Development Of Diabetic Peripheral Neuropathy Research Articles

Decreased plasma neuregulin 4 levels are associated with peripheral neuropathy in Chinese patients with newly diagnosed type 2 diabetes: A cross-sectional study

Neuregulin-4 (Nrg4) is a novel adipokine associated with obesity, hyperglycemia, insulin resistance, dislipidemia, inflammation, and oxidative stress in mice and humans. However, no report has demonstrated the relationship of circulating Nrg4 with diabetic peripheral neuropathy (DPN). The objective of our study was to investigate the relationship between circulating Nrg4 and DPN in a cross-sectional study. Circulating Nrg4 levels were determined with an enzyme-linked immunosorbent assays kit in 132 newly diagnosed type 2 diabetes mellitus (nT2DM) patients and 41 normal controls (NC group). The associations of circulating Nrg4 with other parameters were also analyzed. Circulating Nrg4 levels were significantly lower in nT2DM patients with no DPN than in NC subjects, and were further markedly decreased in nT2DM patients with DPN (P < 0.01 or P < 0.05). Circulating Nrg4 levels were progressively decreased with an increasing number of abnormal DPN screening (P for trend < 0.01). Circulating Nrg4 levels correlated negatively with 8-iso-prostaglandin F2α (8-iso-PGF2α), high-sensitivity C-reactive protein (hs-CRP) and vibration perception threshold (VPT) (all P < 0.01), and 8-iso-PGF2α, hs-CRP, glycated hemoglobin A1c and VPT were independently related factors to circulating Nrg4 in nT2DM patients (P < 0.01 or P < 0.05). Moreover, circulating Nrg4 was significantly associated with the development of DPN even after controlling for anthropometric, biochemical and clinical parameters. Additionally, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Nrg4 to predict DPN was 1.58 ng/mL (sensitivity 90.91%, specificity 54.55%, and area under the curve 0.716). These findings together suggested that circulating Nrg4 levels were reduced in DPN patients and Nrg4 may be a novel adipokine associated with inflammation, oxidative stress, and long-term glycemic control in nT2DM patients.

Correlation Between Different Stages of Diabetic Nephropathy and Neuropathy in Patients with T2DM: A Cross-Sectional Controlled Study

IntroductionEarly detection of diabetic peripheral neuropathy (DPN) is critical in patients with type 2 diabetes mellitus (T2DM) due to the lack of targeted therapy for DPN. We have investigated the relationship between different stages of diabetic nephropathy and DPN in an attempt to elucidate whether albuminuria can be used as an early warning signal of DPN progression.MethodsA total of 217 T2DM patients who met the inclusion criteria were recruited from the Department of Endocrinology, Nanfang Hospital between January 2016 and June 2016. These patients were placed in groups based on urinary albumin excretion rate (UAER) and estimated glomerular filtration rate. Nerve conduction studies, the Semmes–Weinstein monofilament test (SWMT) and the vibration perception threshold (VPT) test were conducted. Multiple linear regression analysis, multivariate logistic regression and receiver-operating characteristic (ROC) analysis were performed to investigate the relationship between different stages of diabetic nephropathy and DPN in these patients.ResultsSignificant differences were observed in the conduction velocity (CV) and amplitude of sensory/motor nerve potential among the T2DM patients at different stages of diabetic nephropathy (all p < 0.05). The UAER and duration of diabetes were found to be independent factors associated with the mean CV and amplitude of sensory/motor nerve potential (all p < 0.05). A disease duration of > 10 years (p = 0.025) and a higher total cholesterol value (p = 0.024) were found to be significantly associated with abnormal SWMT results. A UAER of > 300 mg/24 h (p = 0.007) and a diastolic blood pressure of > 100 mmHg (p = 0.042) were associated with a higher risk for abnormal VPT. A UAER of > 300 mg/24 h (p < 0.001) and a disease duration of > 10 years (p = 0.02) were observed to be significantly correlated with DPN. The ROC analysis showed that the optimal cutoff values of UAER and duration as indicators of DPN were 90.5 mg/24 h and 9.5 years, respectively (both p < 0.001).ConclusionsThe results suggest that diabetic nephropathy is closely associated with the development of DPN in T2DM patients and that UAER and disease duration can be used as warning indicators of DPN progression.Chinese Clinical Trials Register NumberChiCTR-ROC-16007701.

Diagnostic Significance of Serum Levels of Nerve Growth Factor and Brain Derived Neurotrophic Factor in Diabetic Peripheral Neuropathy.

BackgroundOur study aimed to explore the levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in healthy participants, type 2 diabetes mellitus (T2DM) patients, and diabetic peripheral neuropathy (DPN) patients in order to find their effects on DPN.Material/MethodsThe clinical data of 110 healthy participants (age: 57.3±8.2 year, height: 165.4±5.5 cm, weight: 64.1±7.5 kg), 83 T2DM patients (age: 56.5±7.9 year, height: 164.8±6.2 cm, and weight: 63.6±6.6 kg), and 65 DPN patients (age: 58.2±7.3 year, height: 166.7±6.7 cm, weight: 63.1±5.8 kg) were observed. ELISA was applied to detect serum NGF and BDNF levels. Receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic value of serum NGF and BDNF levels in DPN. Logistic regression analysis was performed to analyze risk factors for DPN.ResultsSerum NGF and BDNF levels decreased most in DPN patients. Subsequently, we determined that serum NGF and BDNF levels were correlated with: the course of disease for patients, fasting C-peptide (FCP), 2-hour postprandial C-peptide level (2-h PCP), glycosylated hemoglobin level (HbAlc), and 24-hour urinary microalbumin excretion (24-h UME). ROC curve analysis identified high sensitivity, specificity, and accuracy of NGF and BDNF levels on DPN. Serum levels of NGF and BDNF, course of disease, 2-h PCP level, and postprandial blood glucose level were determined to be risk factors for DPN.ConclusionsOur study highlights that serum levels of NGF and BDNF might be associated with the occurrence and development of DPN.

Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy.

Schwann cells actively interact with axons of dorsal root ganglia (DRG) neurons. Exosomes mediate intercellular communication by transferring their biomaterials, including microRNAs (miRs) into recipient cells. We hypothesized that exosomes derived from Schwann cells stimulated by high glucose (HG) exosomes accelerate development of diabetic peripheral neuropathy and that exosomal cargo miRs contribute to this process. We found that HG exosomes contained high levels of miR-28, -31a, and -130a compared to exosomes derived from non-HG-stimulated Schwann cells. In vitro, treatment of distal axons with HG exosomes resulted in reduction of axonal growth, which was associated with elevation of miR-28, -31a, and -130a and reduction of their target proteins of DNA methyltransferase-3α, NUMB (an endocytic adaptor protein), synaptosome associated protein 25, and growth-associated protein-43 in axons. In vivo, administration of HG exosomes to sciatic nerves of diabetic db/db mice at 7 wk of age promoted occurrence of peripheral neuropathy characterized by impairment of nerve conduction velocity and induction of mechanic and thermal hypoesthesia, which was associated with substantial decreases in intraepidermal nerve fibers. Our findings demonstrate a functional role of exosomes derived from HG-stimulated Schwann cells in mediating development of diabetic peripheral neuropathy.-Jia, L., Chopp, M., Wang, L., Lu, X., Szalad, A., Zhang, Z. G. Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy.

High-Fat Diet Induces Mitochondrial Dysfunction in Saphenous Nerve Axons—A Study by Confocal Microscopy In Vivo

Diabetic peripheral neuropathy (DPN) is a common, progressive and irreversible complication of diabetes (DM). Glucose regulation has no effect on the development and/or progression of the disease in type 2 DM and so, as the prevalence of DM increases, there is a growing unmet need for a mechanism-based therapy. We have examined the effect of high fat diet (HFD, 60% kcal fat) on axonal mitochondrial membrane potential and intra-axonal Ca2+ concentration [Ca2+]i in C56Bl/6 mice, in vivo, using confocal microscopy. The HFD resulted in obesity, hyperglycaemia and glucose intolerance. Mitochondria within saphenous nerve axons of mice fed a HFD for 16 or 36 weeks were significantly depolarised compared with those in mice fed a control diet. Furthermore, HFD mitochondria did not depolarise in response to high frequency electrical stimulation, in contrast to controls where depolarisation is associated with the increased energy demand of sustained impulse conduction. Confocal microscopy revealed that the number of mobile mitochondria was significantly greater in electrically active axons after 16 weeks of HFD, compared with controls, whereas after 36 weeks the number was significantly lower. Histologically, these changes were accompanied by significantly increased labelling for the mitochondrial biogenesis marker PGC1α in neuronal cell bodies at 16 weeks, but a reduction at 36 weeks, consistent with exhaustion of compensatory mechanisms activated early in the disease course. Interestingly, we found that [Ca2+]i was decreased in mice fed a HFD. We conclude that a HFD impairs axonal mitochondrial function early in the course of type 2 MD. Impaired ATP production, especially during sustained impulse activity, may be a mechanism in the development of DPN. Disclosure M. Sajic: None. A. Kanhai: None. G. Dentoni: None. S. Varatharajah: None. L.M. Hinder: None. A. Rumora: None. E.L. Feldman: None. K. Smith: None.

Deletion of the insulin receptor in sensory neurons increases pancreatic insulin levels

Insulin is known to have neurotrophic properties and loss of insulin support to sensory neurons may contribute to peripheral diabetic neuropathy (PDN). Here, genetically-modified mice were generated in which peripheral sensory neurons lacked the insulin receptor (SNIRKO mice) to determine whether disrupted sensory neuron insulin signaling plays a crucial role in the development of PDN and whether SNIRKO mice develop symptoms of PDN due to reduced insulin neurotrophic support. Our results revealed that SNIRKO mice were euglycemic and never displayed significant changes in a wide range of sensorimotor behaviors, nerve conduction velocity or intraepidermal nerve fiber density. However, SNIRKO mice displayed elevated serum insulin levels, glucose intolerance, and increased insulin content in the islets of Langerhans of the pancreas. These results contribute to the growing idea that sensory innervation of pancreatic islets is key to regulating islet function and that a negative feedback loop of sensory neuron insulin signaling keeps this regulation in balance. Our results suggest that a loss of insulin receptors in sensory neurons does not lead to peripheral nerve dysfunction. The SNIRKO mice will be a powerful tool to investigate sensory neuron insulin signaling and may give a unique insight into the role that sensory neurons play in modifying islet physiology.

Sigma 1 receptor mediated HMGB1 expression in spinal cord is involved in the development of diabetic neuropathic pain

No study has been conducted to examine the interactions of sigma-1 receptor (Sigma-1R) and high mobility group box 1 protein (HMGB1) in the development of diabetic peripheral neuropathy. Thus, we examined the effects of streptozotocin (STZ) treatment on expression of HMGB1 in subcellular levels in the dorsal root ganglion (DRG) in both wild-type and Sigma-1R−/− mice and evaluated the effects of repeated intrathecal administrations of selective Sigma-1R antagonists BD1047, agonist PRE-084, or HMGB1 inhibitor glycyrrhizin on peripheral neuropathy in wild-type mice. We found that STZ-induced tactile allodynia and thermal hyperalgesia was associated with increased total HMGB1 expression in DRG. STZ treatment promoted the distribution of HMGB1 into cytoplasm. Furthermore, STZ induced modest peripheral neuropathy and did not alter HMGB1 levels in DRG or the distribution of either cytoplasmic or nuclear HMGB1 in Sigma-1R−/− mice compared to sham control mice. Additionally, repeated stimulation of Sigma-1R in the spinal cord induced tactile allodynia and thermal hyperalgesia at 1 week. This phenomenon was associated with increased cytoplasmic HMGB1 translocation and HMGB1 expression in DRG. Finally, we found that repeated blockade of either Sigma-1R or HMGB1 in the spinal cord after STZ treatment prevent the development of tactile allodynia and thermal hyperalgesia at 1 week. These effects were associated with decreased cytoplasmic HMGB1 translocation and HMGB1 expression in DRG. Taken together, our results suggest that Sigma-1R-mediated enhancement of HMGB1 expression in the DRG is critical for the development of peripheral neuropathy in type 1 diabetes.

Evaluation and Comparison of Blood Parameters in Diabetic Patients with and without Peripheral Neuropathy

Introduction: Diabetic Peripheral Neuropathy (DPN) is the most prevalent and troublesome microvascular complication (50%) of Diabetes Mellitus (DM). The factors involved in the pathogenesis of diabetic neuropathy have not been understood completely. Studies have shown that neuronal dysfunction and inflammation play important roles in the development of DPN. Aim: To evaluate and compare the inflammatory marker Neutrophil to Lymphocyte Ratio (NLR) and serum markers calcium, urea, and uric acid in diabetic patients with and without peripheral neuropathy. Materials and Methods: We prospectively studied 118 diabetic patients who visited Kasturba Hospital, Manipal, Karnataka, India during December 2016- June 2017. After obtaining the ethical approval (IEC 791/2016), the patients were grouped into those with DPN (n=55) and without DPN (n=63). NLR and serum markers calcium, urea, and uric acid were estimated. Results: The data were analysed using Student's t-test and Mann-Whitney U test and revealed a significantly high uric acid (p<0.001) and low calcium levels (p<0.001) in DPN patients compared to controls. The NLR was significantly high in DPN group {2.62 (2.3-3.1)} compared to that {1.9 (1.6-2.4)} in non-DPN group (p<0.001). Conclusion: Monitoring the simple biomarkers routinely in diabetic patients may give an early signal to prevent DPN and thus better management of the patients.

Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation.

PurposeRecent evidence has shown the involvement of inflammation in the development of diabetic peripheral neuropathy (DPN). MicroRNA-146a (miR-146a) is closely involved in the inflammatory response. However, the role of miR-146a in the inflammatory reaction in DPN has not been clarified. This study was designed to explore the role of miR-146a in the regulation of inflammatory responses in DPN.MethodsRats were randomly divided into three groups (n=6 per group): control group, type 2 diabetes mellitus (T2DM) group and DPN group. T2DM and DPN rats were intraperitoneally injected with streptozotocin. Sciatic nerve conduction velocity (NCV) was determined at the 6th week and the 12th week in each group. The expression of microRNAs was detected by quantitative real-time polymerase chain reaction in three sciatic nerves for each group of rats. Expression of inflammatory cytokines in nerve tissues and plasma was measured by Western blot and Bio-Plex Pro™ assays.ResultsThe NCV and expression levels of miR-146a in the DPN group were significantly decreased (P<0.01) compared to the other two groups. Expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the DPN group was significantly increased compared with the control and T2DM groups (P<0.01). Pearson’s correlation analysis showed that the expression level of miR-146a was negatively correlated with the levels of IL-1β, TNF-α and NF-κB.ConclusionmiR-146a is involved in the pathogenesis of DPN, and its expression level is closely related to the inflammatory responses that aggravate sciatic nerve injuries.

Susceptible and Prognostic Genetic Factors Associated with Diabetic Peripheral Neuropathy: A Comprehensive Literature Review.

Type 2 diabetes mellitus (T2D) is a disorder of glucose metabolism. It is a complex process involving the regulation of insulin secretion, insulin sensitivity, gluconeogenesis, and glucose uptake at the cellular level. Diabetic peripheral neuropathy (DPN) is one of the debilitating complications that is present in approximately 50% of diabetic patients. It is the primary cause of diabetes-related hospital admissions and nontraumatic foot amputations. The pathogenesis of diabetic neuropathy is a complex process that involves hyperglycemia-induced oxidative stress and altered polyol metabolism that changes the nerve microvasculature, altered growth factor support, and deregulated lipid metabolism. Recent literature has reported that there are several heterogeneous groups of susceptible genetic loci which clearly contribute to the development of DPN. Several studies have reported that some patients with prediabetes develop neuropathic complications, whereas others demonstrated little evidence of neuropathy even after long-standing diabetes. There is emerging evidence that genetic factors may contribute to the development of DPN. This paper aims to provide an up-to-date review of the susceptible and prognostic genetic factors associated with DPN. An extensive survey of the scientific literature published in PubMed using the search terms “Diabetic peripheral neuropathy/genetics” and “genome-wide association study” was carried out, and the most recent and relevant literature were included in this review.

Peripheral Neuropathy in Children and Adolescents with Insulin-dependent Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) is a chronic immune-mediated disease. Diabetic peripheral neuropathy (DPN) is an important microvascular complication of T1DM. One of the most important risk factors for the development of DPN is poor glycemic control. We evaluated the prevalence of DPN among T1DM patients and determined the association between DPN and glycated hemoglobin (HbA1c) level. The subjects were recruited prospectively upon initial evaluation at Imam Reza Hospital, Mashhad, Iran from Jan 2013 to Jan 2015. Patients with T1DM were selected based on the inclusion criteria (i.e., age of 6≤yr and absence of other co-morbidities). DPN was assessed through electrodiagnostic studies and neurological examinations, while diabetes control was evaluated by measuring the HbA1c level. Fifty patients with T1DM were enrolled in this study. The mean diabetes duration of patients was 8.38±3.79 yr (mean age16.68±6.68 yr). The mean HbA1c level was 8.6±2.1% in patients without DPN and 10.5±3 in those with DPN (P=0.016). Overall, 24% of the subjects were presented with DPN according to nerve conduction velocity study (NCV) findings. A positive correlation was found between NCV and clinical symptoms with signs (P<0.001, r=0.45 and P<0.001, r=0.644, respectively). Sensitivity and specificity of neurological examination for DPN diagnosis were 91.7% and 63.2%, respectively. Poor diabetes control is associated with DPN. Moreover, HbA1c level was used as an index for glycemic control over the past 3 months. Rigid blood glucose control and periodic neurological examinations were the best strategies to prevent DPN.

Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively.

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy

Understanding the interactions between Notch1 and toll-like receptor 4 (TLR4) signaling pathways in the development of diabetic peripheral neuropathy may lead to interpretation of the mechanisms and novel approaches for preventing diabetic neuropathic pain. In the present study, the interactions between Notch1 and TLR4 signaling pathways were investigated by using dorsal root ganglion (DRG) from diabetic neuropathic pain rats and cultured DRG neurons under high glucose challenge. The results showed that high glucose induced not only Notch1 mRNA, HES1 mRNA, and TLR4 mRNA expression, but also Notch1 intracellular domain (NICD1) and TLR4 protein expression in DRG neurons. The proportion of NICD1-immunoreactive (IR) and TLR4-IR neurons in DRG cultures was also increased after high glucose challenge. The above alterations could be partially reversed by inhibition of either Notch1 or TLR4 signaling pathway. Inhibition of either Notch1 or TLR4 signaling pathway could improve mechanical allodynia and thermal hyperalgesia thresholds. Inhibition of Notch1 or TLR4 signaling also decreased tumor necrosis factor-α (TNF-α) levels in DRG from diabetic neuropathic rats. These data imply that the interaction between Notch1 and TLR4 signaling pathways is one of the important mechanisms in the development or progression of diabetic neuropathy.

Protective effects of methanolic extract of Juglans regia L. leaf on streptozotocin-induced diabetic peripheral neuropathy in rats

BackgroundOxidative stress has a pivotal role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complications of diabetes mellitus. There is accumulating evidence that Juglans regia L. (GRL) leaf extract, a rich source of phenolic components, has hypoglycemic and antioxidative properties. This study aimed to determine the protective effects of Juglans regia L. leaf extract against streptozotocin-induced diabetic neuropathy in rat.MethodsThe DPN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats intragastically administered with GRL leaf extract (200 mg/kg/day) before or after the onset of neuropathy, whereas other diabetic rats received only isotonic saline as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic neuropathy various parameters, including histopathology and immunohistochemistry of apoptotic and inflammatory factors were assessed along with nociceptive and biochemical assessments.ResultsDegeneration of the sciatic nerves which was detected in the STZ-diabetic rats attenuated after GRL leaf extract administration. Greater caspase-3, COX-2, and iNOS expression could be detected in the STZ-diabetic rats, which were significantly attenuated after GRL leaf extract administration. Also, attenuation of lipid peroxidation and nociceptive response along with improved antioxidant status in the sciatic nerve of diabetic rats were detected after GRL leaf extract administration. In other word, GRL leaf extract ameliorated the behavioral and structural indices of diabetic neuropathy even after the onset of neuropathy, in addition to blood sugar reduction.ConclusionOur results suggest that GRL leaf extract exert preventive and curative effects against STZ-induced diabetic neuropathy in rats which might be due to its antioxidant, anti-inflammatory, and antiapoptotic properties.Graphical abstractProtection against neuropathy

Associations between individual retinal layer thicknesses and diabetic peripheral neuropathy using retinal layer segmentation analysis

PurposeTo evaluate clinical correlations between the thicknesses of individual retinal layers in the foveal area of diabetic patients and the presence of diabetic peripheral neuropathy (DPN).MethodsThis retrospective, observational cross‐sectional study enrolled a total of 120 eyes from 120 patients. The eyes were divided into three groups: normal controls (n = 42 eyes), patients with diabetes mellitus (DM)(n = 42 eyes) but no DPN, and DM patients with DPN (n = 36 eyes). The primary outcome measures were the thickness of all retinal layers in the central 1 mm zone measured by using the segmentation analysis of spectral domain optical coherence tomography (SD‐OCT). Correlations between the thicknesses of the individual retinal layers and the presence of DPN were also analyzed. Logistic regression analyses were used to determine which change of layer thickness had the most significant association with the presence of DPN.ResultsThe mean thicknesses and the ratios of retinal nerve fiber layers (RNFLs) to total retina thicknesses in the DPN group were 10.77 ± 1.79 μm and 4.10 ± 0.55 percent (%), significantly lower than those in normal controls and the DM with no DPN group (p = 0.014 and p = 0.001, respectively). Logistic regression analyses also showed the decrease in thicknesses of the RNFLs and the INL are significant factors for predicting a higher risk for DPN development (odds ratio = 7.407 and 1.757; p &lt; 0.001 and p = 0.001, respectively).ConclusionsA decrease in the RNFL and the INL thickness was significantly associated with presence of DPN. Using SD‐OCT segmentation method, these structural changes could be used as a potential biomarker for early detection of DPN.

The association between vitamin D level and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus: An update systematic review and meta-analysis

AimRecently, increasing studies have been carried out to explore the association between vitamin D level and the development of diabetic peripheral neuropathy (DPN) in patients with diabetes mellitus (DM). However, because of the shortcoming in study design and sample size, there is still no clear conclusion. We performed this meta-analysis to examine the exact impact of vitamin D deficiency on DPN in type 2 diabetic patients. MethodsVarious databases were searched to identify the potential articles which explored the association between vitamin D level and diabetic peripheral neuropathy in type 2 diabetes. We pooled OR to assess the correlation between vitamin D deficiency and DPN using the random-effects model. The standardized mean difference (SMD) with 95% CI of vitamin D was also calculated to evaluate the vitamin D level between DPN and non DPN in T2DM. ResultsThere was obvious heterogeneity in those included ten studies (I2=94.1%, Cochran Q test P<0.001) using mean and standard deviation (SD) of vitamin D level. In Caucasian, vitamin D level was significantly lower in DPN patients compared with diabetic patients without DPN (SMD=−0.56, I2=16.9%). In Asian, the pooled OR value of vitamin D deficiency was 1.22 (95%CI: 1.17–1.27). Sensitivity analysis showed one study had great influence on this meta-analysis and it still existed after excluded that one. There was no evidence of public bias in meta analysis as showed in Begg test and Egger test. ConclusionThis meta-analysis indicates that vitamin D deficiency is associated with the generation and development of DPN in Caucasian with T2DM, and in Asian, diabetic patients with vitamin D deficiency are 1.22times to suffer from DPN compared with normal vitamin D level. Vitamin D supplementation is urgently needed to prevent the development of DPN in T2DM.

Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice.

Diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD) are common diabetic complications with limited treatment options. Experimental studies show that targeting inflammation using chemokine receptor (CCR) antagonists ameliorates DKD, presumably by reducing macrophage accumulation or activation. As inflammation is implicated in DPN development, we assessed whether CCR2 and CCR5 antagonism could also benefit DPN. Five-week-old ob/ob mice were fed a diet containing MK-0812, a dual CCR2-CCR5 receptor antagonist, for 8 weeks; DPN, DKD and metabolic phenotyping were then performed to determine the effect of CCR inhibition. Although MK-0812 reduced macrophage accumulation in adipose tissue, the treatment had largely no effect on metabolic parameters, nerve function or kidney disease in ob/ob mice. These results conflict with published data that demonstrate a benefit of CCR antagonists for DKD and hyperglycaemia. We conclude that CCR signaling blockade is ineffective in ob/ob mice and suspect that this is explained by the severe hyperglycaemia found in this model. It remains to be determined whether MK-0812 treatment, alone or in combination with improved glycaemic control, is useful in preventing diabetic complications in alternate animal models.

Changes in Nociceptive Thresholds and Adenylyl Cyclase System Activity in Skeletal Muscles in Rats with Acute and Mild Type 1 Diabetes

Diabetic peripheral neuropathy (DPN) is one of the commonest complications of type 1 diabetes mellitus (DM1). The aims of the present work were to study the dynamics of the development of pain-type DPN and the functional status of the hormone-sensitive adenylyl cyclase signal system (ACSS) in the skeletal muscle of rats with models of acute and mild DM1 and to investigate the influences on these of insulin therapy using different routes of hormone administration – intranasal and peripheral. The nociceptive threshold in rats decreased in both models of DM1; the stimulatory effects of guanine nucleotides (GIDP) and adrenergic agonists (isoproterenol, BRL-37344) on adenylyl cyclase (AC) also decreased. The AC-stimulating effect of relaxin decreased in animals with acute DM1, while the change in mild DM1 was minor. Peripheral administration of insulin to rats with acute DM1 increased the nociceptive threshold and partially restored the AC effect of the β3 agonist BRL-37344. Intranasal administration of insulin to rats with mild DM1 also led to an increase in the nociceptive threshold and partially restored basal and BRL-37344-stimulated AC activity in the skeletal muscle of diabetic animals. Thus, skeletal muscle in rats with acute and mild DM1 showed impaired nociceptive sensitivity and ACSS function, which was partially restored by treatment of animals with insulin given peripherally (acute DM1) or intranasally (mild DM1).

Association of aldose reductase gene polymorphism (C-106T) in susceptibility of diabetic peripheral neuropathy among north Indian population

Aim/HypothesisPolymorphism in aldose reductase (ALR) gene at nucleotide C(−106)T (rs759853) in the promoter region is associated with susceptibility to development of diabetic peripheral neuropathy. The aim of this study was to detect the association of the C (−106)T polymorphism of ALR gene and its frequency among patients with type 2 diabetes mellitus with and without peripheral neuropathy. MethodsThe study subjects were divided into three groups. Group I included 356 patients with diabetes having peripheral neuropathy. Group II included 294 patients with diabetes without peripheral neuropathy and group III included 181 healthy subjects. Genotyping of ALR C(−106)T SNPs was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing methods. The genetic risk among the groups was compared and tested by calculating odds ratio with 95% class interval. ResultsALR 106TT genotype was significantly higher in group I compared to group II with an odds ratio of 2.12 (95% CI: 1.22–3.67; p<0.01). Recessive model (CC+CT vs. TT), as well as T allele distribution also showed significant association to develop neuropathy with relative risk of 1.97 (95% CI: 1.16–3.35; p<0.01) and 1.36 (95% CI: 1.07–1.72; p=0.01) respectively. Conclusion/InterpretationIn conclusion, the ALR C-106T polymorphism was associated with higher risk of peripheral neuropathy in patients with type 2 diabetes mellitus.

Mediators of diabetic neuropathy: is hyperglycemia the only culprit?

Diabetic peripheral neuropathy (DPN) is a disabling, highly prevalent complication of both type 1 and type 2 diabetes mellitus (T1DM and T2DM). Large clinical studies support the concept that, in addition to hyperglycemia, components of the metabolic syndrome (MetS) may underlie the pathogenesis of DPN, especially in T2DM. This review will present the evidence supporting the MetS and its individual components as potential causal factors for the development of neuropathy. In addition to poor glycemic control and duration of diabetes, components of MetS such as dyslipidemia, obesity, and hypertension may have an important impact on the prevalence of DPN. Obesity and prediabetes have the most data to support their role in neuropathy, whereas hypertension and dyslipidemia have more mixed results. Nonmetabolic factors, such as genetic susceptibility, age, height, sex, smoking, and alcohol, have also been highlighted as potential risk factors in peripheral neuropathy, although the exact contribution of these factors to DPN remains unknown. DPN is a chronic and disabling disease, and the accurate identification and modification of DPN risk factors is important for clinical management. Recent data support a role for components of the MetS and other risk factors in the development of DPN, offering novel targets beyond hyperglycemia for therapeutic development.