Development Of Diabetic Peripheral Neuropathy Research Articles

A study on the possible role of date fruit on the electrophysiology and neuropathic changes in diabetic polyneuropathy.

Diabetes mellitus (DM) is a chronic metabolic disease with many neurovascular complications particularly diabetic peripheral neuropathy (DPN) that is mostly developed secondary to much release of reactive oxygen species (ROS, the potential mediators of DM-induced oxidative stress). The aim of the present study is to evaluate the possible neuroprotective role of Date Fruit Extract (DFE), an antioxidant nutrient, in ameliorating the DPN in streptozotocin-induced diabetic rats. Forty adult male rats were used in this study. They were divided into 4 equal groups. Group I (Control group). Group II (DEF group), supplemented orally with 250mg/kg DFE daily for 6 weeks, Group III (Diabetic group): The rats were rendered diabetic through their injection with 50 mg/kg streptozotocin (STZ) intraperitoneally and Group IV (Diabetic-DFE group). At the end of 6 weeks-experimental period; fasting serum glucose, serum insulin, glycosylated hemoglobin (Hb A1ic), tumor necrosis factor alpha (TNF-) (as an index of inflammation), glutathione peroxidase enzyme (GPX) (as an index of the tissue antioxidant enzyme defense activity) and malondialdehyde (MDA) (a tissue marker of oxidative stress and lipid peroxidation) were measured. In addition, to ensure the development of DPN in the rats, the thermal pain threshold of the rats was assessed through a paw withdrawal latency (PWL) using the hot plate analgesia meter. In addition, Nerve Conduction Velocity (NCV) of the isolated sciatic nerves of the rats was assessed. The results revealed that the untreated diabetic group exhibited a significant increase of the serum glucose, Hb A1ic, serum MDA and serum TNF- together with a significant decrease of serum insulin and

Role of miR-146a of the peripheral blood mononuclear cell in the pathogenesis of type 2 diabetic peripheral neuropathy

Objective To explore the possible role of miR-146a in the pathogenesis of diabetic peripheral neuropathy(DPN) by investigating the correlation of miR-146a level in the peripheral blood mononuclear cells(PBMCs)with tumor necrosis factor α(TNF-α), interleukin-6(IL-6), and C reactive protein(CRP). Methods The expression levels of miR-146a in the PBMCs were measured using realtime PCR in 81 patients and 34 healthy individuals. The correlation of miR-146a expression with clinical parameters was analyzed. Results Compared to those in the healthy individuals and patients without DPN, miR-146a level was significantly decreased in diabetic patients with DPN while TNF-α, CRP, IL-6, HbA1C, systolic blood pressure, and homeostasis model assessment of insulin resistance index(HOMA-IR) were significantly increased(all P<0.05). Duration of diabetes, blood uric acid, serum creatinine, and urinary albumin to creatinine ratio in diabetics with DPN were higher compared with diabetics without DPN(all P<0.05). The expression level of miR-146a was negatively correlated with diabetes duration, HOMA-IR, HbA1C, TNF-α, and IL-6. Multiple linear regression showed that HOMA-IR, HbA1C, TNF-α, and IL-6 were independent factors of miR-146a. Conclusion miR-146a may be involved in the development of DPN through inflammation, glucose metabolism, and insulin resistance. (Chin J Endocrinol Metab, 2016, 32: 552-555) Key words: Diabetes mellitus, type 2; miR-146a; Diabetic peripheral neuropathy; Tumor necrosis factor α; Interleukin-6

Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis.

Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95% confidence interval (95% CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95% CI 1.12-1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95% CI 1.08-1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P < 0.05). Subgroup analysis by country indicated that the MTHFR 677 C>T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN.

Ameliorative Effect and Underlying Mechanisms of Total Triterpenoids from &lt;i&gt;Psidium guajava&lt;/i&gt; Linn (Myrtaceae) Leaf on High-Fat Streptozotocin-induced Diabetic Peripheral Neuropathy in Rats

Purpose: To investigate whether the total triterpenoids extracted from Psidium Guajava leaves (TTPGL) attenuate the development of diabetic peripheral neuropathy in rats by regulating the NF-κB pathway of the inflammatory process and its signaling mediators.Methods: All the Sprague Dawley rats used were maintained in a clean environment on a 12 h light/12h dark cycle. High-fat feeding and intraperitoneal injection of 40 mg/kg streptozotocin (STZ) were used to induce diabetes in the rats. The rats were randomly divided into 5 groups: diabetic mellitus (DM) group; TTPGL - 30 group, TTPGL - 60 group and TTPGL - 120 group treated by intragastric administration (i.g) with 30, 100 and 120 mg/kg/day TTPGL, respectively. The well-established drug, rosiglitazone (RSG, 3 mg/k/d, i.g.), was used as positive control. Normal rats served as control group. Nerve conduction velocity and sensitive tests were measured on weeks 1, 4 and 8. After 8 weeks administration, expression of pro-inflammatory molecules (TNF - α, IL - 6 and iNOS) and tissue proteins (Akt, IKKα, and NF – κB - p65) were evaluated to assess biochemical changes.Results: Compared to DM group, TTPGL (especially 120 mg / kg dose) treatment improved (p &lt; 0.05) physical functions and provided neuronal protection in high - fat/streptozotocin - induced peripheral neuropathy rats. We found that the expressions of several pro - inflammatory factors such as tumor necrosis factor - α (TNF - α), IL - 6 and inducible nitric oxide synthase (iNOS) were highly suppressed (p &lt; 0.05 or p &lt; 0.01) by TTPGL in sciatic nerve. Mechanism analysis indicated that the ameliorative effect of TTPGL, in part, is through suppression of the expression of pro - inflammatory cytokines by NF - κB pathway mediation.Conclusion: TTPGL offers a potential therapeutic approach for the treatment of diabetic peripheral neuropathy.Keywords: Triterpenoids, Psidium Guajava, Diabetic peripheral neuropathy, Pro inflammatory cytokines, NF-κB pathway

Effects of High Glucose on Cell Viability and Differentiation in Primary Cultured Schwann Cells: Potential Role of ERK Signaling Pathway.

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus and hyperglycemia is considered to be the major factor in the development and progression of DPN. Because of the contribution of Schwann cells (SCs) to the pathology of DPN, we investigated the effects of high glucose on cell proliferation, apoptosis and differentiation in primary cultured SCs. Cell Counting Kit-8 (CCK-8) assay and Hoechst staining showed that high glucose inhibited SCs proliferation and increased apoptosis ratio in time and concentration dependent manner. Western blot and real-time quantitative PCR analysis revealed that the major myelin proteins and genes expressions including P0, MAG and Krox-20, were downregulated time dependently in SCs exposed to high glucose from 48 to 96h. To further elucidate the underlying pathogenic mechanisms, we also explored the role of ERK signaling pathway in high glucose induced SC injury, which has been proved to drive demyelination of peripheral nerves. The western blot analysis showed that compared with control group phosphorylation level of ERK was increased by 14.3% in SCs exposed to high glucose for 72h (P<0.01). Using immunocytochemistry analysis, we observed that the ERK specific inhibitor U0126 blocked the ERK activation induced by high glucose and reversed the inhibitory effect of high glucose on P0 expression. Taken together, these results suggest that high glucose can cause damage in primary cultured SCs and may exert the inhibitory effect on SC differentiation and myelination through ERK signaling activation.

Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging.

Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include distressing painful neuropathic symptoms and insensitivity to trauma that result in foot ulcerations and amputations. Several recent studies have implicated poor glycemic control, duration of diabetes, hyperlipidemia (particularly hypertryglyceridaemia), elevated albumin excretion rates, and obesity as risk factors for the development of DPN. However, similar data are not available for painful DPN. Moreover, although there is now strong evidence for the importance of peripheral nerve microvascular disease in the pathogenesis of DPN, peripheral structural biomarkers of painful DPN are lacking. However, there is now emerging evidence for the involvement of the central nervous system in both painful and painless DPN afforded by magnetic resonance imaging. This review will focus on this emerging evidence for central changes in DPN, hitherto considered a peripheral nerve disease only.

Xanthine Oxidase Activity in Type 2 Diabetes Mellitus Patients with and without Diabetic Peripheral Neuropathy.

This study investigated the relationship between serum xanthine oxidase (XOD) activity and the occurrence of diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. Serum XOD activity, ischemia-modified albumin (IMA), uric acid (UA), albumin, glycated hemoglobin (HbA1c), advanced glycation end products (AGE), total free thiols, atherogenic index of plasma (AIP), and body mass index (BMI) were measured in 80 T2DM patients (29 with and 51 without DPN), and 30 nondiabetic control subjects. Duration of diabetes, hypertension, medication, and microalbuminuria was recorded. Serum XOD activities in controls, non-DPN, and DPN were 5.7 ± 2.4 U/L, 20.3 ± 8.6 U/L, and 27.5 ± 10.6 U/L (p < 0.01), respectively. XOD activity was directly correlated to IMA, UA, BMI, HbA1c, and AGE, while inversely correlated to serum total free thiols. A multivariable logistic regression model, which included duration of diabetes, hypertension, AIP, HbA1c, UA, and XOD activity, revealed HbA1c [OR = 1.03 (1.00–1.05); p = 0.034] and XOD activity [OR = 1.07 (1.00–1.14); p = 0.036] as independent predictors of DPN. Serum XOD activity was well correlated to several other risk factors. These results indicate the role of XOD in the development of DPN among T2DM patients.

HLA class II alleles and risk for peripheral neuropathy in type 2 diabetes patients.

The potential impact of human leukocyte antigen (HLA) genotype variations on development of diabetic peripheral neuropathy (DPN) is not well determined. This study aimed to identify the association of HLA class II alleles with DPN in type 2 diabetes (T2D) patients. Totally 106 T2D patients, 49 with DPN and 57 without DPN, and 100 ethnic-matched healthy controls were analyzed. Both groups of the patients were matched based on sex, age, body mass index (BMI) and duration of T2D. Polyneuropathy was diagnosed using electrodiagnostic methods. HLA-DRB1 and DQB1 genotyping was performed in all subjects by the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. T2D patients with DPN showed higher frequencies of HLA-DRB1*10 and DRB1*12 alleles compared to control group (P = 0.04). HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype were associated with a decreased risk for developing DPN in T2D patients (P = 0.02 and P = 0.05 respectively). Also, patients with severe neuropathy showed higher frequencies of DRB1*07 (P = 0.003) and DQB1*02 (P = 0.02) alleles than those with mild-to-moderate form of neuropathy. The distribution of DRB1 and DQB1 alleles and haplotypes were not statistically different between all patients and healthy controls. Our findings implicate a possible protective role of HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype against development of peripheral neuropathy in T2D patients. Therefore, variations in HLA genotypes might be used as genetic markers for prediction and potentially management of neuropathy in T2D patients.

Preventive Effects of the Chinese Herbal Medicine Prescription Tangkuei Decoction for Frigid Extremities on Sciatic Neuropathy in Streptozotocin-Induced Diabetic Rats.

Ischemia and hypoxia are important physiological changes in diabetic peripheral neuropathy (DPN). Chinese herbal medicine prescription Tangkuei Decoction for Frigid Extremities (TDFE) is useful for increasing blood flow. To help determine whether TDFE could protect the peripheral nerves of diabetic patients from the degeneration caused by high blood glucose, TDFE was administered to streptozotocin-induced diabetic rats for 6 or 12 weeks. Plantar thermal stimulation reaction time thresholds, sciatic nerve conduction velocities, and the levels of HIF-1α mRNA, HIF-1α protein, VEGF protein, and the endothelial marker vWF in sciatic nerves were measured at the end of the sixth and twelfth weeks. The thermal thresholds and sciatic nerve conduction velocities of the rats differed after 12 weeks, and the sciatic nerves of the diabetic rats that were given TDFE displayed higher levels of HIF-1α protein, VEGF protein, and HIF-1α mRNA than those of the diabetic model rats. The results at 6 weeks differed from those at 12 weeks. These results suggest that the early preventive application of TDFE effectively delayed the development of DPN and that TDFE increased HIF-1α mRNA levels in the sciatic nerves of diabetic rats through 12 weeks of treatment.

Effect of levetiracetam versus gabapentin on peripheral neuropathy and sciatic degeneration in streptozotocin-diabetic mice: Influence on spinal microglia and astrocytes

Peripheral diabetic neuropathy develops in diabetic patients. The current study tested the antiallodynic and antihyperalgesic effects of the anticonvulsant drug, levetiracetam compared with the standard drug, gabapentin, in a model of streptozotocin-induced peripheral diabetic neuropathy. Male albino mice were injected intraperitoneally with streptozotocin (40mg/kg) for five consecutive days to induce type 1 diabetes mellitus. After development of peripheral diabetic neuropathy, mice were then treated orally with 10 doses of levetiracetam or gabapentin (or vehicle). The effect of multiple doses of levetiracetam on the histopathology of sciatic nerve and spinal cord was tested. Furthermore, the effect of levetiracetam on the spinal expression of microglia and astrocytes was examined in comparison with gabapentin. Results indicated that the highest dose of levetiracetam and all doses of gabapentin increased the withdrawal threshold in von Frey test. Furthermore, all doses of levetiracetam and gabapentin prolonged the reaction time exhibited by diabetic mice tested in hot plate test. Both drugs provided protection for the sciatic nerve and the spinal cord. In addition, levetiracetam (20 and 40mg/kg) decreased spinal immunostaining for CD11b (microglia marker) and glial fibrillary acidic protein (GFAP, astrocytes marker) however; the high dose of gabapentin (40mg/kg) reduced the spinal immunostaining for GFAP only. In conclusion, levetiracetam produced antiallodynic and antihyperalgesic effect in diabetic mice with favorable effects on sciatic nerve and spinal cord that were accompanied by downregulation of the spinal expression of microglia and astrocytes. Thus, levetiracetam may have promise in alleviating neuropathic pain in diabetic patients.

Exogenous brain-derived neurotrophic factor relieves pain symptoms of diabetic rats by reducing excitability of dorsal root ganglion neurons

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking of effective treatments. Enhanced excitability of dorsal root ganglion (DRG) neuron plays a crucial role in the progression of diabetic neuropathic hyperalgesia. Brain-derived neurotrophic factor (BDNF) is known as a neuromodulator of nociception, but whether and how BDNF modulates the excitability of DRG neurons in the development of DPN remain to be clarified. This study investigated the role of exogenous BDNF and its high-affinity tropomyosin receptor kinase B (TrkB) in rats with streptozotocin-induced diabetic neuropathic pain. The results showed that continued intrathecal administration of BDNF to diabetic rats dramatically alleviated mechanical and thermal hyperalgesia, as well as inhibited hyperexcitability of DRG neurons. These effects were blocked by pretreatment with TrkB Fc (a synthetic fusion protein consisting of the extracellular ligand-binding domain of the TrkB receptor). The expression of BDNF and TrkB was upregulated in the DRG of diabetic rats. Intrathecal administration of BDNF did not affect this upregulation. These data provide novel information that exogenous BDNF relieved pain symptoms of diabetic rats by reducing hyperexcitability of DRG neurons and might be the potential treatment of painful diabetic neuropathy.

Sensory Functions, Balance, and Mobility in Older Adults With Type 2 Diabetes Without Overt Diabetic Peripheral Neuropathy: A Brief Report.

This study examined possible subtle degradation in sensory functions, balance, and mobility in older adults with type 2 diabetes (T2D) prior to overt development of diabetic peripheral neuropathy (DPN). Twenty-five healthy controls (HC group, age = 74.6 ± 5.4) and 35 T2D elderly without DPN (T2D group, age = 70.6 ± 4.7) were recruited. Sensory assessment included vibrotactile sensitivity, bilateral caloric weakness, and visual contrast sensitivity. Self-report measures comprised of Activity-Specific Balance Confidence (ABC), Human Activity Profile-adjusted activity scores (HAP-AAS), falls, and mobility disability. Performance measures included modified Timed-Up and Go (mTUG), Clinical Test of Sensory Integration for Balance (mCTSIB), and Frailty and Injuries (FICSIT-4) balance test. T2D group demonstrated significantly worse bilateral caloric weakness, marginally higher threshold of vibrotactile sensitivity and lower visual contrast sensitivity, and as well as signifcantly lower HAP-AAS. A significantly higher proportion of the T2D group failed mCTSIB Condition 4 than in the HC group. Subtle changes in multiple sensory systems of older adults with T2D may reduce redundancy available for balance control while performing challenging activities much before DPN development.

RETRACTED ARTICLE: Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis

Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95 % confidence interval (95 % CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95 % CI 1.12–1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95 % CI 1.08–1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN.

Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin.

Hyperhomocysteinemia and vitamin B12 deficiency may be involved in the development of diabetic peripheral neuropathy (DPN). Metformin therapy may reduce vitamin B12 plasma levels, thus contributing to DPN. The purposes of this cross-sectional study were to assess (1) the potential associations of DPN with serum levels of homocysteine (tHcy), B-vitamins, and/or the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation; (2) the influence of chronic treatment with metformin on tHcy and B-vitamins concentrations and, finally, (3) to evaluate whether, by this influence, metformin is a risk factor for DPN in a group of type 2 diabetic outpatients. Our data showed that fasting tHcy, folate, and vitamin B12 levels and the MTHFR C677T genotype distribution were comparable between subjects with (n = 79, 30 %) and without DPN (n = 184, 70 %). Metformin-treated subjects (n = 124, 47 %) showed significantly lower levels of vitamin B12 (P < 0.001), but the prevalence of DPN was not different when compared to those not treated with this drug (33 vs. 27 %, P = NS). At univariate regression analysis, DPN was associated with age, duration of diabetes, HbA1c, creatinine levels, and the presence of coronary heart disease (CHD), and negatively with HDL-C concentrations (P < 0.05 all), but at multivariate regression analysis, high creatinine levels (P = 0.06), low HDL-C levels (P = 0.013), and a higher prevalence of CHD (P = 0.001) were the only variables independently associated with DPN in this population. In conclusion, in these type 2 diabetic outpatients circulating levels of tHcy, folate, and the MTHFR C677T mutation are not associated with DPN, which was predicted by creatinine levels, CHD, and dyslipidemia. Metformin therapy is associated with a mild vitamin B12 level reduction, but not with DPN.

Pharmacokinetics of the transdermal delivery of benfotiamine.

Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy. A single application of 10mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24h. At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals. This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.

Microvessel permeability correlates with diabetic peripheral neuropathy in early stage of streptozotocin-induced diabetes rats

AimsThis study aims to explore the alterations in microvessel permeability in the sciatic nerve and whether they are associated with the development of diabetic peripheral neuropathy (DPN) during the early stage of diabetes in rats. MethodsSprague–Dawley rats were injected with streptozotocin and assessed at 0, 2, 4, and 8weeks. Rats in the control group received the vehicle. Changes in sciatic nerve pathology, nerve conductive velocity (NCV), permeability of microvessel, and levels of vascular endothelial growth factor (VEGF) were examined. ResultsThe morphology and NCV of sciatic nerves showed signs of abnormality as early as 2weeks after streptozotocin injection. The microvessel permeability as monitored by water and Evans blue content of sciatic nerve had increased dramatically at 4 and 8weeks. The water and Evans blue content both negatively correlated with NCV. VEGF was found in axons as well as the myelin sheaths in diabetic rats but not in control rats. ConclusionsThe permeability of sciatic nerves was associated with the development of DPN in the early stage of diabetes in rats. Increased expression of VEGF may have a crucial role in changes in microvessel permeability and DPN.

Increased aortic stiffness predicts future development and progression of peripheral neuropathy in patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study.

Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication that is strongly associated with poor glycaemic control and also with a worse prognosis. We aimed to evaluate the predictors of the development and progression of DPN in a cohort of high-risk patients with type 2 diabetes. In a prospective study, 477 patients with type 2 diabetes were clinically assessed for the presence of DPN at baseline and after a median follow-up of 6.2 years (range 2-10 years). Clinical laboratory data were obtained at study entry and throughout the follow-up. Aortic stiffness was assessed by the carotid-femoral pulse wave velocity (cf-PWV) at baseline. Multivariate Poisson regression analysis was used to examine independent predictors of the development/progression of DPN. At baseline, 135 patients (28%) had DPN, and during follow-up 97 patients (20%) had either a new development or a worsening of DPN. Patients who showed a development or progression of DPN were taller and had a longer duration of diabetes, a greater prevalence of other microvascular complications and hypertension, greater aortic stiffness and poorer glycaemic control than patients who did not have new or progressive neuropathy. After adjustments for the baseline prevalence of DPN, the patient's age and sex, and the time interval between DPN assessments; an increased aortic stiffness (cf-PWV >10 m/s) were predictive of new/progressive DPN (incidence rate ratio 2.04, 95% CI 1.28, 3.23; p = 0.002). Other independent predictors were the mean first-year HbA1c level (p = 0.05), nephropathy (p = 0.006), arterial hypertension (p = 0.06) and height (p = 0.03). Increased aortic stiffness at baseline predicts the future development or progression of peripheral neuropathy, independent of diabetic metabolic control, suggesting a physiopathological link between macrovascular and microvascular abnormalities in type 2 diabetes.

Capsule Commentary on Clair et al., The Effect of Cigarette Smoking on Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis

In this study, Clair et al. use a systematic review and meta-analysis to describe and quantify the association between smoking and a microvascular complication of diabetes—diabetic peripheral neuropathy (DPN). The odds of being a smoker were higher in patients who developed DPN.1 This was observed in prospective studies that adjusted for covariates (HbA1c etc.), that studied type 1 patients (n = 3854), and that had a follow-up period of ≥ 5 years. It was not seen among type 2 diabetics (n = 1317 patients) and with a follow-up period < 5 years. Smoking has been identified as a risk factor for progression of microvascular complications in type 1 and nephropathy in type 2 diabetes.2,3 It is thought to be a risk factor for development of type 2 diabetes mellitus (DM).4 The relationship between smoking and other microvascular complications (retinopathy, neuropathy) in type 2 DM is unclear. In fact, one of the largest prospective studies (n = 903 patients) concluded that smoking might offer “protection” against development and progression of retinopathy.5 A similar signal of “protection” could be inferred from this study’s analyses of type 2 DM patients, although it could also be argued that the analysis was underpowered. Prospective studies that are suitably powered are needed in type 2 diabetes patients. If this signal of “protection” is replicated, it certainly opens up avenues for investigating novel compounds for treating a costly complication. It also raises the question, “Does the natural history of microvascular complications differ between patients with type 1 and type 2 diabetes?”. The association seen in type 1 patients, combined with its propensity to worsen insulin resistance in type 2 patients, should serve as some among the many reasons to encourage tobacco cessation in our diabetic patients. Further studies are needed to define risk factors and to understand the epidemiology of this debilitating condition. This study adds to the wealth of evidence suggesting smoking as a risk factor for the development of DPN in patients with type 1 diabetes and raises important questions about DPN in type 2 patients.

Significance of functional GRP78 polymorphisms in predicting the onset of type 2 diabetic peripheral neuropathy in Chinese population

Objective:The objective of this study is to investigate the significance of functional GRP78 polymorphisms in predicting the risk of type 2 diabetic peripheral neuropathy in Chinese population.Methods:Between the years of 2006 and 2010, a total of 295 definitely diagnosed type 2 diabetes mellitus (T2DM) patients were included into our study cohort and followed for 3 years. At baseline and annual re-examinations, the patients underwent physical examinations, laboratory tests and evaluation of Michigan diabetic neuropathy score (MDNS). Age, gender, disease course, waist-hip circumference ratio (WHR), body mass index (BMI), triglycerine (TG), total cholesterol (Tch), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glycosylated haemoglobin (HbA1c), uric acid elimination rate (UAER) and uric acid (UA) were recorded and GRP78 polymorphisms were tested by direct sequencing. The prognostic significance of GRP78 polymorphisms were analysed using monovariate and multivariate logistic regression.Results:Three years after baseline, 32.9% (97/295) of the T2DM patients had suffered the development of diabetic peripheral neuropathy and GRP78 rs391957 promoter polymorphism is a significant risk factor for the onset of type 2 diabetic peripheral neuropathy. In monovariate regression model, the OR values of GRP78 rs391957 promoter polymorphism were 2.233 (C/T) and 2.734 (T/T). As for the model calibrated with demographic and laboratory indexes, the OR values were, respectively, 2.124 (C/T) and 2.423 (T/T).Conclusion:Our study suggested that the GRP78 rs391957 promoter polymorphism is a potential risk factor for type 2 diabetic peripheral neuropathy.

Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes.

Several studies have suggested that bilirubin, a potent innate antioxidant, plays a protective role against cardiovascular and microvascular disease. This study investigated the association between serum concentrations of total bilirubin (TB) and the presence of diabetic peripheral neuropathy (DPN) in Korean diabetic patients. This cross-sectional study involved 1207 patients aged more than 30 years with type 2 diabetes. DPN was assessed according to clinical symptoms and physical examinations using Michigan Neuropathy Screening Instrument examination score, 10-g monofilament sensation, and current perception threshold. The subjects were stratified into gender-specific tertiles based on TB values, and the relationship between the TB values and DPN was analyzed. Compared with patients within the lowest TB tertile, those with higher TB levels consisted of patients with shorter duration of diabetes, lower HbA1c, better renal function, and less autonomic neuropathy, retinopathy, and albuminuria. Serum TB levels were inversely associated with DPN. In multivariate analysis for the development of DPN after adjusting for potential confounding factors including retinopathy, albuminuria, and autonomic neuropathy, the TB levels were inversely associated with the presence of DPN, both as a continuous variable [odds ratio (OR) per log standard deviation (SD) 0.79; 95% confidence interval (CI) 0.65-0.97; P = 0.022] and when categorized in tertiles (the highest vs. the lowest tertile; OR 0.63; 95% CI 0.40-0.99; P = 0.046). Low serum bilirubin levels are significantly associated with DPN, independently of classic risk factors and other microvascular complications. Further investigation is necessary to determine whether serum bilirubin has a prognostic significance on DPN.