present for three or more months. After a long latent period, various malignant neoplasms may form. Most frequent is the basal cell carcinoma, followed by squamous cell carcinoma.

Not out of the woods yet: "Diabetic neuropathy" or "neuropathy associated with diabetes"?

The most frequent diabetic complication, diabetic neuropathy, lacks accessible objective assessments. The concept and definition of diabetic neuropathy should be rethought to achieve the successful development of diagnostic and therapeutic methods.

Multifocal Neuroarthropathy of the Knee and Foot Induced by Physical Training of the Lower Extremities in a Patient With Latent Autoimmune Diabetes in Adults.

Charcot neuroarthropathy is a progressive arthropathy associated with neuropathy. In patients with diabetes, Charcot neuroarthropathy mostly affects the foot. In the present case, we encountered a rare presentation of Charcot neuroarthropathy of the knee and foot in a patient with latent autoimmune diabetes in adults. The patient, who may have developed the disease as a result of inappropriate physical exercise, was treated with total knee arthroplasty.

Thermal gradient ring reveals thermosensory changes in diabetic peripheral neuropathy in mice.

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.