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Continuous glucose monitoring (CGM)-derived metrics have been used to accurately assess glycemic variability (GV) to facilitate management of diabetes mellitus, yet their relationship with diabetic peripheral neuropathy (DPN) is not fully understood. We performed a systematic review and meta-analysis to evaluate the association between GV metrics and the risk of developing DPN. Nine studies totaling 3,649 patients with type 1 and type 2 diabetes mellitus were included. A significant association was found between increased GV, as indicated by metrics including standard deviation (SD) with OR and 95% CI of 2.58 (1.45-4.57), mean amplitude of glycemic excursions (MAGE) with OR and 95% CI of 1.90 (1.01-3.58), mean of daily difference (MODD) with OR and 95% CI of 2.88 (2.17-3.81) and the incidence of DPN. Our findings support a link between higher GV and an increased risk of DPN in patients with diabetes. These findings highlight the potential of GV metrics as indicators for the development of DPN, advocating for their inclusion in diabetes management strategies to potentially mitigate neuropathy risk. Longitudinal studies with longer observation periods and larger sample sizes are necessary to validate these associations across diverse populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To assess sensory neuropathy development after severe COVID-19., Methods: Patients with severe COVID-19 underwent assessment of neuropathic symptoms, tendon reflexes, and quantitative sensory testing to evaluate vibration (VPT), cold (CPT), warm (WPT) and heat perception thresholds (HPT) within 1-3 weeks of admission and after 1-year., Results: 32 participants with severe COVID-19 aged 68.6 ± 12.4 (18.8 % diabetes) were assessed. At baseline, numbness and neuropathic pain were present in 56.3 % and 43.8 % of participants, respectively. On the feet, VPT, WPT, and HPT were abnormal in 81.3 %, CPT was abnormal in 50.0 % and HPT on the face was abnormal in 12.5 % of patients. At 1-year follow-up, the prevalence of abnormal VPT (81.3 % vs 50.0 %, P < 0.01), WPT (81.3 % vs 43.8 %, P < 0.01), and HPT (81.3 % vs 50.0 %, P < 0.01) decreased, with no change in CPT (P = 0.21) on the feet or HPT on the face (P = 1.0). Only participants without diabetes recovered from an abnormal VPT, CPT, and WPT. Patients with long-COVID (37.5 %) had comparable baseline VPT, WPT and CPT with those without long-COVID (P = 0.07-0.69)., Conclusions: Severe COVID-19 is associated with abnormal vibration and thermal thresholds which are sustained for up to 1 year in patients with diabetes. Abnormal sensory thresholds have no association with long-COVID development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Phi Med Europe S.L. provided the NerveCheck Master device and funded the study. M.N. Odriozola, S. Odriozola, M.B. Odriozola and A. Odriozola are the owners and inventors of the NerveCheck Master. We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship and are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2023. Published by Elsevier B.V.)

Aims: To investigate the prevalence of peripheral artery disease (PAD) and diabetic peripheral neuropathy (DPN) and the associated risk factors among Chinese patients with type 2 diabetes mellitus., Methods: A cross-sectional study was conducted using data between November 1, 2018, and December 31, 2022. PAD was defined as ABI ≤ 0.9. DPN diagnosis involved specialized physician assessments using questionnaires and vibration perception threshold tests. Logistic regression analysis was used to identify related factors. We also evaluated the association between the clustering of risk factors and disease incidence., Results: The study population comprised 13,315 patients (mean age: 63.3 years). 4.9 % of the patients had PAD and 43.9 % had DPN. Multivariate regression analysis revealed advanced age, smoking, hypertension, coronary heart disease, dyslipidemia, elevated HbA1c, and uric acid levels as independent risk factors for PAD. For DPN, independent risk factors included advanced age, female gender, hypertension, coronary heart disease, elevated total cholesterol, triglycerides, lipoprotein(a), fasting plasma glucose, HbA1c, alkaline phosphatase, cystatin C, albumin-to-creatinine ratio, and elevated homocysteine levels, whereas apolipoprotein A was a protective factor. The clustering of risk factors was prevalent and associated with higher disease risk., Conclusions: Our study contributed to identifying high-risk individuals and improving lower limb health among diabetic individuals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Diabetic neuropathy is a common complication of diabetes that affects up to 50% of patients during the course of the disease; 20-30% of the patients also develop neuropathic pain. The mechanisms underlying neuropathy are not known in detail, but both metabolic and vascular factors may contribute to the development of neuropathy. The development of the most common type of neuropathy is insidious, often starting distally in the toes and feet and gradually ascending up the leg and later also involving fingers and hands. The symptoms are mainly sensory with either sensory loss or positive symptoms with different types of paresthesia or painful sensations. In more advanced cases motor dysfunction may occur, causing gait disturbances and falls. The diagnosis of neuropathy is based on history and a careful examination, which includes a sensory examination of both large and small sensory nerve fiber function, as well as an examination of motor function and deep tendon reflexes of the lower limbs. Attention needs to be paid to the feet including examination of the skin, joints, and vascular supply. Nerve conduction studies are rarely needed to make a diagnosis of neuropathy. In patients with clear motor deficit or with an asymmetrical presentation, additional electrophysiological examination may be necessary. Early detection of diabetic neuropathy is important to avoid further irreversible injury to the peripheral nerves., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The diabetic neuropathies represent the commonest long-term complications of diabetes, and may be the presenting feature of Type 2 diabetes. In clinical practice, distal symmetrical polyneuropathy (DSPN) and the autonomic neuropathies are the most frequently seen forms of diabetic neuropathy. The 2017 American Diabetes Association classification system for the neuropathies of diabetes are in general use. Treatment challenges remain and the need for revised recommendations and further discussion of management of severely painful DSPN that does not fully respond to conventional medical management is clear, especially in light of the recent opioid crisis in the USA., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Andrew Boulton has been consultant for Advanced Oxygen Therapy, Inc. and a speaker for Advanced Oxygen Therapy, Inc., Nevro, Novo Nordisk, and Pfizer.]., (Copyright © 2023. Published by Elsevier B.V.)

Background: Diabetic microvascular complications, including diabetic kidney disease (DKD), retinopathy (DR), and neuropathy (DN), were major causes of morbidity and mortality in diabetic patients worldwide. It has been suggested that urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were not the only indicators of renal function impairment in DKD and that they were also associated with diabetic peripheral neuropathy (DPN) which might affect nerve conduction velocity (NCV). As 30-40% of DPN patients had no subjective symptoms, while current perception threshold (CPT) could detect sensory nerve damage at an early stage. As a result, we aimed to investigate correlation between UACR, eGFR and CPT in DKD patients., Methods: A total of 273 DKD patients from the First Affiliated Hospital of Kunming Medical University from January 2018 to June 2020 were enrolled to complete the CPT test. CPT values of the bilateral median nerve and superficial and deep peroneal nerves at 2000 Hz, 250 Hz, and 5 Hz were collected., Results: In normoesthesia and hypaesthesia patients with DKD, MDRD-eGFR correlated negatively with TC (r = -0.135, P = 0.037), left superficial peroneal and deep peroneal nerve 2000 Hz CPT (r = -0.205, P = 0.001) and right superficial peroneal and deep peroneal nerve 2000 Hz CPT (r = -0.154, P = 0.017). Besides, left and right superficial peroneal and deep peroneal nerve 2000 Hz CPT correlated with CKD-EPI-eGFR and UACR. Multivariate logistic regression analysis found left superficial peroneal and deep peroneal nerve 2000 Hz CPT was independently associated with both MDRD-eGFR and CKD-EPI-eGFR., Conclusion: Decreased MDRD-eGFR and CKD-EPI-eGFR were expected to be a predictor of peripheral nerve injury in normoesthesia and hypaesthesia patients with DKD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: The pathophysiological alteration of diabetic neuropathic pain (DNP) in brain is unclear. Here we aimed to explore the metabolomic characteristics of brain in rats over the progression of DNP through metabolomic analysis., Methods: Adult rats were randomly divided into control group and DNP group. Body weight, blood glucose and behavioral assessment of neuropathic pain were measured every week after streptozotocin (STZ) injection. Finally, the brains of 2 rats from control group and 6 rats from DNP group were removed every 4 weeks after STZ injection for metabolomics analysis., Results: After 4 weeks of STZ-injection, the rats with diabetes developed DNP, which was characterized as mechanical allodynia and thermal nociception. As for metabolomic analysis, differentially expressed metabolites (DE metabolites) showed a dynamic alteration over the development of DNP and affected several KEGG pathways associated with amino acid metabolism. Furthermore, the expression of l-Threonine, l-Methionine, d-Proline, l-Lysine and N-Acetyl-l-alanine were significantly decreased at all time points of DNP group. The amino acids which were precursor of analgesic neurotransmitters were downregulated over the progression of DNP, including l-tryptophan, l-histidine and l-tyrosine., Conclusions: The impairment of amino acid metabolism in brain might contribute to the progression of DNP through decreasing analgesic neurotransmitters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Aims: To characterize the distribution and severity of sensory neuropathy using a portable quantitative sensory testing (QST) device in diabetic patients (DM) hospitalized with severe COVID-19 infection., Methods: Four patients with diabetes and severe SARS-CoV-2 requiring non-invasive ventilation for a protracted duration underwent clinical, laboratory and radiologic assessment and detailed evaluation of neuropathic symptoms, neurological assessment, QST on the dorsum of the foot and face using NerveCheck Master with assessment of taste and smell., Results: All four subjects developed neuropathic symptoms characterized by numbness in the feet with preserved reflexes. QST confirmed symmetrical abnormality of vibration and thermal thresholds in both lower limbs in all patients and an abnormal heat pain threshold on the face of two patients and altered taste and smell., Conclusions: Severe COVID-19 infection with hypoxemia is associated with neuropathic symptoms and widespread sensory dysfunction in patients with DM., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Our objective was to assess whether increased duration of metformin therapy is associated with incident peripheral neuropathy (PN) in older Veterans with diabetes., Methods: Using national Veterans Affairs registry data from 2002 to 2015, we examined Veterans (50 + years) with diabetes. Long-term metformin therapy was defined as prescription ≥ 500 mg/day, filled for ≥ 6 consecutive months. Metformin therapy duration was examined both as continuous and categorical measures. Incident PN was defined by medical chart review. We estimated unadjusted and adjusted (variables selecteda priori)odds ratios (OR) and 95% confidence intervals (CI) using logistic regression., Results: The study included n = 210,004 individuals (mean ± SD: age: 66.2 ± 8.4 yrs, 96% male) prescribed metformin for 47.0 ± 34.0 months. Nineteen percent developed PN during follow-up. After adjusting for age, body mass index, duration of time receiving health care within the VA, smoking status, alcohol abuse, and vitamin B12 testing and treatment, the number of months of metformin treatment was associated with elevated odds for incident PN (aOR (metformin treatment - continuous) = 1.009 (95% CI = 1.009, 1.010); aOR (metformin treatment - categorical (ref: 6-<18 months): 18-<44.1 months = 1.57 (1.51-1.63), 44.1-<61 months = 2.05 (1.97-2.14), 61 + months = 2.69 (2.58-2.79), all p-values < 0.0001)., Conclusion: Our study suggests that Veterans treated for at least 18 months with metformin are approximately 2-3 times more likely to develop PN than those treated at least six, but<18 months. Future studies are needed to determine whether the association we found may be due to a decline in vitamin B12 status following metformin initiation., (Published by Elsevier B.V.)

Aims: To test the performance of the cardiac vagal tone (CVT) derived from a 5-minute ECG recording compared with the standardized cardiovascular autonomic reflex tests (CARTs)., Methods: Cross-sectional study included 56 well-phenotyped adults with type 1 diabetes (19-71 years, 2-54 years disease-duration). Autonomic testing included: standardized CARTs obtained with the VAGUS™, CVT, and indices of heart rate variability (HRV) obtained at 24- and 120-hour, and electrochemical skin conductance assessed with SUDOSCAN®. ROC AUC and cut-off values were calculated for CVT to recognize CAN based on ≥ 2 (established CAN, n = 7) or 1 (borderline CAN, n = 9) abnormal CARTs and compared to HRV indices and electrochemical skin conductance., Results: Established CAN: The cut-off CVT value of 3.2LVS showed 67% sensitivity and 87% specificity (p = 0.01). Indices of HRV at either 24-hour (AUC > 0.90) and 120-hour (AUC > 0.88) performed better than CVT. Borderline CAN: The cut-off CVT value of 5.2LVS indicated 88% sensitivity and 63% specificity (p = 0.07). CVT performed better than HRV indices (AUC < 0.72). Electrochemical skin conductance (AUC:0.63-0.72) had lower sensitivity and specificity compared with CVT., Conclusions: Implementation of CVT with a clinically applicable cut-off value may be considered a quicker and accessible screening tool which could ultimately decrease the number of unrecognized CAN and initiate earlier prevention initiatives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Continuous glucose monitoring (CGM)-derived time-in-range (TIR) of 3.9-10 mmol/L is associated with diabetic retinopathy in type 2 diabetes (T2DM), but its relationship to peripheral nerve function has not been previously investigated. To explore the association between the TIR and nerve conduction study parameters in patients with T2DM, we performed a cross-sectional analysis., Methods: A total of 740 patients with T2DM were enrolled in this study. All of the participants were divided into tertiles according to the TIR (TIR low: ≤53%; TIR medium: 54-76%; TIR high: ≥77%). Composite Z-scores of nerve conduction velocity (CV), latency, and amplitude were calculated. The linear correlation between the TIR and composite nerve function Z-score was evaluated and risk assessment was analysed using binary logistic regression., Results: The composite Z-score of the CV and amplitude increased with higher TIR and the composite Z-score of latency significantly decreased as the TIR tertiles increased (all P trend < 0.05). After adjusting for age, diabetes duration, height, weight and other confounding factors, higher TIR was associated with a higher composite Z-score of CV (β = 0.230, P < 0.001), amplitude (β = 0.099, P = 0.010), and lower composite Z-score of latency (β = -0.172, P < 0.001). The risk of TIR tertiles and low composite Z-score of CV remained significant even after adjustment of HbA1c (TIR medium: OR = 0.48, P = 0.001; TIR high: OR = 0.41, P < 0.001)., Conclusions: Higher TIR tertiles were independently associated with better peripheral nerve function. CGM-derived TIR may be a promising approach to screen patients for further assessment of possible diabetic peripheral neuropathy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: To evaluate the natural history of gastric emptying in type 2 diabetes., Methods: 12 patients with type 2 diabetes (7 female; age 65.6 ± 1.2 years; duration of known diabetes 22.9 ± 1.5 years) were invited to return for repeat measurements of gastric emptying using the same dual-labelled solid and liquid meal, a mean of 14.0 ± 0.5 years after their initial study. Blood glucose levels, glycated haemoglobin, upper gastrointestinal symptoms and autonomic nerve function at baseline and follow up were also compared., Results: Gastric emptying of solids was more rapid at follow up than at baseline (period effect P < 0.05), while emptying of liquids was comparable at baseline and follow up (period effect P = 0.2). Gastric emptying of the solid component was abnormally slow (based on T100min) in 6 subjects at baseline and 1 subject at follow up. Liquid emptying was abnormally slow in 6 subjects at baseline, and 5 subjects at follow up. Two patients were insulin treated at baseline, and 6 at follow up. HbA1c was higher at follow up (P < 0.05); however, fasting blood glucose (P = 0.6), postprandial blood glucose excursions (P = 0.07), autonomic nerve function (P > 0.999), and total upper gastrointestinal symptom score (P = 0.1) did not differ., Conclusions: In patients with long-term type 2 diabetes, gastric emptying of solids and liquids does not usually become more delayed over time, and abnormally slow gastric emptying of solids may improve., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: This study is amid at investigating the associations, and interactions of serum lipid biomarkers with microvascular complications of type 2 diabetes (T2D)., Methods: A nested case-control study was conducted within an ongoing prospective study on patients with T2D. Microvascular complications of T2D including diabetic neuropathy, diabetic retinopathy and diabetic nephropathy were investigated. A total of 444 cases with at least one of the microvascular complications of T2D and 439 age- and gender-matched controls free of any of the chronic microvascular complications of T2D were included. The associations and interactions of a panel of serum lipid biomarkers with the microvascular complications of T2D were investigated., Results: Serum triglyceride had the strongest association with microvascular complications of T2D (crude model: β=0.632, P value=0.045). Each standard deviation increment in serum TG was associated with 3.7 times increased frequency of microvascular complications. Despite high density lipoprotein cholesterol (HDL-C), serum apolipoprotein A1 (Apo A1) was positively associated with the presence of diabetic neuropathy. Each standard deviation increment in serum ApoA1 was associated with increased frequency of diabetic neuropathy (OR, 1.2, 95% CI, (1.1-1.3), P value=0.006). The frequency of diabetic neuropathy was higher in 2nd and 3rd quartiles of serum Lp(a) compared to diabetic patients in the first quartile (OR, 5.52, 95% (1.17-25.8), P value=0.047)., Conclusions: ApoA1 but not HDL-C is straightly associated with diabetic neuropathy. Even Slight rise in serum Lp(a) is associated with increased frequency of diabetic retinopathLipid variables could serve as specific predictors of vascular complications in diabetes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Neuropathy is a common diabetic complication that can result in significant disability. Few treatment options exist to reverse this process., Methods: We conducted a one-way crossover cohort study comparing intensive medical treatment and islet cell transplantation for type 1 diabetes on the change in nerve conduction velocity over six years., Findings: For subjects with some neuropathy at baseline (Z score below -1), nerve conduction velocity significantly improved post-transplant (slope (0.073±0.042) while it worsened in medically treated patients (-0.136±0.081) (p<.05)., Interpretation: Islet cell transplantation improves nerve conduction velocity and could be further investigated as a treatment for neuropathy in type 1 diabetes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of our study was to assess the association between the TLR4 Asp299Gly polymorphism and vascular complications in patients with type 2 diabetes., Methods: We examined 1090 patients with T2DM and 716 healthy controls. All subjects were genotyped for the Asp299Gly polymorphism by polymerase chain reaction (PCR) and restriction analysis., Results: The genotype frequencies of the Asp299Gly polymorphism were similar in T2DM patients and controls (p=0.512 and 0.311, respectively). The polymorphism was analyzed in subgroups of patients with macro- and microvascular complications. The distribution of genotypes was significantly different between patients with CVD and those without CVD. A significant increase of G allele frequency was observed in CVD+ patients, with odds ratio 2.06 (1.27-3.34), p=0.0035. The same effect was found when patients with diabetic retinopathy were compared with those without it (OR for G allele 2.12, 95% CI 1.43-3.12, p=0.0002). There were no statistically significant differences in genotype distribution between patients with diabetic nephropathy or neuropathy and those without these complications., Conclusions: The results of our study demonstrated that the G allele of the Asp299Gly polymorphism of the TLR4 gene is associated with increased risk of cardiovascular disease and diabetic retinopathy in type 2 diabetes patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aim: The association between thyroid stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to diabetic peripheral neuropathy (DPN) has not been studied. The aim of this study was to explore the relationship between TSH and DPN in Chinese patients with T2DM., Methods: In this cross-sectional study, 605 patients with T2DM were enrolled. Subclinical hypothyroidism (SCH) was defined as an elevated TSH level (>4.0mIU/L) and a normal free thyroxine level. DPN was evaluated by neurological symptoms, neurological signs, and electromyogram., Results: Serum TSH levels were significantly higher in DPN and signs of DPN compared with non-DPN T2DM patients (both P<0.01).The prevalence of DPN and signs of DPN in SCH subjects was higher than that in euthyroid subjects (both P<0.01). Spearman's correlation analysis showed that the serum TSH level was positively associated with DPN (r=0.172, P<0.01). A significant independent association between TSH and DPN was found by multiple logistic regression analysis after adjusting for potential confounding variables [odds ratio (OR)=1.365, P<0.01]. The patients were sequentially assigned to quartiles according to TSH level. Compared with quartile 1, patients in quartile 2 (P<0.01), quartile 3 (P=0.01), and quartile 4 (P<0.01) had a higher risk of DPN. Receiver-operating characteristic curve analysis revealed that the optimal cutoff point of TSH to indicate DPN was 3.045mIU/L in men and 2.94mIU/L in women., Conclusion: TSH level is independently associated with DPN in Chinese population with T2DM. A high serum TSH level may be a potential risk factor for DPN., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Diabetic neuropathy (DNP) is a frequent and serious complication of diabetes mellitus (DM) that leads to progressive and length-dependent loss of peripheral nerve axons. The purpose of the present study is to assess the neuroprotective effects of levetiracetam (LEV) on DNP in a streptozotocin (STZ)-induced DM model in rats., Methods: Adult Sprague-Dawley rats were administered with STZ (60mg/kg) to induce diabetes. DNP was confirmed by electromyography (EMG) and motor function test on 21st day following STZ injection. Study groups were assigned as follows; Group 1: Naïve control (n=8), Group 2: DM+1mL/kg saline (n=12), Group 3: DM+300mg/kg LEV (n=10), Group 4: DM+600mg/kg LEV (n=10). LEV was administered i.p. for 30 consecutive days. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and total anti-oxidant capacity), histological and immunohistochemical analysis of sciatic nerves (TUNEL assay, bax, caspase 3, caspase 8 and NGF) were performed to evaluate the efficacy of LEV., Results: Treatment of diabetic rats with LEV significantly attenuated the inflammation and fibrosis in sciatic nerves and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves showed a considerable increase in bax, caspase 3 and caspase 8 and a decrease in NGF expression in saline-treated rats whereas LEV significantly suppressed apoptosis markers and prevented the reduction in NGF expression. Besides, LEV considerably reduced plasma lipid peroxides and increased total anti-oxidant capacity in diabetic rats., Conclusions: The results of the present study suggest that LEV may have therapeutic effects in DNP through modulation of anti-oxidant and anti-apoptotic pathways., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of this study is to evaluate the role of current perception threshold (CPT) measurement in peripheral neuropathy in type 1 diabetic patients by using the Neurometer(®), a nerve measuring instrument., Methods: 52 patients with type 1 diabetes mellitus with a disease duration of less than five years and normal neuropathy symptom score (NSS), neuropathy disability score (NDS) and sensory nerve conduction velocity (SCV), and 40 healthy controls were enrolled in this study. Measurement of CPT using the Neurometer(®) at 2000, 250 and 5 Hz assesses function in the bilateral median nerve and sural nerve in all studied cases. We also evaluated the glycated hemoglobin, microalbuminuria, urinary albumin/creatinine ratio and other metabolism indexes of all patients., Results: The CPT of the bilateral median nerve and sural nerve was significantly lower in diabetic patients (P<0.01). Moreover, the number of median nerve injuries in the diabetic group (left side 8/52, right side 8/52) is significantly different from the number of its ipsilateral sural nerve injuries (left side 28/52, right side 22/52) (left side P<0.01, right side P<0.01). By comparing those with DPN and those without DPN in the diabetic group, DPN groups had significantly higher glycated hemoglobin (t=2.518, P<0.05). Using binary logistic regression, high glycated hemoglobin was identified to be an independent risk factor of DPN incidence (OR (95% CI): 1.317 (1.013 -1.712), P<0.05)., Conclusion: These data suggest that CPT is useful in early detection of peripheral neuropathy in patients with type 1 diabetes mellitus. Patients with diabetic peripheral neuropathy, the lower limb nerve is more vulnerable than the upper limb nerve. In addition, patients with DPN had higher glycated hemoglobin which is an independent risk factor of DPN., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: To determine the prevalence and risk factors for painful diabetic peripheral neuropathy (PDPN) and evaluate sleep impairment and quality of life in patients with PDPN., Methods: Data from the Korean Diabetes Association Neuropathy Study Group were used to evaluate 3999 patients with type 2 diabetes. PDPN was diagnosed using visual analogue scales (VAS) and medical history. The patients were asked to answer the Brief Pain Inventory-Short Form (BPI-SF), Medical Outcomes Study Sleep (MOS-Sleep) Scale, EuroQol (EQ-5D), and VAS., Results: Among the patients with diabetic peripheral neuropathy (n=1338), 577 (43.1%) were diagnosed with PDPN (14.4% of all patients with type 2 diabetes). PDPN was independently associated with age, female gender, fasting plasma glucose, hypertension, and previous cerebrovascular events. All pain severity and interference measures were higher in patients with PDPN than in non-PDPN patients, and patients with PDPN reported more impaired sleep and lower EQ-5D and VAS scores., Conclusions: The prevalence of PDPN in Koreans was comparable to that in Western populations. PDPN may impair sleep and quality of life compared with non-PDPN, and physicians should carefully consider pain symptoms in patients with diabetic peripheral neuropathy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Of 151 youth with type 1 diabetes who were screened for peripheral neuropathy, and received nerve conduction studies, 11% were diagnosed with Diabetic Peripheral Neuropathy (DPN). DPN can occur in young children, with short diabetes duration, and good diabetes control. National guidelines for screening children for DPN should be developed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aims: Hyperglycemia causes generation of free radicals which leads to oxidative stress and apoptosis in various cells. The present study was undertaken to investigate the correlation between oxidative stress and apoptotic markers in lymphocytes of diabetic patients with chronic non healing wounds., Methods: Thirty healthy, thirty uncontrolled type 2 diabetes mellitus (T2DM) and thirty uncontrolled T2DM with chronic, non healing, neuropathic diabetic foot patients were included in this study. Indices of oxidative stress inside the lymphocyte lysate were estimated by measuring content of superoxide dismutase (SOD), Catalase, Glutathione and malonaldialdehyde (MDA). Protein expression studies of pro and anti apoptotic markers were carried out to elucidate their possible involvement in diabetic context., Results: SOD and MDA activity was significantly higher in the lymphocytes of diabetic patients having chronic, non healing diabetic wound as compared with healthy (p<0.001); whereas catalase and GSH activity was significantly reduced (p<0.001) in the same group. Expressions of pro apoptotic markers (Caspase-3, Fas and Bax) were significantly higher whereas reduced expression of anti-apoptotic marker (Bcl-2) were obtained in lymphocytes of diabetic and non diabetic individuals., Conclusions: Hyperglycemia confers pro apoptotic manifestations which are mostly through altered indices of oxidative stress within lymphocytic milieu., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aim: To explore the relationship between plasma total homocysteine concentration and diabetic neuropathy in Chinese patients with type 2 diabetes., Methods: Chinese patients with type 2 diabetes (n=249) were enrolled in a cross-sectional hospital based study. Diabetic neuropathy status was documented by presence of clinical signs and confirmed by electromyography. Plasma total homocysteine concentration was measured using fluorescence polarization immunoassay. Traditional risk factors for diabetic neuropathy were obtained from fasting blood samples and interviewer-questionnaire., Results: Plasma total homocysteine levels were higher in subjects with diabetic neuropathy than without (12.8 (9.2-14.8) μmol/l vs. 8.0 (7.7-9.1) μmol/l, p=0.005). The association of homocysteine with diabetic neuropathy was independent of major traditional risk factors for diabetic neuropathy (duration of diabetes, HbA1c) and determinants of higher homocysteine concentration (age, gender, serum folate and vitamin B12, renal status, and Biguanide use) (OR: 1.12 (1.00-1.25), p=0.042). Furthermore, per increase of 4.0 μmol/l plasma homocysteine was related to neuropathy, after controlling for per unit increase of other factors (OR: 1.17 (0.94-1.33), p=0.045)., Conclusion: Plasma total homocysteine concentration was independently associated with occurrence of diabetic neuropathy in Chinese people. Future prospective studies are warranted to clarify the relationship., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Distal symmetrical polyneuropathy (DSP) is the most common type of diabetic neuropathy, but often difficult to diagnose reliably. We evaluated the cross-sectional association between three point-of-care devices, Vibratron II, NC-stat(®), and Neurometer(®), and two clinical protocols, MNSI and monofilament, in identifying those with DSP, and/or amputation/ulcer/neuropathic pain (AUP), the two outcomes of major concern. This report presents data from 195 type 1 diabetic participants of the Epidemiology of Diabetes Complications (EDC) Study attending the 18-year examination (2004-2006). Participants with physician-diagnosed DSP, AUP or who were abnormal on the NC-stat, and the Vibratron II, MNSI, and monofilament were older (p<0.05) and had a longer duration of diabetes (p < 0.05). There was no difference by sex for DSP, AUP, or any testing modality, with the exception of NCstat (motor). The Vibratron II and MNSI showed the highest sensitivity for DSP (>87%) and AUP (>80%), whereas the monofilament had the highest specificity (98% DSP, 94% AUP) and positive predictive value (89% DSP, 47% AUP), but lowest sensitivity (20% DSP, 30% AUP). The MNSI also had the highest negative predictive value (83%) and Youden's Index (37%) and currently presents the single best combination of sensitivity and specificity of DSP in type 1 diabetes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aims: To determine the relationships between cardiovascular autonomic neuropathy (CAN) and autonomic symptoms, clinical parameters and diabetic complications in type 2 diabetes (T2DM)., Methods: The results of autonomic symptoms, clinical parameters, diabetes complications and cardiovascular reflex (CVR) tests of 674 T2DM were analyzed., Results: Significant correlations were found between CAN risk and age (p=0.019), duration of diabetes (p=0.008), HbA1c (p<0.001), systolic blood pressure (p=0.006), nephropathy (p<0.001), retinopathy (p<0.001), and QTc interval (p<0.001), but not BMI and hyperlipidemia. Patients with retinopathy or proteinuria had increase risk of CAN, and proliferative diabetic retinopathy (PDR) was the most significant risk factor (odds ratio: 6.85; 95% CI: 2.32-20.20) for CAN. Eighty-three percent of patients complained of autonomic symptoms; and the more symptoms complained, the higher the prevalence of CAN. Impotence was the only single symptom associated with CAN risk. Additional CAN risks were also observed when patients with multiple symptoms and/or complications in combinations., Conclusions: Our results implied that patients with multiple symptoms and/or complications in combinations have increased CAN risk, and this may provide additional information for clinicians to identify T2DM at risk of having CAN.

The aim of this study was to evaluate the relationship between the diagnosis of metabolic syndrome (MetS) or its components and the prevalence of microvascular and macrovascular complications in 130 Japanese type 2 diabetic patients. Out of the 130 patients, 58.5% satisfied the criteria of the MetS as defined by the IDF guideline. The results of logistic regression analysis with adjustment for three variables (age, gender and duration of diabetes) revealed that the presence of MetS as defined by the IDF guideline was not independently related to the presence of proliferative retinopathy, proteinuria, neuropathy, or macrovascular disease in the diabetic patients. The waist circumference per se was not associated with diabetic neuropathy, retinopathy, nephropathy, or macrovascular diseases. These results suggest that neither the presence of MetS, as defined by the IDF guideline, nor the waist circumference was associated with the presence of either microvascular or macrovascular complications in Japanese type 2 diabetic patients.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an ubiquitous DNA-binding protein involved in the cellular response to various genotoxic agents. Excessive PARP-1 activation is known to lead to the depletion of intracellular NAD+ and ATP pools and hence to threat cell survival. Therefore, PARP-1 could be involved in neuronal death and contribute to the development of diabetic polyneuropathy (DPN). This study addressed the association of Leu54Phe and Val762Ala polymorphisms of PARP-1 with DPN in Russian type 1 diabetic (T1D) patients. Eighty-six T1D patients with severe DPN and 93 T1D patients with no clinical signs of DPN have been studied by a polymerase chain reaction restriction fragment length polymorphism approach. Using Fisher's exact test revealed the association of the Phe54 and Val762 variants of PARP-1 (odds ratio (OR), 1.66 and 2.88, respectively) with increased risk of DPN in T1D. These results suggest that the PARP1 gene is involved in the pathogenesis of diabetic neuropathy in a Russian population. Additionally, a logistic regression analysis revealed a significant association between the neurological variances such as vibration detection threshold (OR, 2.08), vibration and temperature perception thresholds (OR, 1.32 and 1.67, respectively), and sensory and motor nerve conduction velocities (OR, 2.34 and 2.58, respectively), with DPN.

To test a simplified protocol to screen type 2 diabetic patients (DM2) for distal polyneuropathy (DPN), 80 outpatients and 45 controls answered a symptom questionnaire, underwent a directed examination (pin-prick, tuning fork, monofilament, ankle jerk, cold spatula and walking on heels), autonomic tests, and an electroneurophysiological study (EMG). Symptoms were also analysed as scores. DPN was diagnosed in the presence of abnormal EMG (or autonomic neuropathy), plus one symptom or one abnormal objective finding. Symptoms were equally frequent in patients (56%) and controls (35%, P=0.20). Objective findings were more frequent in patients (62/80 versus 11/45; P<0.05). The 60 DM2 patients with DPN were older, with longer diabetes duration and more often hypertensive than those without DPN. The 15 patients unable to walk on heels had DPN (sensitivity 20.8%, specificity 100%, positive predictive value 100% and negative predictive value 12.3%). The 12 patients able to walk on heels but with three or more abnormal tests had DPN (sensitivity 21.1%, specificity 100%, positive predictive value 100% and negative predictive value 15.1%). Isolated signs and symptoms do not identify patients with DPN. Patients with higher degrees of impairment can be identified by six simple ambulatory tests, reducing in one-third the need for EMG.

Prevalence of complications of type 2 diabetes in a remote Australian Indigenous community was measured as part of a population survey of risk factors for diabetes and cardiovascular disease. Information was obtained from history, clinical examination, blood sample and medical records. Forty-three diabetic participants (six newly diagnosed) were assessed from a sample of 339 (12% diabetes prevalence); mean age 50 (range 31-67), duration of diabetes 5.6 (0-15) years, 40% male. Risk factors/complications: 70% with >/= 25, 50% cigarette smokers, HbA1c 8.5 (S.D. 2.9)%, cholesterol 4.8 (0.8)mmol/l, triglycerides 2.7 (1.6)mmol/l, HDL 0.83 (0.2)mmol/l; 60% had albuminuria (micro 38%, macro 22%), 47% were hypertensive, 7% (n = 2) had retinopathy, 24% had peripheral neuropathy, none had peripheral vascular disease, 14% had documented coronary vascular and one participant cerebrovascular disease. Of 37 with previously diagnosed diabetes: 43% were on aspirin, 65% on metformin, 80% with albuminuria on ACE inhibitors. Four additional diabetic participants (not studied) were receiving renal dialysis elsewhere. The results demonstrate on the one hand, very high indices of cardiovascular risk (smoking, hypertension, dyslipidaemia and albuminuria) and on the other, good quality primary health care providing good detection and follow up management of type 2 diabetic patients.

This study examined healthcare costs for medication-using diabetic patients in Taiwan and predicted which factors were associated with costs. We analyzed claims data from the National Health Insurance (NHI) program in Taiwan from 1998 to 1999. The approach included estimates of costs attributable to diabetes, diabetes-related complications, comorbidity incurred by diabetic patients. A multiple regression model was used to assess the contribution of patients' characteristics in 1998 on outpatient, inpatient, and total costs in 1998 and 1999. The prevalence of medication-using patients with diabetes was 2.6% in 1998 and 2.8% in 1999. Costs of healthcare were 13.3% of total costs of NHI in 1998 versus 13.0% in 1999. Health services delivered near the end of life consumed large portions of medical dollars. The three most prevalent clinical associations of diabetes were congestive heart failure, neuropathy, and ischemic heart disease. Adjusted for demographic and clinical characteristics in 1998, this model could explain 8.0, 9.3, and 12.5%, respectively, of the cost variation in outpatient, inpatient, and total costs in 1999.

Postural stability was measured in 50 patients classified into two diabetic groups: insulin-dependent diabetes mellitus (IDDM: n = 27), and diabetic patients with bilateral cutaneous sensory deficit in the foot (CD: n = 23). All patients were matched to 50 non-diabetic controls on age, weight and gender variables. The integrity of cutaneous sensory information at the foot was assessed using a monofilament test. Static and dynamic balance was evaluated using an objective balance test involving computer-controlled dual force platforms enclosed by a visual surround. The apparatus provided six test conditions designed to systematically manipulate or eliminate visual, vestibular or somatosensory information. Scores for the six tests, and a derived composite balance score together with movement strategy scores were used for data analysis. For all six tests and composite score CD patients revealed significant postural instability compared to controls. Additionally, the CD group recorded reduced strategy scores indicating an atypical shift from ankle to hip strategy movement as postural control was stressed. IDDM patient test scores were not significantly different from control data on any pairwise comparison. Results indicated significant balance loss associated with CD putting the individual at increased risk for falling and compromising foot mechanics.

The level of erythrocyte aldose reductase protein (AR-p) was determined in diabetic patients as well as in 76 healthy controls by a two-site enzyme-linked immunosorbent assay. No significant difference in the mean AR-p level was demonstrated between the healthy and diabetic individuals. Based on the results of seven nerve function tests, 95 non-insulin-dependent diabetes mellitus (NIDDM) patients were classified into two groups: Group I, without demonstrable neuropathy ( < or = 1 abnormal test results); Group II, overt neuropathy ( > or = 2 abnormal results). The AR-p level was significantly higher in Group II than that in Group I. Multivariate logistic regression analysis identified two independent risk factors for overt neuropathy: longer duration of diabetes after clinical diagnosis (odds ratio, 1.15 per year; 95% confidence interval, 1.05-1.25) and a higher level of AR-p (odds ratio, 1.92 per 1 ng mgHb(-1); 95% confidence interval, 1.39-2.65). On 31 patients the AR-p level was re-assessed after a 12-month follow-up period. Irrespective of improved or stable HbA(1c) levels during the follow-up period, no apparent alteration in the level of AR-p was demonstrated. These results suggest that erythrocyte AR-p level may affect the susceptibility or development of diabetic neuropathy in NIDDM patients.

In 97 IDDM and 64 NIDDM patients aged under 65 years, we evaluated the relationship between autonomic neuropathy (AN) and retinopathy, nephropathy, glycemic control and cardiovascular risk factors. Diabetes duration and HbA1 were significantly higher and body mass index was significantly lower in IDDM patients with AN compared to those without. In NIDDM only age was significantly higher in neuropathic patients. AN was associated with retinopathy in both IDDM (chi2 = 10, P < 0.03) and NIDDM patients (chi2 = 14, P < 0.007), while only in IDDM albumin excretion was significantly higher in patients with AN. Blood pressure (BP) was significantly higher in both IDDM and NIDDM patients with AN compared to those without. There were no differences in smoking and serum lipids between patients with and those without AN. We performed a multiple regression analysis using autonomic score, index of cardiovascular tests impairment, as the dependent variable and age, diabetes duration, body mass index, HbA1, albumin excretion, cholesterolemia, triglyceridemia, systolic BP, and retinopathy as independent variables. With this model in IDDM autonomic score was only related to body mass index (r = -0.29, P < 0.05), to HbA1 (r = 0.46, P < 0.001), and to systolic BP (r = 0.24, P < 0.05), while in NIDDM it was only related to systolic BP (r = 0.54, P < 0.001). In conclusion, AN was related to age in NIDDM, and to diabetes duration and glycemic control in IDDM. AN was associated with retinopathy, with nephropathy (only in IDDM), and with BP levels, but not with dyslipidemia, smoking, or obesity. Excess mortality rate observed in diabetic AN cannot be referred to an association with cardiovascular risk factors.

In an attempt to identify the potential risk factors for diabetic neuropathy in patients recently diagnosed as diabetics, 742 non-insulin-dependent diabetics under 70 years of age who had been diagnosed as diabetics less than 5 years before the initial visit were examined in a cross-sectional study conducted at a university hospital. Neuropathy was defined as the presence of symptoms consistent with distal polyneuropathy, or the absence of tendon reflexes. Of the patients, 21% displayed neuropathy in this study, with no differences between the genders. Age was higher, duration of diabetes was longer, body mass index was lower, and fasting plasma glucose level was higher in patients with neuropathy than in those without neuropathy, for both genders. Body height, maximal body mass index, ethanol use, smoking status, systolic and diastolic blood pressure and serum cholesterol level did not differ between the two groups. Logistic regression analysis showed that fasting plasma glucose level (chi 2 = 28.2) was a major determinant for neuropathy independent of diabetes duration (9.5), age (6.2) and maximal body mass index (3.9). Tight glycemic control from the onset of diabetes was concluded to be essential for the prevention of diabetic distal polyneuropathy.

Human and animal studies were performed to investigate the causes of diabetic autonomic neuropathy. Human diabetics, with and without autonomic neuropathy, were measured for plasma catecholamine response to insulin hypoglycemia and for urinary catecholamine excretion. In streptozotocin-diabetic rats, plasma catecholamine response and tissue catecholamine concentrations were measured at various stages of the disease. As the duration of the diabetic state lengthens in rats, there is a time-proportional stepwise decrease in plasma catecholamine response. This is similar to the clinical course observed in human diabetics, which also includes a reduction of catecholamine excretion after the appearance of autonomic neuropathy. After 6 weeks of diabetes, rat tissue is found to have an increased concentration of catecholamines; this may represent a compensatory reaction to the difficulties of secretion. At 13 weeks of diabetes, tissue catecholamine concentrations return to almost normal, when plasma responses have disappeared. These results suggest that the impaired secretion of catecholamines in diabetics may be a cause of diabetic autonomic neuropathy.