Phenotypical characterization of exteroceptive sensation and pain symptoms on diabetic patients.

BACKGROUD: Diabetic neuropathy (DN) is one of the most common complications of diabetes, affecting about half of individuals with the disease. Among the various symptoms of DN, the development of chronic pain stands out and manifests as exacerbated responses to sensorial stimuli. The conventional clinical treatments used for general neuropathy and associated painful symptoms, still brings uncomplete and unsatisfactory pain relief. Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities which difficult the correct diagnosis of sensory comorbidities and consequently, the appropriate chronic pain management. AIMS: Herein, we aimed to demonstrate the existence of different sensory profiles on diabetic patients by investigating epidemiological and clinical data on the symptomatology of a group of patients with DN. METHODS: This is a longitudinal and observational study, with a sample of 57 volunteers diagnosed with diabetes from outpatient day clinic of Hospital Universitário of the University of São Paulo-Brazil. After being invited and signed the Informed Consent Form (ICF), patients were submitted to clinical evaluation and filled out pain and quality of life questionnaires. They also performed quantitative sensory test (QST) and underwent skin biopsy for correlation with cutaneous neuropathology. RESULTS: Data demonstrate that 70% of the studied sample presented some type of pain, manifesting in a neuropathic or nociceptive way, what has a negative impact on the life of patients with DM. We also demonstrated a positive association between pain and anxiety and depression, in addition to pain catastrophic thoughts. Three distinct profiles were identified in the sample, separated according to the symptoms of pain: (i) subjects without pain; (ii) with mild or moderate pain; (iii) subjects with severe pain. We also identified through skin biopsy that diabetic patients presented advanced sensory impairment, as a consequence of the degeneration of the myelinated and unmyelinated peripheral fibers. This study characterized the painful symptoms and exteroceptive sensation profile in these diabetic patients, associated to a considerable level of sensory degeneration, indicating, and reinforcing the importance of the long-term clinical monitoring of individuals diagnosed with DM, regarding their symptom profiles and exteroceptive sensitivity.

Prevalence of Painful Diabetic Peripheral Neuropathy Among Saudi Patients With Diabetes in Al Ahsa: A Cross-Sectional Study.

Background and aim Diabetic neuropathy is one of the most common long-term complications of diabetes. A frequent presentation of neuropathy is painful diabetic peripheral neuropathy (PDPN), which is associated with morbidity and disability among patients with diabetes. This study aims to estimate the prevalence of PDPN and its associated factors among patients with type 2 diabetes mellitus (T2DM) attending primary healthcare (PHC) in Al Ahsa. Methodology A cross-sectional study was conducted on patients with diabetes at National Guard PHC clinics in Al Ahsa, Saudi Arabia. An interview-administered questionnaire was used to collect information about clinicodemographic characteristics, and the Douleur Neuropathique-4 (DN4) questionnaire was used to identify the presence of PDPN.  Results A total of 342 patients with T2DM were included. The prevalence of PDPN was 29.8%. Patients' ages ranged from 25-70 years, with a mean age of 48.5 ± 12.3 years. The majority were female (118, 52.6%), with obesity detected among 115 (33.6%) individuals. Significant predictors of PDPN included noncompliance to treatment (odds ratio [OR] = 5.9, P = 0.001), female gender (OR = 3.5, P = 0.001), presence of other comorbidities (OR = 1.7, P = 0.001), and diabetes duration exceeding 15 years (OR = 1.5, P = 0.001). Conclusions This study revealed that PDPN was frequent among patients with diabetes in Al Ahsa, which was at an intermediate frequency relative to reported national and global literature levels. Identifying patients who are at high risk and implementing timely interventions are crucial.

The Relationship Between Diabetic Neuropathy and Uric Acid/High-Density Lipoprotein Ratio in Patients With Type-2 Diabetes Mellitus.

BACKGROUND: We aimed to investigate whether there was a relationship between diabetic peripheral distal neuropathy (DPDN), one of the most common chronic complications in patients with type 2 diabetes mellitus (T2DM), and the uric acid/HDL ratio, which can be used as an indicator of poor metabolic status. METHODOLOGY: The study consisted of a total of 150 subjects, including 50 patients with T2DM (group 1) who were determined to have diabetic peripheral distal neuropathy with electroneuromyography (ENMG), 50 patients with T2DM who were determined to not have DPDN in their ENMG (group 2), and 50 healthy individuals (group 3). Participants' serum fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), uric acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were analyzed. The uric acid/HDL-C ratio (UHR) was calculated. The relationship between UHR and other parameters was evaluated in all three groups. RESULTS: Patients with T2DM who had diabetic neuropathy (group 1), did not have diabetic neuropathy (group 2), and healthy subjects (group 3) were similar in terms of age and gender (p=0.066, p=0.185). Groups 1 and 2 were similar in terms of the duration of diabetes and FBG values (p=0.825, p=0.572), but these values were lower in group 3 than in groups 1 and 2 (p<0.05). HbA1c did not differ significantly between groups 1 and 2 (p=0.607). Creatinine levels were similar in the three groups. Uric acid levels were significantly higher in group 1 than in group 2 (p=0.040), but there was no significant difference between groups 1 and 3 or between groups 2 and 3 (p>0.05). UHR was significantly lower in group 1 than in groups 2 and 3 (p<0.001), but no significant difference was found between groups 2 and 3. CONCLUSION: In our study, we found that the UHR level of the group with diabetic neuropathy was statistically significant compared to the levels of the other two groups. However, no significant difference was found between the patients with diabetes who did not have neuropathy and the healthy group. Based on the findings of our study, we can say that the UHR level is a predictor of the microvascular complications of diabetes.

Relationship between deep and superficial sensitivity assessments and gait analysis in diabetic foot patients.

Peripheral neuropathy is a prevalent complication of diabetes that can lead to gait impairment and its adverse consequences. This study explored the potential utility of different parameters of gait analysis using a single sensor unit as a simple tool to detect peripheral neuropathy in 85 diabetic patients (DP) with diabetic foot in whom different somato-sensitivity tests in the feet were performed. Gait spatiotemporal parameters were examined by sensor inertial measurement placed in the lumbar area, while the superficial sensitivity pathway was assessed by nociception tests and deep sensitivity was examined by light touch-pressure and vibration sensitivity tests. Correlations between each sensory test and gait parameters were analysed in a logistic regression model in order to assess if gait parameters are associated with two different sensory pathways. Impaired deep sensory pathways were significantly (P < .05) correlated with lower gait speed, reduced cadence, smaller stride length, longer stance periods, and a higher risk of falling on the Tinetti Scale, while all gait parameters were significantly (P < .01) correlated with the superficial sensory pathway. Type 2 diabetics have significantly (P < .05) higher impairment in vibratory sensitivity than type 1 diabetics, and the years with diabetes mellitus (DM) diagnosis have a significant (P < .05) association with reduced vibration sensitivity. These findings indicate relationships between the deep sensory pathway and gait impairments in DP measured by inertial sensors, which could be a useful tool to diagnose gait alterations in DP and to evaluate the effect of treatments to improve gait and thus the risk of falls in diabetic patients.

The Association Between Physical Activity and Peripheral Neuropathy in Diabetic Patients: A Cross-Sectional Multicenter Study From Saudi Arabia.

Background Peripheral diabetic neuropathy (PDN) is a serious consequence of diabetes mellitus (DM) that can impair quality of life and result in physical disability. This study aimed to investigate the relationship between physical activity and the severity of PDN among a sample of Saudi diabetic patients in Medina city, Saudi Arabia. Methodology A total of 204 diabetic patients participated in this multicenter, cross-sectional study. A validated self-administered questionnaire was distributed electronically to patients on-site during follow-up. Physical activity and diabetic neuropathy (DN) were assessed using the validated International Physical Activity Questionnaire (IPAQ) and the validated Diabetic Neuropathy Score (DNS), respectively. Results The mean (SD) age of the participants was 56.9 (14.8) years. The majority of the participants reported low physical activity (65.7%). The prevalence of PDN was 37.2%. There was a significant correlation between the severity of DN and the duration of the disease (p = 0.047). Higher neuropathy score was noticed in those with hemoglobin A1C (HbA1c) level ≥7 compared to those with lower HBA1c (p = 0.045). Overweight and obese participants had higher scores compared to normal-weight participants (p = 0.041). The severity of neuropathy decreased significantly when the level of physical activity increased (p = 0.039). Conclusions There is a significant association between neuropathy and physical activity, body mass index, duration of diabetes mellitus, and HbA1c level.

Factors associated with changes in plantar pressure of people with peripheral diabetic neuropathy.

Abstract: Diabetic neuropathy is one of the main complications of Diabetes Mellitus, which can lead to loss of protective sensation, motor, and plantar pressure alteration, generating deformities, abnormal gait and mechanical trauma to the feet. Objective: to evaluate the distribution of plantar pressure, sensorimotor changes, balance and associated factors to plantar pressure changes in people with peripheral diabetic neuropathy. Method: Cross-sectional study conducted with individuals registered in the primary public health service of a city in the east of São Paulo - Brazil. The sample was composed by people with Diabetes Mellitus and Peripheral Neuropathy identified by the Michigan Screening Instrument. It were investigated variables such as sensory-motor changes, static and dynamic plantar pressure using baropodometry and balance using the Berg scale. A significance level of 5% was adopted for all tests used. Results: Of the 200 individuals evaluated, 52.55% had no plantar protective sensitivity, the static evaluation did not demonstrated changes in the peak of plantar pressure, however in the dynamics the mean in the right foot was 6.0 (±2) kgf/cm2 and 6,7 (±1.62) kgf/cm2 on the left foot, the center of static pressure on the right foot was lower (10.55 ± 3.82) than on the left foot (11.97 ± 3.90), pointing hyper plantar pressure. The risk of falling was high, ranging from 8 to 56 points, with an average of 40.9 (±10.77). Conclusion: The absence of protective plantar sensitivity, increased pressure, biomechanical changes lead to loss of balance and are predictive of complications in the feet due to diabetic neuropathy.

A Prospective Observational Study Comparing the Efficacy and Safety of Duloxetine and Pregabalin in Diabetic Peripheral Neuropathic Pain.

Background and aims Peripheral neuropathy is a frequent complication of long-standing diabetes mellitus that adversely affects the quality of life. Pregabalin (anticonvulsant) and duloxetine (antidepressant) are often prescribed for diabetic peripheral neuropathic pain. This study aimed to determine and compare the efficacy and safety of pregabalin and duloxetine in patients with diabetic peripheral neuropathic pain. Materials and methods This prospective observational study was conducted at District Headquarter (DHQ) Hospital, Daggar, Buner district, Pakistan, from February 15 to July 15, 2022, after approval from the Institutional Research and Ethical Review Board. Confirmation of diabetic peripheral neuropathy was based on the history of diabetes mellitus and vibration perception threshold (VPT) using a biothesiometer. The cut-off was set at 15 volts. VPT of more than 15 volts was considered confirmatory for peripheral neuropathy. Patients were divided equally into two groups. Baseline visual analog scale (VAS) score was recorded for all patients. Tablet pregabalin 300 mg daily was administered for four weeks to one group, while tablet duloxetine in 60 mg strength daily was administered to the other group. VAS score after four-week treatment was recorded and compared. Adverse events experienced by the patient were also noted. Results A total of 86 patients were enrolled. The patient ages ranged from 30 to 80 years. Baseline characteristics, including mean age, mean BMI, and mean disease duration of duloxetine versus pregabalin group, were 50.30 ± 8.55 versus 48.20 ± 8.99 years, 23.47 ± 1.23 versus 23.10 ± 1.59 kg/m2 and 21.64 ±7.41 versus 20.04±6.37 months respectively. Duloxetine effectively controlled peripheral neuropathic pain in 81.4% of patients compared to pregabalin in 74.4% of patients. Severe drug-related adverse reactions were observed in 4.6% of patients with duloxetine compared to 0% with pregabalin. Conclusion Duloxetine and pregabalin effectively reduce diabetes-related peripheral neuropathic pain. However, duloxetine has slightly better outcomes than pregabalin. The safety profile of pregabalin is better than duloxetine.

Cognitive function in diabetic persons with peripheral neuropathy: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study is to improve our knowledge of cognitive function in individuals with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus and with peripheral diabetic neuropathy (DPN). METHODS: A systematic review and meta-analysis was performed of publications included in PubMed, Scopus, PsycInfo and Web of Science databases until November 2021. The study was registered in PROSPERO (CRD42021229163). RESULTS: A total of 832 articles were identified, 19 of which were selected. The presence of DPN was associated with global cognitive impairment in the T1DM persons in two studies (p=0.046;p=0.03)    and T2DM persons in four (p<0.00;p<0.02;p=0.011;p≤0.05)     . Differences in specific dimensions - memory, attention, and psychomotor speed - were found in both kinds of diabetes. The meta-analysis showed that the individuals with T2DM and DPN presented a lower mean cognitive performance than those without DPN (-1.0448;95%CI:-1.93%;-0.16%). Depression was associated with impaired cognitive function in these diabetic persons (p < 0.01). CONCLUSION: The review reveals the great variability in instruments and methodologies, while providing results that support the presence of both global and domain-specific cognitive impairment in diabetic persons with DPN.

Treatment of Painful Diabetic Neuropathy-A Narrative Review of Pharmacological and Interventional Approaches.

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available for this condition. Recommended pharmacotherapies include anticonvulsive agents, antidepressant drugs, and topical capsaicin; and tapentadol, which combines opioid agonism and norepinephrine reuptake inhibition, has also recently been approved for use. Additionally, several neuromodulation therapies have been successfully used for pain relief in PDN, including intrathecal therapy, transcutaneous electrical nerve stimulation (TENS), and spinal cord stimulation (SCS). Recently, 10 kHz SCS has been shown to provide clinically meaningful pain relief for patients refractory to conventional medical management, with a subset of patients demonstrating improvement in neurological function. This literature review is intended to discuss the dosage and prospective data associated with pain management therapies for PDN.

Statins and Neuropathic Pain: A Narrative Review.

The frequently prescribed drug class of statins have pleiotropic effects and have been implicated in neuropathic pain syndromes. This narrative review examines studies of statin-induced neuropathic pain which to date have been conducted only in animal models. However, the pathophysiology of diabetic neuropathy in humans may shed some light on the etiology of neuropathic pain. Statins have exhibited a paradoxical effect in that statins appear to reduce neuropathic pain in animals but have been associated with neuropathic pain in humans. While there are certain postulated mechanisms offering elucidation as to how statins might be associated with neuropathic pain, there is, as the American Heart Association stated, to date no definitive association between statins and neuropathic pain. Statins are important drugs that reduce cardiovascular risk factors and should be prescribed to appropriate patients with these risk factors but some of this population is also at elevated risk for neuropathic pain from other causes.

The Role of Iron and Nerve Inflammation in Diabetes Mellitus Type 2-Induced Peripheral Neuropathy.

Peripheral diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Previous studies showed an association between dietary iron load and inflammation in the development of PDN in a rat model of type 1 diabetes (T1D). Here we investigated the role of iron and neural inflammation in development of PDN in a animal model of obesity and type 2 diabetes (T2D). 3-month-old db/db mice were fed with a high, standard or low iron diet for 4 months. High iron chow lead to a significant increase in motor nerve conduction velocities compared to mice on standard and low iron chow. Direct beneficiary effects on lowering blood glucose and HbA1c concentrations were shown in the high iron treated diabetic mice. Numbers of pro-inflammatory M1 macrophages were reduced in nerve sections, and anti-inflammatory M2 macrophages were increased in db/db mice on high iron diet compared to other groups. These results confirm and extend our previous findings in STZ-diabetic rats by showing that dietary non-hem iron supplementation may partly prevent the development of PDN in opposition to iron restriction. The identification of these dietary iron effects on the metabolic and inflammatory mechanisms of PDN supports a role of dietary iron and leads us to suggest testing for iron levels in human diabetic patients.

Ultrasound elastography in the evaluation of peripheral neuropathies: a systematic review of the literature.

Peripheral neuropathy is associated with an increase in intraneural pressure, and hence ultrasound elastography seems to be an ideal method to detect early stages of this condition based on changes in the affected nerve stiffness. The aim of this systematic review was to analyse the applicability of strain elastography (SE) and shear wave elastography (SWE) in the evaluation of peripheral nerves in patients with neuropathy of various aetiologies. Published evidence shows clearly that ultrasound elastography can accurately diagnose many types of peripheral neuropathies (carpal tunnel syndrome and other entrapment neuropathies, diabetic peripheral neuropathy and peripheral neuropathy associated with other systemic diseases), sometimes at the stages at which the condition is still asymptomatic. However, it is still unclear whether elastographic changes within the nerves precede functional anomalies detectable on nerve conduction studies. Also, relatively little is known about the relationship between the stiffness of peripheral nerves and the severity of peripheral neuropathy and its underlying condition. Based on the reproducibility data, SWE seems to be superior to SE. Nevertheless, the sources of heterogeneity in the peripheral nerve stiffness in healthy persons need to be identified, and the sets of reference values for specific peripheral nerves need to be determined. Finally, the potential confounding effect of hardening artefacts, such as bones, on the stiffness of peripheral nerves needs to be verified. After addressing all these issues, elastographic evaluation of peripheral nerve stiffness might become a reliable, easily accessible, and convenient diagnostic test performed routinely in patients with various peripheral neuropathies.

Diabetes-induced Neuropathic Mechanical Hyperalgesia Depends on P2X4 Receptor Activation in Dorsal Root Ganglia.

Peripheral diabetic neuropathy (PDN) manifests in 50-60% of type I and II diabetic patients and is the major cause of limb amputation. Adequate therapy for PDN is a current challenge. There are evidences that the activation of the P2X4 receptor (P2X4R) expressed on microglial cells of the central nervous system takes part in the development of neuropathic pain. However, there is an open question: Is P2X4R activation on dorsal root ganglia (DRG) involved in the development of neuropathic pain? To answer this question, this study verified the involvement of P2X4R expressed in DRG cells on diabetes-induced neuropathic mechanical hyperalgesia in rats. We found that intrathecal or ganglionar (L5-DRG) administration of a novel P2X4R antagonist (PSB-15417) or intrathecal administration of oligodeoxynucleotides (ODN)-antisense against the P2X4R reversed diabetes-induced neuropathic mechanical hyperalgesia. The DRG of the diabetic neuropathic rats showed an increase in P2X4R expression, and the DRG immunofluorescence suggested that P2X4R is expressed mainly in satellite glial cells (SGC). Finally, our study showed a functional expression of P2X4R in SGCs of the rat's DRG, because the P2X4R agonist BzATP elicits an increase in intracellular calcium concentration in SGCs, which was reduced by PSB-15417. These findings indicate that P2X4R activation in DRG is essential to diabetes-induced neuropathic mechanical hyperalgesia. Therefore, this purinergic receptor in DRG could be an interesting therapeutic target for quaternary P2X4R antagonists that do not cross the hematoencephalic barrier, for the control of neuropathic pain, preserving central nervous system functions.

TRPA1 Antagonists for Pain Relief.

Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission. TRPA1 is a final common pathway for a large number of chemically diverse pronociceptive agonists generated in various pathophysiological pain conditions. Thereby, pain therapy using TRPA1 antagonists can be expected to be a superior approach when compared with many other drugs targeting single nociceptive signaling pathways. In experimental animal studies, pharmacological or genetic blocking of TRPA1 has effectively attenuated mechanical and cold pain hypersensitivity in various experimental models of pathophysiological pain, with only minor side effects, if any. TRPA1 antagonists acting peripherally are likely to be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals), while centrally acting TRPA1 antagonists are expected to be optimal for attenuating pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries). In an experimental model of peripheral diabetic neuropathy, prolonged blocking of TRPA1 has delayed the loss of nociceptive nerve endings and their function, thereby promising to provide a disease-modifying treatment.

Nonalcoholic fatty liver disease is associated with an increased prevalence of distal symmetric polyneuropathy in adult patients with type 1 diabetes.

AIMS: Presently, data on the association between nonalcoholic fatty liver disease (NAFLD) and distal symmetric polyneuropathy in people with diabetes are scarce and conflicting. The aim of this retrospective, cross-sectional study was to examine whether NAFLD was associated with an increased prevalence of distal symmetric polyneuropathy in type 1 diabetic adults. METHODS: We studied all white type 1 diabetic outpatients (n = 286, 42.3% male, mean age 43 ± 14 years, median diabetes duration 17 [10-30] years), who participated in a foot screening program at our adult diabetes clinic after excluding those who had excessive alcohol consumption and other known causes of chronic liver disease. NAFLD was diagnosed by ultrasonography. Distal symmetric polyneuropathy was detected using the Michigan Neuropathy Screening Instrument method and the biothesiometer Vibrotest. RESULTS: Overall, the prevalence rates of NAFLD and distal symmetric polyneuropathy were 52.4% and 35.3%, respectively. Patients with NAFLD had a substantially increased prevalence of distal symmetric polyneuropathy compared to their counterparts without NAFLD (51.0% vs. 17.1%, p < 0.001). In univariate analysis, NAFLD was associated with an approximately 5-fold increased risk of prevalent distal symmetric polyneuropathy (odds ratio [OR] 5.32, 95% confidence interval [CI] 3.1-9.3, p < 0.001). This association remained significant even after adjustment for age, sex, diabetes duration, hemoglobin A1c, diabetic retinopathy, smoking, metabolic syndrome, chronic kidney disease and carotid artery stenoses ≥ 40% (adjusted-OR 2.23, 95% CI 1.1-4.8, p < 0.05). CONCLUSIONS: Our results show that NAFLD, diagnosed by ultrasonography, is strongly associated with an increased risk of distal symmetric polyneuropathy in type 1 diabetic adults, independently of several cardio-metabolic risk factors.

Plantar pressures are higher in cases with diabetic foot ulcers compared to controls despite a longer stance phase duration.

BACKGROUND: Current international guidelines advocate achieving at least a 30 % reduction in maximum plantar pressure to reduce the risk of foot ulcers in people with diabetes. However, whether plantar pressures differ in cases with foot ulcers to controls without ulcers is not clear. The aim of this study was to assess if plantar pressures were higher in patients with active plantar diabetic foot ulcers (cases) compared to patients with diabetes without a foot ulcer history (diabetes controls) and people without diabetes or a foot ulcer history (healthy controls). METHODS: Twenty-one cases with diabetic foot ulcers, 69 diabetes controls and 56 healthy controls were recruited for this case-control study. Plantar pressures at ten sites on both feet and stance phase duration were measured using a pre-established protocol. Primary outcomes were mean peak plantar pressure, pressure-time integral and stance phase duration. Non-parametric analyses were used with Holm's correction to correct for multiple testing. Binary logistic regression models were used to adjust outcomes for age, sex and body mass index. Median differences with 95 % confidence intervals and Cohen's d values (standardised mean difference) were reported for all significant outcomes. RESULTS: The majority of ulcers were located on the plantar surface of the hallux and toes. When adjusted for age, sex and body mass index, the mean peak plantar pressure and pressure-time integral of toes and the mid-foot were significantly higher in cases compared to diabetes and healthy controls (p < 0.05). The stance phase duration was also significantly higher in cases compared to both control groups (p < 0.05). The main limitations of the study were the small number of cases studied and the inability to adjust analyses for multiple factors. CONCLUSIONS: This study shows that plantar pressures are higher in cases with active diabetic foot ulcers despite having a longer stance phase duration which would be expected to lower plantar pressure. Whether plantar pressure changes can predict ulcer healing should be the focus of future research. These results highlight the importance of offloading feet during active ulceration in addition to before ulceration.

Gait parameters of people with diabetes-related neuropathic plantar foot ulcers.

BACKGROUND: Foot ulceration associated with diabetic peripheral neuropathy is a global concern. Biomechanical investigation allows the identification of gait abnormalities that may adversely affect ulcer healing. The objective of this case-control study was to compare the gait parameters of cases with diabetes-related foot ulcers to controls. METHODS: Three-dimensional movement analyses were performed on 21 people with diabetes-related neuropathic plantar foot ulcers (cases), 69 people with diabetes without a foot ulcer history (diabetes controls) and 56 healthy controls. Outcome data were reported as mean differences, 95% confidence intervals and Cohen's d effect sizes. Binary logistic regressions were used to adjust for age, sex and body mass index. FINDINGS: People with foot ulcers had a smaller plantar flexion (Cohen's d=-0.6 vs. diabetes controls and d=-0.8 vs. healthy controls), knee flexion (d=-0.6 vs. diabetes controls and d=-1.0 vs. healthy controls) and pelvic obliquity (d=-0.9 vs. diabetes controls and d=-0.7 vs. healthy controls) (all P<0.05). They also had a significantly greater range of anterior-posterior ground reaction force (d=1.0 vs. diabetes controls and d=1.7 vs. healthy controls) and total vertical ground reaction force (d=0.9 vs. diabetes controls and d=1.1 vs. healthy controls) and significantly slower walking speed and smaller step length compared to controls (all P<0.05). INTERPRETATION: People with plantar foot ulcers have considerably different gait parameters to controls. Whether the observed gait parameters contributed to the ulcer development or are a response to the ulcer is currently unclear and needs further investigation.

Alternatives to the Streptozotocin-Diabetic Rodent.

The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat and mouse models of type 1 diabetes. This chapter will review the creation and use of other rodent models that have been developed in order to investigate the contribution of factors besides insulin deficiency to the development and progression of diabetic neuropathy as it occurs in obesity, type 1 or type 2 diabetes. Diabetic peripheral neuropathy is a complex disorder with multiple mechanisms contributing to its development and progression. Even though many animal models have been developed and investigated, no single model can mimic diabetic peripheral neuropathy as it occurs in humans. Nonetheless, animal models can play an important role in improving our understanding of the etiology of diabetic peripheral neuropathy and in performing preclinical screening of potential new treatments. To date treatments found to be effective for diabetic peripheral neuropathy in rodent models have failed in clinical trials. However, with the identification of new endpoints for the early detection of diabetic peripheral neuropathy and the understanding that a successful treatment may require a combination therapeutic approach there is hope that an effective treatment will be found.

The role of nerve inflammation and exogenous iron load in experimental peripheral diabetic neuropathy (PDN).

BACKGROUND: Iron is an essential but potentially toxic metal in mammals. Here we investigated a pathogenic role of exogenous iron in peripheral diabetic neuropathy (PDN) in an animal model for type 1 diabetes. METHODS: Diabetes was induced by a single injection of streptozotocin (STZ) in 4-month-old Sprague-Dawley rats. STZ-diabetic rats and non-diabetic rats were fed with high, standard, or low iron diet. After three months of feeding, animals were tested. RESULTS: STZ-rats on standard iron diet showed overt diabetes, slowed motor nerve conduction, marked degeneration of distal intraepidermal nerve fibers, mild intraneural infiltration with macrophages and T-cells in the sciatic nerve, and increased iron levels in serum and dorsal root ganglion (DRG) neurons. While motor fibers were afflicted in all STZ-groups, only a low iron-diet led also to reduced sensory conduction velocities in the sciatic nerve. In addition, only STZ-rats on a low iron diet showed damaged mitochondria in numerous DRG neurons, a more profound intraepidermal nerve fiber degeneration indicating small fiber neuropathy, and even more inflammatory cells in sciatic nerves than seen in any other experimental group. CONCLUSIONS: These results indicate that dietary iron-deficiency rather than iron overload, and mild inflammation may both promote neuropathy in STZ-induced experimental PDN.

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.