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We present a compelling case of uncontrolled diabetes, who initially presented as diabetic lumbosacral radiculoplexus neuropathy (DLRPN), with radicular pain in the right lower limb (LL) followed by asymmetric weakness of both LLs (right greater than left) with wasting in the medial compartment of the right thigh and significant sensory loss in the bilateral sural and right saphenous nerve distribution. Electrophysiology was suggestive of right lumbosacral radiculoplexus neuropathy. Incidentally, the patient tested positive for HIV-1 at our tertiary care center. CSF analysis revealed markedly elevated protein levels (>400 mg/dL) with lymphocytosis, a red flag for DLRPN. This observation led to further workup. Nerve biopsy showed large collections of perivascular endoneurial and epineurial lymphoid inflammatory cells, which favored an alternative diagnosis. This case highlights the intricate interplay between HIV infection, diabetes, and neurologic manifestations, challenging the initial clinical suspicion of DLRPN. This study emphasizes the importance of considering atypical presentations of neuropathy, especially in the context of coexisting medical conditions, and emphasizes the significance of comprehensive diagnostic workup, including CSF studies and nerve biopsy, for an accurate diagnosis.

Diabetic neuropathy, including autonomic neuropathy is a serious complication related to type 2 diabetes mellitus (T2D). The vagus nerve (VN) is the longest nerve in the autonomic nervous system, and since diabetic neuropathy manifests first in longer nerves, the VN is commonly affected in early diabetic autonomic neuropathy. The use of high-resolution ultrasound for peripheral and cranial nerve imaging has significantly increased over the past 2 decades. The aim of the study is to compare the cross-sectional area of the VN in patients with T2D to that of a control cohort without T2D. A total of 52 VN cross-sectional areas were recorded from patients with T2D. A total of 56 VN cross-sectional areas were also recorded from asymptomatic subjects without T2D. In each subject, high-resolution ultrasound imaging of the bilateral VNs was performed in the short-axis between the common carotid artery and the internal jugular vein. The VN cross-sectional areas were recorded and compared. In the patients with T2D, HbA1c and fasting blood glucose levels were obtained as well as the duration of T2D in years and correlated with the cross-sectional areas. The bilateral VN cross-sectional areas were similar in both cohorts. Additionally, no correlation was seen between the VN cross-sectional areas, demographics, or clinical data of T2D. Our study demonstrated normal VN cross-sectional areas in patients with T2D without any significant relation with the patients' demographic or clinical data., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aimed to determine whether there is an association between the age at menopause (AM) and diabetic microvascular complications. This cross-sectional study included 298 postmenopausal women with type 2 diabetes mellitus. They were divided into 3 groups according to AM (in years; group 1: AM < 45 years, n = 32; group 2:45 ≤ AM < 50 years, n = 102; group 3: AM ≥ 50 years, n = 164). Clinical data related to the duration of type 2 diabetes, body mass index, smoking status, hypertension status, AM, biochemical indices, and diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) were collected. Logistic regression analysis was performed to identify the association between the AM and diabetic microvascular complications. No statistical differences were observed in the prevalence of diabetic retinopathy, chronic kidney disease, or diabetic peripheral neuropathy between the groups. After adjusting for possible confounders, AM did not correlate with the presence of diabetic retinopathy (β = 1.03, 95% confidence interval [CI]: 0.94-1.14, P = .511), chronic kidney disease (β = 1.04, 95% CI: 0.97-1.12, P = .280), and diabetic peripheral neuropathy (β = 1.01, 95% CI: 0.93-1.09, P = .853). Our findings suggest that early menopause (age < 45 years) was not associated with microvascular diabetic complications. Further prospective studies are needed to clarify this issue., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The relationship between autophagy and diabetic peripheral neuropathy (DPN) has been highlighted in few reports. Using an animal model, the authors investigated the relationship between autophagy and DPN, focused particularly on changes in autophagy in Schwann cells., Methods: The ultrastructural features of DPN mice were evaluated in vivo using transmission electron microscopy. Dysfunction of autophagy in DPN was evaluated using immunofluorescence microscopy and Western blot analysis of proteins related to autophagy, including Beclin1, LC3, and p62. Reactive oxygen species levels were measured in vitro in glucose-treated Schwann cells. Dysfunction of autophagy in glucose-treated Schwann cells was examined by immunofluorescence microscopy and Western blot analysis., Results: Reduced myelin thickness and axonal shrinkage were observed in the sciatic nerves of DPN mice. Reactive oxygen species levels were increased in Schwann cells treated with high glucose ( P < 0.05). The expression of Beclin1 was increased in DPN mice and Schwann cells treated with high glucose ( P < 0.05), whereas the expression of LC3-II/LC3-I ratio and p62 were decreased in DPN mice and Schwann cells treated with high glucose ( P < 0.05)., Conclusions: These results suggest that increased levels of reactive oxygen species induced by high glucose may contribute to autophagy dysfunction in Schwann cells. Autophagy dysfunction especially in Schwann cells may be an underlying cause of DPN., Clinical Relevance Statement: This study presents the pathological mechanism of diabetic peripheral neuropathy., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: Information about the impact of diabetic neuropathy (DN) on outcomes after pancreas transplantation (PT) is scarce. We assessed the independent relationship between DN markers with both graft survival and incident cardiovascular disease (CVD) after transplantation., Methods: A cohort study in individuals with type 1 diabetes and end-stage kidney disease who underwent PT between 1999 and 2015 was conducted. DN was assessed with vibration perception thresholds (VPTs) and orthostatic hypotension (pre-PT and 6 mo, 2-3, 5-6, and 8-10 y after transplantation). Pretransplantation and posttransplantation DN markers were related with graft failure/dysfunction and incident CVD during follow-up., Results: We included 187 participants (70% men, age 39.9 ± 7.1 y, diabetes duration 27.1 y), with a median follow-up of 11.3 y. Abnormal VPTs (≥25 V) were observed in 53%. After transplantation, VPTs improved (22.4 ± 8.4 pretransplant versus 16.1 ± 6.1 V at 8-10 y post-PT; P < 0.001); additionally, the prevalence of abnormal VPTs decreased (53% pretransplant versus 24.4% at 8-10 y; P < 0.001). After adjusting for age, sex, diabetes duration, blood pressure, body mass index, and previous CVD, pretransplant VPTs ≥25 V were independently associated with pancreas graft failure/dysfunction (hazard ratio [HR], 2.01 [1.01-4.00]) and incident CVD (HR, 2.57 [1.17-5.64]). Furthermore, persistent abnormal VPTs after 6 mo posttransplantation were associated with the worst outcomes (HR, 2.80 [1.25-6.23] and HR, 3.19 [1.14-8.96], for graft failure/dysfunction and incident CVD, respectively)., Conclusions: In individuals with type 1 diabetes and end-stage kidney disease, PT was associated with an improvement of VPTs. This simple and widely available DN study was independently associated with pancreas graft function and CVD posttransplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: As one of the most challenging complications in the management of diabetes mellitus, painful diabetic peripheral neuropathy (PDPN) is accompanied by various clinical manifestations, including numbness, burning, coldness, and other sensory abnormalities in the extremities. Meanwhile, PDPN seriously affects the life quality of patients and causes great pain. Western medicine mostly provides symptomatic treatments, such as antioxidants, aldose reductase inhibitors, nerve nutrition, microcirculation improvement, and analgesic drugs on the basis of blood sugar control. Although certain efficacy has been achieved, the problem has not been solved at root. Mudan granules have some advantages in the treatment of PDPN, but there is insufficient high-quality clinical studies to verify this. Therefore, the purpose of this study was to evaluate the efficacy and safety of Mudan granules in treating PDPN., Methods: A randomized, double-blind, placebo, and parallel-controlled trial design was used to study the efficacy and safety of Mudan granules in the treatment of PDPN. In this study, 93 patients with painful diabetic neuropathy were recruited and randomly divided into a treatment group and a placebo group based on 1:1. The treatment group was given Mudan granules and the control group accepted placebo treatment, and the basic treatment was performed according to the recommended guidelines. During the treatment period, the patients' visual analog scores, clinical efficacy, Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) scores, nerve conduction velocity, and drug-induced adverse reactions were observed at baseline after 8 and 10 weeks., Discussion: This study will evaluate the efficacy and safety of Mudan granules in treating PDPN. The experimental results will provide evidence support to treat PDPN with Mudan granules., Trial Registration: DOI 10.17605/OSF.IO/5CE32., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cardiac autonomic neuropathy (CAN) is a significant cause of morbidity and mortality for people with type 1 (T1D) and type 2 (T2D) diabetes. Heart rate variability (HRV) has been shown to be a marker of CAN with 24-hour Holter monitoring being a robust modality to assess HRV., Methods: To investigate the impact of hypoglycemia on CAN and its potential reversibility with islet transplantation, we compared HRV assessment by 24-hour Holter monitor on a total of 109 subjects from 5 cohorts: (1) T1D with recurrent severe hypoglycemia and on waiting list for islet transplant, (2) T1D following islet cell transplantation (ICT), (3) T2D without hypoglycemia, (4) individuals with prediabetes, and (5) controls without diabetes. SD of the normal-normal interval, square root of the mean squared differences of successive normal-normal intervals (rMSSD) and total spectral power were analyzed., Results: There was no significant difference in HRV parameters between T1D subjects and T1D post ICT suggesting CAN is not reversible at a median of 4 years postislet transplant. There was a significant difference in controls and T1D in rMSSD and between controls and T2D in total power. The differential effect on rMSSD in T1D and T2D suggests potential greater impact of hypoglycemia on rMSSD., Conclusions: Achieving euglycemia after ICT may not reverse CAN once established with no significant difference in HRV parameters at a median of 4 years postislet transplant. Differential effects of T1D as compared with T2D on CAN were identified., Competing Interests: The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. As apelin is an adipocytokine closely associated with diabetes, this study explored the clinical significance of serum apelin levels in patients with type 2 DPN before and after treatment., Methods: In total, 44 patients with T2DM without DPN (non-DPN group), 41 patients with DPN who received antihyperglycemic treatment (DPN-A group), 44 patients with DPN who received antihyperglycemic treatment combined with nutritional neurotherapy (DPN-B group), and 40 healthy control individuals (NC group) were selected continuously enrolled in the present study. Enzyme-linked immunosorbent assays (ELISA) were performed to determine serum levels of apelin and tumor necrosis factor-α (TNF-α). Related apelin, fasting blood glucose (FBG), glycosylated hemoglobin A1c, TNF-α, body mass index, fasting C peptide, and nerve conduction velocity (NCV) were recorded in each group before and after treatment., Results: Serum levels of apelin and TNF-α were higher in patients with diabetes than those in the NC group, as well as in the DPN group as compared to the non-DPN group; furthermore, some NCV values were significantly reduced in the DPN group. After treatment, the serum levels of apelin, TNF-α, and FBG reduced in patients with diabetes; moreover, apelin levels were found significantly lower in the DPN-B group as compared to the DPN-A group, while some NCV values significantly increased in the DPN-B group. Apelin was negatively correlated with part of NCV values and positively correlated with TNF-α and FBG (P < .01)., Conclusion: Our results show that the increase in serum apelin levels is an important clinical reference index for DPN, while a decrease indicates that the DPN treatment is effective., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Diabetic peripheral neuropathy (DPN) is 1 of the most common clinical complications of diabetes, which seriously affects the quality of life of patients and causes a substantial economic burden on diabetes care. The pathogenesis of DPN is complex. There is no targeted treatment method, and mainstream treatment methods have low efficacy and large side effects. Traditional Chinese medicine has rich clinical experience in the prevention and treatment of diabetic peripheral neuropathy, which has dramatically improved the quality of life of patients. It is clinically proven that traditional Chinese medicine fumigants (TCMF) have apparent effects in treating diabetic peripheral neuropathy. Therefore, we aim to systematically review the effectiveness and safety of TCMF for DPN., Methods: We will search the following databases: PubMed, Embase, Cochrane Library, MEDLINE, the China National Knowledge Infrastructure, the Chinese Biomedical Literature Database, Cqvip Database, and Wanfang Data. Besides, we will also search for clinical trial registrations, potential grey literature, relevant conference abstracts, and reference lists of established studies. The studies published from the inception of the database to November 2020 will be retrieved. The randomized controlled trials on TCMF for DPN will be included. Also, we will search for clinical trial registrations, potential grey literature, relevant conference abstracts, and reference lists of established studies. The main result is clinical efficacy and nerve conduction velocity. Fasting blood glucose, 2 hours postprandial blood glucose, blood lipid, glycosylated hemoglobin, and adverse events are secondary results. We will perform the analyses using RevMan V.5.3 software., Results: This study will provide a high-quality comprehensive evaluation of the efficacy and safety of TCMF in the treatment of DPN., Conclusions: This systematic review will evaluate the effectiveness and safety of TCMF in the treatment of DPN, and provide the latest evidence for clinical application., Inplasy Registration Number: INPLASY2020110137., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: This article provides an up-to-date review of the manifestations of neuropathy seen in the setting of diabetes and other metabolic disorders., Recent Findings: Although a number of metabolic disorders cause or are associated with peripheral neuropathy, the neuropathies associated with glucose dysregulation make up the vast majority of cases. Recent investigations have determined major differences in the neuropathies associated with type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is closely linked to glycemic control, whereas neuropathy in type 2 diabetes is linked to dyslipidemia, central obesity, hypertension, insulin resistance, and glucose control. Although length-dependent axonal distal symmetric polyneuropathy is the most common clinical presentation, diabetes is also associated with acute, asymmetric, painless, and autonomic neuropathies., Summary: The prevalence of diabetes and metabolic syndrome is increasing across the globe. The need to recognize and treat the wide array of clinical manifestations of neuropathy detected in individuals with metabolic disorders will continue to grow. As a consequence, an increasing number of well-trained physicians who can manage these patients is needed. At present, treatment is largely focused on prevention and symptomatic management. Investments into funding for both basic and clinical science are necessary to bring novel therapeutic interventions into clinical practice.

Background: Painful diabetic neuropathy (PDN) is one of the main and severe complications of diabetic patients, which not only accelerates the occurrence of ulcers of diabetic foot and amputation of lower extremities but also severely affects the quality of life. It is common that vitamin D deficiency in diabetic patients and especially in these patients diagnosed with diabetic peripheral neuropathy. Previous studies have proved that there is an apparent vitamin D deficiency in PDN patients, and vitamin D supplementation can effectively improve patients' pain symptoms and neurologic function. However, the evidence of these studies is unconvincing. Therefore, our research objective is to explore the effectiveness and security of vitamin D supplements on PDN., Methods: We will include randomized controlled trials on vitamin D supplementation in the treatment of PDN. And we will retrieve 8 electronic databases concerning this theme. The English databases mainly retrieve PubMed, Web of Science, Embase, and the Cochrane Library, while CNKI, VIP, CBM, and Wanfang database will be used to retrieve the Chinese Literature. There is no definite time limit for retrieval literatures, and the languages will be limited to Chinese and English. Besides, some clinical registration tests and gray literatures are also researched by us. The primary outcomes of our study are the amelioration of pain symptoms and assessment of peripheral nerve function. And some changes of biochemical indicators including fasting blood glucose, 2 hours postprandial blood glucose, glycosylated hemoglobin, calcium, and serum vitamin D level from preintervention and postintervention, adverse events will be regarded as secondary outcomes. The Review Manager RevMan5.3 will be used for meta-analysis of studies are included., Results: In this systematic review and meta-analysis, higher quality data evidence on vitamin D supplementation for PDN will be provided., Conclusion: Our study will eventually provide a proof of the efficacy and safety of vitamin D supplementation in patients with PDN, and to add a new option for the prevention and treatment of PDN patients., Inplasy Registration Number: INPLASY202050065.

Objective: Impaired baroreflex function is an early indicator of cardiovascular autonomic imbalance. Patients with type 2 diabetes mellitus (T2D) have decreased baroreflex sensitivity (BRS), however, whether the neural BRS (nBRS) and mechanical component of the BRS is altered in those with high metabolic risk (HMR, impaired fasting glucose and metabolic syndrome) or with overt T2D, is unknown. We examined this in a community-based observational study, the Paris Prospective Study III (PPS3). Approach and Results: In 7626 adults aged 50 to 75 years, resting nBRS (estimated by low-frequency gain, from carotid distension rate and RR [time elapsed between two successive R waves] intervals) and mechanical BRS were measured by high-precision carotid echotracking. The associations between overt T2D or HMR as compared with subjects with normal glucose metabolism and nBRS or mechanical BRS were quantified using multivariable linear regression analysis. There were 319 subjects with T2D (61±6 years, 77% male), 1450 subjects with HMR (60±6 years, 72% male), and 5857 subjects with normal glucose metabolism (59±6 years, 57% male). Compared with normal glucose metabolism, nBRS was significantly lower in HMR subjects (β=-0.07 [95% CI, -0.12 to -0.01]; P =0.029) and in subjects with T2D (β=-0.18 [95% CI, -0.29 to -0.07]; P =0.002) after adjustment for confounding and mediating factors. Subgroup analysis suggests significant and independent alteration in mechanical BRS only among HMR patients who had both impaired fasting glucose and metabolic syndrome., Conclusions: In this community-based study of individuals aged 50 to 75, a graded decrease in nBRS was observed in HMR subjects and patients with overt T2D as compared with normal glucose metabolism subjects.

Purpose: In diabetes mellitus (DM), upper extremity entrapment neuropathies are suggested to be a component of polyneuropathy (PNP). Our aim is to examine the presence of ulnar neuropathy at the elbow (UNE) and its relation to other findings including PNP in symptomatic and asymptomatic type-2 DM patients who were admitted for routine examinations., Methods: The study included all cases referred for electromyography because of type-2 DM between November 2017 and May 2018. Demographic and clinical characteristics were recorded. Routine electromyography examinations in all cases included the following: bilateral motor conduction of the median, ulnar, peroneal, and tibial nerves and sensory conduction of the median, ulnar, and sural nerves. For ulnar nerve examination, stimuli were given at the wrist, below the elbow, and above the elbow. Electrophysiological findings were evaluated according to the American Association of Neuromuscular and Electrodiagnostic Medicine criteria., Results: Eighty-two patients with type-2 DM and 144 upper extremities were included in the study. Of the 82 patients who participated in the study, 3 had findings suggesting ulnar neuropathy, and electrophysiology confirmed UNE in only one. Electrophysiological studies showed UNE in 36 patients. Other diagnoses identified by electrophysiology were carpal tunnel syndrome and PNP. Ulnar neuropathy at the elbow was more commonly associated with PNP compared with carpal tunnel syndrome. Gender and PNP were independent risk factors for the development of UNE., Conclusions: Although the majority of diabetic patients were asymptomatic for the UNE, approximately one third of all patients with DM were found to have UNE. Ulnar neuropathy at the elbow is closely related with PNP.

Objective: To determine the effect of an intervention involving muscular ankle strengthening and feet sensory stimuli to improve gait speed and balance in older adults with diabetes mellitus type 2 (DM2)., Design: A clinical trial with concealed allocation, assessor blinding, and intention-to-treat analysis., Participants: The trial enrolled 66 people 60 years or older with DM2 who were physically independent (did not require assistance with activities of daily living)., Intervention: The experimental group performed 12 weeks of plantiflexor and dorsiflexor muscle strengthening exercises with resistance bands, proprioceptive exercises on balance boards and a buoy, and plantar sensory stimulation with bristle brushes and cloths, as well as general foot care instructions. The control group received foot care instructions only., Outcome Measures: The primary outcome was plantar cutaneous sensibility as measured with Semmes-Weinstein monofilaments. Secondary outcomes included muscular strength (plantar flexion and dorsiflexion torque as measured with an isokinetic dynamometer), gait speed, and balance (total displacement area, mediolateral displacement, anteroposterior displacement, mediolateral displacement speed, and anteroposterior displacement speed) on right and left bipedal and unipedal supports., Results: In comparison with the control group, the experimental group demonstrated improved plantar cutaneous sensibility on the right foot (3.46 points; 95% confidence interval [CI], 3.85-9.80), left foot (3.46 points; 95% CI, 4.06-9.76), and an increase in gait speed (0.15 m/s; 95% CI 0.12-0.42). There were no meaningful changes in participants' ankle muscle strength or balance., Conclusions: This study showed that plantar cutaneous sensory stimulation can improve foot sensibility and increase the gait speed of older adults with DM2. However, there were no meaningful dorsiflexor or plantiflexor gains after 12 weeks.

Objective: This study seeks to use the relative refractory period, a sensitive parameter for detecting early change in peripheral polyneuropathies, as a tool for early detection of diabetic polyneuropathy., Design: The relative refractory period of the median and sural sensory nerves was measured in 57 diabetic patients (male 31, female 26) and 23 healthy controls (male 16, female 7). The shortest interstimulus interval, where the latency of the response to the second stimulus recovers to normal, was defined as the relative refractory period., Results: The relative refractory period of the median and sural nerves were significantly longer in diabetic patients (3.6 msec, P < 0.001, and 3.8 msec, P < 0.001, respectively) than in the control group (3.0 msec in both nerves). Relative refractory period values of both nerves were also significantly prolonged compared with the control group, even in diabetic patients without diabetic polyneuropathy based on conventional conduction studies (3.3 msec, P = 0.002, for median nerve; 3.5 msec, P < 0.001, for sural nerve) or without any clinical symptoms and signs (3.3 msec, P = 0.007, for median nerve; 3.5 msec, P = 0.001, for sural nerve)., Conclusions: The relative refractory period was prolonged in diabetic patients even before other electrophysiologic abnormalities or clinical findings appeared. These results suggest that the relative refractory period can be a possible early indicator of diabetic polyneuropathy.

Background: Vitamin D is a fat-soluble vitamin that is related to the health of the human body and is an indispensable nutrient for human beings. Some studies indicated that type 2 diabetes mellitus (T2DM) with diabetic peripheral neuropathy (DPN) may be associated with vitamin D deficiency, but the current understanding of this point of view remains controversial. This study aimed to evaluate the correlation between serum 25-hydroxyl vitamin D (25 [OH] D) concentration and DPN in patients with T2DM by a meta-analysis, and to provide a reference for doctors., Methods: Relevant studies were selected from the PubMed, Cochrane Library, China National Knowledge Infrastructure, VIP databases, and Wanfang Data Knowledge Service Platform databases dating from 2000 to December 2017. A total of 75 articles related to serum 25 (OH) D and DPN were selected from 2000 to December 2017. Based on the inclusion and exclusion criteria of the literature, a quality assessment was conducted using the Newcastle-Ottawa scale, and a meta-analysis was performed by RevMan5.3 statistical software., Results: Thirteen studies that involved a total of 2814 type 2 diabetic patients were finally included into the meta-analysis. Meta-analysis results, heterogeneity test showed that, P < .000 01, I = 92%, calculation by random effect model revealed that, the serum concentration of 25 (OH) D in T2DM combined with DPN group was lower than that in the group without DPN (weighted mean difference = -0.74, 95% confidence interval: -1.03 to -0.46) CONCLUSIONS:: Vitamin D is associated with type 2 DPN (DPN), and vitamin D deficiency can lead to an increased risk of type 2 DPN. However, more high-quality research is needed.

Diabetes mellitus is the leading cause of polyneuropathy in the Western world. Diabetic neuropathy is a frequent complication of diabetes and may have great clinical transcendence due to pain and possible ulceration of the lower extremities. It is also a relevant cause of morbidity and mortality in patients with diabetes. Although the cause of polyneuropathy in patients with diabetes is only partially known, it has been associated with chronic hyperglycemia suggesting the possible etiopathogenic implication of advanced glycosylation end products. The strategy of choice in the medical management of diabetic neuropathy is early detection since glycaemic control and the use of certain drugs may prevent or slow the development of this disease. Diabetic neuropathy most often presents with a dysfunction of unmyelinated C-fibers, manifested as an alteration of the sweat reflex of the eccrine glands. This dysfunction can now be demonstrated using a newly developed technology which measures dermal electrochemical conductivity. This noninvasive test is easy and cost-effective. The aim of the present study is to evaluate the feasibility and effectiveness of dermal electrochemical conductance measurement (quantitative expression of the sudomotor reflex) as a screening test for the diagnosis of diabetic neuropathy in patients in primary care.

To investigate the relationship among anemia, physiological serum bilirubin levels, and cardiovascular autonomic neuropathy (CAN) in subjects with type 2 diabetes. In total, 2230 subjects with type 2 diabetes were evaluated in this cross-sectional study. CAN was diagnosed with a cardiovascular reflex test. The prevalence of anemia was greater in subjects with CAN. In multivariable analysis, the relationship between anemia and CAN remained statistically significant after adjusting for the risk factors (odds ratio [OR] 1.39; 95% confidence interval [CI] 1.07-1.80, P = .015). Additional adjustment for serum bilirubin concentrations abolished this relationship (OR 1.20, 95% CI 0.91-1.58, P = .189). Anemia is positively associated with the prevalence of CAN in subjects with type 2 diabetes. In addition, our results suggest that the putative increased CAN risk associated with anemia might be mediated by a correlated decrease in serum bilirubin levels.

Objective: To examine whether variations in fasting plasma glucose (FPG), as measured by the coefficient of variation (CV), is a predictor of diabetic polyneuropathy (DPN) risk, considering glycated hemoglobin (HbA1c) and other traditional risk factors., Methods: Type 2 diabetic patients enrolled in the National Diabetes Care Management Program were ≥30 years of age and free of DPN (n = 36,152). They were enrolled in 2002-2004 and were monitored until 2011. The related factors were analyzed using Cox proportional hazards regression models., Results: During an average 7.23 years of follow-up, a total of 7,219 incident cases of DPN were identified, with a crude incidence rate of 27.62/1,000 person-years (25.83 for men and 29.31 for women). After multivariate adjustment, both FPG-CV and HbA1c were significant predictors of DPN, with corresponding hazard ratios of 1.14 (95% confidence interval [CI] 1.05-1.23) and 1.15 (95% CI 1.06-1.24) for FPG-CV in the fourth to fifth quintiles and 1.13 (95% CI 1.07-1.20) for HbA1c ≥7%. This finding maintained consistency after excluding potential confounders in the sensitivity analysis, further validating the results., Conclusions: FPG-CV and HbA1c ≥7% were potent predictors of DPN in type 2 diabetic patients. The associations among HbA1c, glycemic variability, and DPN suggest a linked pathophysiologic mechanism, which may play a crucial role in clinical risk assessments., (© 2017 American Academy of Neurology.)

Objective: The aim of this study was to investigate the effect of 8 wks of moderate-intensity aerobic exercise on postural control during quiet standing in type 2 diabetic peripheral neuropathy., Methods: Individuals were included in the study if they had type 2 diabetes with clinical neuropathy, defined by a minimum score of 7 on the Michigan Diabetic Neuropathy Score, following which the patients were randomly assigned to an 8-wk program by computer-generated random number tables to study or control group. Repeated-measures analysis of variance was used for data analysis (P < 0.05 was considered significant)., Results: After final randomization, there were 36 patients in the study group and 45 in the control group. On comparison of results for control and study groups using repeated-measures analysis of variance only in the eyes closed on foam condition was there was a significant difference between the two groups for sway velocity along the x-axis (df1, df2 = 1, 18, F = 3.86, P = 0.04) and mediolateral displacement (df1, df2 = 1, 18, F = 4.04, P = 0.03)., Conclusion: Aerobic exercise training could exert a therapeutic effect on center of pressure movement only along the x-axis in the eyes closed condition on foam surface during quiet standing.

Neurofilament (NF), one of the major axonal cytoskeletal proteins, plays a critical role in degenerative diseases in both the central and the peripheral nervous systems. The aim of this study is to explore the relationship between serum phosphorylated neurofilament-heavy chain (pNF-H) and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes.Serum pNF-H concentrations were measured by ELISA in hospitalized patients with and without DPN (n = 118). DPN was assessed by clinical symptoms, signs, and electromyography.Compared with the non-DPN group (311.98 [189.59-634.12] pg/mL), the confirmed group (605.99 [281.17-1332.78] pg/mL) patients had the higher serum pNF-H levels (P = 0.007). DPN was significantly correlated with C-peptide (r = -0.269), total cholesterol (TC) (r = 0.185), and pNF-H (r = 0.258). Serum pNF-H levels were independently associated with DPN (P = 0.004), even after adjusting for age, sex, duration of diabetes, fasting plasma glucose, glycosylated hemoglobin A1c, TC, C-peptide, urinary albuminto/creatinine ratio, and estimated glomerular filtration rate. Compared with pNF-H quartile 1 (referent), patients in quartile 3 (odds ratio [OR], 3.977; 95% confidence interval [CI], 1.243-12.728; P = 0.021) and quartile 4 (OR, 10.488; 95% CI, 3.020-34.429; P = 0.000) had the higher risk of DPN after adjusting for the confounders.Serum pNF-H levels might be associated with the DPN, and the correlationship between serum pNF-H and DPN should be further studied.

Purpose of Review: There has been an advance in our understanding of the mechanisms of diabetic nephropathy over the past few years and much of that has occurred because of studies in animal models of diabetic nephropathy., Recent Findings: Studies in animal models of diabetic nephropathy, especially in mice, have underlined the multifactorial nature of the pathogenesis of the disease process and the recognition that these models only partly replicate the changes found in human disease. Despite these limitations, recent animal model studies have identified a number of new, specific molecular abnormalities that point to pathways and specific molecules as potential targets for preventive or therapeutic intervention. These specific targets include the diabetic nephropathy related decreases in endothelial nitric oxide synthase activity and renal dopamine production and the increases in Nrf-2, JAK/STAT, and mammalian target of rapamycin complex 1 signaling. These and other altered signaling pathways are described in this review. We emphasize the use of a unique investigative resource, Nephromine, to utilize a library of mRNA expression data obtained from the kidney biopsies of humans with diabetic nephropathy, to compare and validate findings in mouse models with human disease., Summary: Several new pathways have been implicated in the progression of diabetic nephropathy through studies of animal models. Some of these appear to be altered in human diabetic nephropathy and may be targets for therapy.

Purpose: The purpose of this study was to investigate the effect of diabetes, motor nerve impairment, and training status on neuromuscular function by concurrent assessment of the torque-velocity relationship and muscle fiber conduction velocity (MFCV)., Methods: Four groups were studied (n = 12 each): sedentary patients with diabetes in the first (lower) and fourth (higher) quartile of motor nerve conduction velocity (D1 and D4, respectively), trained diabetic (TD) patients, and nondiabetic sedentary control (C) subjects. Maximal isometric and isokinetic contractions were assessed over a wide range of angular velocities for the elbow flexors and knee extensors to evaluate the torque-velocity relationship. Simultaneously, MFCV was estimated from surface electromyography of the vastus lateralis and biceps brachii., Results: Isometric strength was similar among groups. The dynamic strength of elbow flexors was reduced in patients with diabetes at the higher contraction speeds. The strength of knee extensors was lower in sedentary patients with diabetes at all velocities considered, with significantly lower values in D1 than that in D4 at 60°, 90°, and 120°·s(-1), whereas it was similar between TD and C subjects, especially at low contraction velocities. At the vastus lateralis, but not the biceps brachii, MFCV was lower in D1 and D4 as compared with TD and C subjects, showing similar values., Conclusions: Muscle weakness in diabetes affects also the upper limb, although to a lower extent than the lower limb, is only partly related to motor nerve impairment, and is dependent on contraction velocity. Exercise training might counteract diabetes-induced alterations in muscle fiber contractile properties and MFCV.

To develop a rapid optimized technique of wide-field imaging of the human corneal subbasal nerve plexus. A dynamic fixation target was developed and, coupled with semiautomated tiling software, a rapid method of capturing and montaging multiple corneal confocal microscopy images was created. To illustrate the utility of this technique, wide-field maps of the subbasal nerve plexus were produced in 2 participants with diabetes, 1 with and 1 without neuropathy. The technique produced montages of the central 3 mm of the subbasal corneal nerve plexus. The maps seem to show a general reduction in the number of nerve fibers and branches in the diabetic participant with neuropathy compared with the individual without neuropathy.This novel technique will allow more routine and widespread use of subbasal nerve plexus mapping in clinical and research situations. The significant reduction in the time to image the corneal subbasal nerve plexus should expedite studies of larger groups of diabetic patients and those with other conditions affecting nerve fibers. The inferior whorl and the surrounding areas may show the greatest loss of nerve fibers in individuals with diabetic neuropathy, but this should be further investigated in a larger cohort.

Background: Lidocaine is used clinically for tactile allodynia associated with diabetes-induced neuropathy. Although the analgesic effect of lidocaine through suppression of microglial activation has been implicated in the development of injury-induced neuropathic pain, its mechanism of action in diabetes-induced tactile allodynia has not yet been completely elucidated., Methods: To evaluate the effects of lidocaine on microglial response in diabetic neuropathy, streptozotocin (STZ)-injected mice received a continuous infusion of lidocaine (vehicle, 2, or 10%) from day 14 to day 21 after STZ injection. On day 21, microglial accumulation and p38 mitogen-activated protein kinase activation in the dorsal horn were evaluated. In vitro, the effects of lidocaine on cell viability, chemotactic response to monocyte chemotactic protein-1, and induction of proinflammatory mediators were examined in interferon (IFN)-γ-stimulated primary microglial cells., Results: Continuous systemic administration of lidocaine in the early progression of tactile allodynia produced long-lasting analgesic effects in STZ-treated mice. Lidocaine significantly reduced accumulation and p38 phosphorylation of microglial cells in the dorsal horn. In vitro, lidocaine down-regulated IFN-γ-induced gene induction of inducible oxide synthase and interleukin-1β. Pretreatment with lidocaine significantly reduced chemotactic response to monocyte chemotactic protein-1 of IFN-γ-activated microglial cells., Conclusion: Lidocaine alleviates STZ-induced tactile allodynia, possibly by modulating the p38 pathway in spinal microglial cells. Inhibiting microglial activation by lidocaine treatment early in the course of diabetes-induced neuropathy represents a potential therapeutic strategy for tactile allodynia.

Background: Patients with diabetes mellitus have accelerated progression of heart failure and often have impaired cardiac sympathetic innervation. The present study examines the implications for heart failure progression of cardiac sympathetic denervation, assessed by I-123 metaiodobenzylguanidine imaging, in diabetic compared with nondiabetic subjects., Methods and Results: We evaluated 343 diabetic and 618 nondiabetic subjects with New York Heart Association class II or III heart failure and a left ventricular ejection fraction ≤35% over a median follow-up of 17 months. A multivariable Cox proportional hazards model was used to examine the influence of clinical variables, b-type natriuretic peptide, plasma norepinephrine, left ventricular ejection fraction, and I-123 metaiodobenzylguanidine imaging parameters on time to a heart failure event. The late heart-to-mediastinum (H/M) ratio and the interaction term of diabetes mellitus with the prospectively selected late H/M ratio <1.6 were independent predictors of heart failure progression, providing incremental prognostic information beyond that available from all other variables. In diabetic subjects, late H/M ratio <1.6 was associated with a 2.99-fold greater 2-year rate of heart failure progression (33.5%) than late H/M ratio ≥1.6 (11.2% event rate)., Conclusions: The combination of diabetes mellitus and I-123 metaiodobenzylguanidine H/M ratio is an independent predictor of heart failure progression, confirming the high risk of diabetic subjects with impaired cardiac sympathetic nerve function.

Purpose of Review: In the last decade the importance of the podocyte in maintaining the integrity of the glomerular filtration barrier and prevention of albuminuria has become obvious. The leading cause of renal failure in the developed world is diabetic nephropathy. This has a defined natural history of progressive albuminuria. The two fundamental cellular changes that occur in diabetes mellitus are a failure of insulin to signal to cells and an environment of hyperglycaemia. The emerging role of these factors on the biological function of the podocyte will be reviewed., Recent Findings: Hyperglycaemia causes both deleterious and protective cellular pathways to be initiated in the podocyte, which communicate with other cell types in the glomerulus. Furthermore, the podocyte is an insulin-sensitive cell which can be directly modulated by factors that increase and decrease its sensitivity to insulin., Summary: Our understanding of the cellular processes that affect the podocyte in diabetes and insulin resistance has progressed greatly in recent years and hopefully will result in new treatment strategies against the leading cause of renal failure in the developed world.

Diabetes mellitus (DM) is a major health problem worldwide, which affects 18.2 million individuals (6.3% of the population) in the United States. Currently, the prevalence of Type 1 DM in the United States is estimated to be 1,000,000 individuals, and 30,000 new cases are diagnosed each year. In addition to end-stage renal disease (ESRD), DM is associated with blindness, accelerated atherosclerosis, dyslipidemia, cardio- and cerebrovascular disease, amputation, poor quality of life, and overall lifespan reduction. It accounts for more than 160,000 deaths per year in the United States alone. In 2002, the annual national direct and indirect costs of Types 1 and 2 DM exceeded $130 billion, which included hospital and physician care, laboratory tests, pharmaceutical products, and patient workdays lost because of disability or premature death. Hyperglycemia alone or in concert with hypertension is the primary factor influencing the development of major diabetic complications. From 1990 to 2001, the number of existing ESRD cases to DM increased by more than 300%, while the rate per million populations increased from 167% to 491%. The number is expected to grow 10-fold by 2030 to 1.3 million accounting for 60% of ESRD population. To date, DM is the leading indication for transplantation and is the cause of ESRD in more than 40% of all transplant recipients each year.

As we learn more about the pathophysiology of diabetes mellitus, we find that there is more yet to be learned. This may sound like a trite statement, but in reality it is true. The following article reviews the basic pathophysiology of both type 1 diabetes mellitus and type 2 diabetes mellitus as we understand it today. It continues on to reveal the "things that go wrong" when there is too much or too little glucose available to the body organs and especially to the brain. The article points out the signs and symptoms to be aware of when the person is in the acute state of diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic coma (or state), and severe hypoglycemia. It concludes with important considerations when the individual is in one of these acute states and contributes key points related to the control of diabetes when the person is in the state of compromise.

The first purpose of this article is to examine general signaling transduction processes that become deranged in diabetes and the means by which they damage cells. However, among the cells that can be damaged by diabetes, the primary sensory neurons, also known as dorsal root ganglion (DRG) neurons, are uniquely sensitive. Damage to these cells results in diabetic peripheral neuropathy (DPN), one of the costliest and most common diabetic complications. Therefore, the second purpose of this article is to focus attention on factors that make these cells particularly vulnerable to hyperglycemic damage. Some clinical inferences are drawn from these considerations. Finally, limitations in our knowledge about the effects of diabetes on signaling in DRG neurons are illustrated in an overview of the basic research literature.

Background: Histologic findings of diabetic nephropathy (DN) are observed in allografts of patients with pretransplant (PreTx) diabetes mellitus (DM) and in patients who develop DM posttransplant (PostTx). Patients with allograft biopsies (Bx) were retrospectively studied to determine the incidence of recurrent and de novo DN and to ascertain what, if any, risk factors predispose to histologic DN in either patient population., Methods: From the renal transplant services at four hospitals from 1992 to 2000, the authors identified all patients with PreTxDM and PostTxDM (n=81). Those with renal biopsies performed >/=18 months PostTx were classified according to the presence or absence of histologic DN (Bx-positive, n=23; Bx-negative, n=35). Patients were then subdivided into four categories-recurrent DN (n=16), de novo DN (n=7), no recurrent DN (n=27), and no de novo DN (n=8)-for analyses., Results: Among these 58 patients, 74.1% had PreTx and 25.9% had PostTx diabetes. Of those with histologic DN, 69.6% were recurrent DN and 30.4% were de novo DN, making de novo DN at least as likely to develop as recurrent DN. After the onset of diabetes in the de novo population, the time to development of histologic DN was similar in the recurrent and the de novo patients (6.68+/-3.86 years vs. 5.90+/-3.13 years, P=0.66) and more rapid than previously reported. Apart from a more frequent family history of hypertension in patients with allograft DN compared with those without allograft DN, known risk factors for the development of native DN did not significantly differ among patients in the four cohorts. Proposed risk factors related to transplantation did not correlate with the development of recurrent or de novo DN., Conclusion: Among patients with histologic DN, de novo DN occurred at least as frequently as recurrent DN, and the time to onset of histologically apparent DN was more rapid than previously reported. Neither the usual clinical predictors of DN nor clinical variables related to transplantation clearly distinguished the group with DN from the group without it, potentially implicating novel mechanisms in its pathogenesis.

Many women with diabetes develop complications of their chronic disease that may have a tremendous impact on their quality of life and their ultimate prognosis. Because Type 1 diabetes often begins at a very early age, it is quite common for women in their child-bearing years to be affected by these complications. As described in this article, diabetic complications and pregnancy may significantly affect each other, but it is not always easy to predict the course of either and to counsel these patients accordingly. Nevertheless, it appears that only in rare occasions should women with diabetes be advised against pregnancy, and that in most situations, with careful and knowledgeable management, a favorable outcome of pregnancy can be expected both for the mother and her infant.

The mechanism of neuropathic pain in the diabetic limb is far from clear. Phantom limb pain likewise is of obscure aetiology. The development of typical pain in an absent leg in a patient with diabetes many years after the amputation stimulates thought as to the mechanism, not only of neuropathic pain, but also of phantom limb pain. A 58-year-old man was diagnosed with type 2 diabetes 44 years after having undergone left below knee amputation for congenital AV malformation, at the age of 13. Eight months before the diagnosis of diabetes he began to complain of pain in the leg on the amputated side-pain very similar to that described in typical diabetic neuropathy. This was followed by similar pain in the right leg. MR scan of the spine revealed a small syringohydromyelia of the thoracic cord in addition to a prolapse of disc at L(5)/S(1) level on the left side, which was first noted 5 years previously. There were no other features of S(1) compression. The typical neuropathic character of the pain involving both the amputated and the intact limbs that developed with the diagnosis of type 2 diabetes suggest that the neuropathic pain may originate from centres higher than peripheral nerves.

Streptozotocin (STZ)-induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy to assess the efficacies of potential analgesic agents. We have established this model, and here we question whether the changes in nocifensive reflex activity, used as a measure of hyperalgesia, are genuinely indicative of peripheral neuropathy or may rather be attributed to the extreme poor health of the animals. For comparison we have examined animals with peripheral neuropathy induced by partial ligation of the sciatic nerve. Diabetic animals were chronically ill, with reduced growth rate, polyuria, diarrhoea, and had enlarged and distended bladders. Indicative of their poor health, diabetic animals showed markedly reduced motor activity. In contrast, following partial sciatic nerve ligation rats showed none of these adverse effects and their motor activity was not different to naive animals. Diabetic animals displayed marked mechanical hyperalgesia, and some thermal hypoalgesia. Morphine and L-baclofen partially reversed established STZ-induced mechanical hyperalgesia, whilst the NK-1 receptor-antagonist RP-67580, the NMDA-antagonists MK801 and ketamine, and the nitric oxide synthase inhibitor L-NAME were without significant effect. Morphine and L-baclofen produced greater reversal of mechanical hyperalgesia following partial nerve ligation, although RP67580 and MK801 showed little or no activity. These data confirm previous findings that STZ-induced diabetes in rats produces long-lasting mechanical, but not thermal hyperalgesia. In our experience this mechanical hyperalgesia is largely resistant to a range of pharmacological tools. However, we feel that the profound ill-health of the animals, together with the poor activity of a range of potential analgesic drugs, must raise questions on the predictive value of these animals as a model for the human condition of chronic diabetic pain seen in patients receiving long-term insulin treatment, as well as ethical concerns on the use of the animals themselves.

A large epidemiological study has documented that one-third of diabetic patients have peripheral neuropathy. Diabetes duration, poor glycaemic control, smoking and hypertension are all independent predictors of the incidence of diabetic polyneuropathy. High prevalence of autonomic dysfunctions, both sympathetic and parasympathetic, has been found in patients with nonalcoholic chronic liver disease. The pathogenesis of metabolic neuropathy is unclear; even immunologic factors might play a role in the development of diabetic autonomic neuropathy. No specific treatments are available for these neuropathies. Correction of metabolic derangement is fundamental, as shown by the amelioration of peripheral nerve function obtained after successful simultaneous pancreas-kidney transplantation. The therapeuthic potentials of neurotrophins for the prevention and treatment of diabetic neuropathy have to be confirmed in future studies.

Epidemiological studies have documented a high prevalence of diabetic neuropathy. The risk of lower leg amputation is increased three to four times in patients with clinical signs of neuropathy and ankle weakness is more common than hitherto recognized. Increased nerve hydration and increased expression of low affinity p75 receptor for neurotrophins suggest new therapeutic potentials for the prevention of diabetic neuropathy.

We assessed cerebral blood flow in 78 diabetic patients (40 Type 1 and 38 Type 2) with no previous history of central nervous system disease using 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) and found areas of severe hypoperfusion in 36% of them. All cerebral anatomical regions showed abnormalities related to hypoperfusion, but they were most frequently seen in the fronto-temporal region, followed by the occipital and parietal regions. 99Tcm-HMPAO SPET has been shown to be able to detect subclinical alterations in blood flow in diabetes, a finding that may account for the high prevalence of cerebrovascular disease seen in these patients. This technique could, therefore, play an important role in future preventative strategies.

Cranial mononeuropathies, particularly ophthalmoplegia and facial palsy, are common entities in the diabetic population. Simultaneous multiple cranial neuropathies due to diabetes are much less common, however. We present three patients with this entity.

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)