Diabetic Neuropathies

Diabetes mellitus (DM), a worldwide high prevalence disease, is associated with a large variety of rheumatic manifestations. For most of these affections, pathophysiologic correlations are not well established. Some of them, such as diabetic cheiroarthropathy, neuropathic arthritis, diabetic amyotrophy, diabetic muscle infraction, are considered intrinsic complications of DM. For others, like diffuse idiopathic skeletal hyperostosis or reflex sympathetic dystrophy, DM is considered a predisposing condition. In most cases, these affections cause pain and disability, affecting the quality of life of diabetic patients, but once correctly diagnosed, they often respond to the treatment, that generally requires a multidisciplinary team. This article reviews some epidemiological, clinical, diagnostic and therapeutic aspects of these conditions.

BackgroundE‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl]‐morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.MethodsMechanical and thermal response thresholds were tested on 7‐, 13‐, 14‐ and 15‐week‐old ZDF rats treated with saline or with E‐52862 acutely administered on week 13, followed by sub‐chronic administration (14 days). Axonal peripheral activity (skin–saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15‐week‐old ZDF rats treated with saline or E‐52862 and in LEAN rats.ResultsZucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single‐dose ...

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of o...

To determine the relative efficacy and adverse effects of antidepressants and anticonvulsants in the treatment of diabetic neuropathy and postherpetic neuralgia, published reports were identified from a variety of electronic databases, including Medline, EMBASE, the Cochrane Library and the Oxford Pain Relief Database, and from two previously published reviews. Additional studies were identified from the reference lists of retrieved reports. The relative benefit (RB) and number-neededto-treat (NNT) for one patient to achieve at least 50% pain relief was calculated from available dichotomous data, as was the relative risk (RR) and number-needed-to-harm (NNH) for minor adverse effects and drug related study withdrawal. In diabetic neuropathy, 16 reports compared antidepressants with placebo (491 patient episodes) and three compared anticonvulsants with placebo (321). The NNT for at least 50% pain relief with antidepressants was 3.4 (95% confidence interval 2.6-4.7) and with anticonvulsants 2.7 (2.2-3.8). In postherpetic neuralgia, three reports compared antidepressants with placebo (145 patient episodes) and one compared anticonvulsants with placebo (225), giving an NNT with antidepressants of 2.1 (1.7-3) and with anticonvulsants 3.2 (2.4-5). There was little difference in the incidence of minor adverse effects with either antidepressants or anticonvulsants compared with placebo, with NNH (minor) values of about 3. For drug-related study withdrawal, antidepressants had an NNH (major) of 17 (11-43) compared with placebo, whereas with anticonvulsants there was no significant difference from placebo. Antidepressants and anticonvulsants had the same efficacy and incidence of minor adverse effects in these two neuropathic pain conditions. There was no evidence that selective serotonin reuptake inhibitors (SSRIs) were better than older antidepressants, and no evidence that gabapentin was better than older anticonvulsants. In these trials patients were more likely to stop taking antidepressants than anticonvulsants because of adverse effects.

To determine the relative efficacy and adverse effects of antidepressants and anticonvulsants in the treatment of diabetic neuropathy and postherpetic neuralgia, published reports were identified from a variety of electronic databases, including Medline, EMBASE, the Cochrane Library and the Oxford Pain Relief Database, and from two previously published reviews. Additional studies were identified from the reference lists of retrieved reports. The relative benefit (RB) and number-neededto-treat (NNT) for one patient to achieve at least 50% pain relief was calculated from available dichotomous data, as was the relative risk (RR) and number-needed-to-harm (NNH) for minor adverse effects and drug related study withdrawal. In diabetic neuropathy, 16 reports compared antidepressants with placebo (491 patient episodes) and three compared anticonvulsants with placebo (321). The NNT for at least 50% pain relief with antidepressants was 3.4 (95% confidence interval 2.6-4.7) and with anticonvulsants 2.7 (2.2-3.8). In postherpetic neuralgia, three reports compared antidepressants with placebo (145 patient episodes) and one compared anticonvulsants with placebo (225), giving an NNT with antidepressants of 2.1 (1.7-3) and with anticonvulsants 3.2 (2.4-5). There was little difference in the incidence of minor adverse effects with either antidepressants or anticonvulsants compared with placebo, with NNH (minor) values of about 3. For drug-related study withdrawal, antidepressants had an NNH (major) of 17 (11-43) compared with placebo, whereas with anticonvulsants there was no significant difference from placebo. Antidepressants and anticonvulsants had the same efficacy and incidence of minor adverse effects in these two neuropathic pain conditions. There was no evidence that selective serotonin reuptake inhibitors (SSRIs) were better than older antidepressants, and no evidence that gabapentin was better than older anticonvulsants. In these trials patients were more likely to stop taking antidepressants than anticonvulsants because of adverse effects.

Background: Diabetic shoes, which are commonly referred to as therapeutic shoes and extra depth shoes, can be categorized under comfort shoes or orthopedic shoes. The purpose of these specially designed footwear options is to preserve and improve foot health by reducing the risk of skin breakdown for those diagnosed with diabetes and suffering from foot abnormalities or deformities. Improper and poorly fitting footwear can cause problems such as calluses, ulcers and blisters that can lead to infection and ultimately even amputation. Objectives: To decrease footwear problems by designing and developing diabetics and orthopedics footwear. To design, simulate and manufacture a diabetic shoe and to contribute to the further development of diabetic footwear as reasonable products for the consumer market. Methods: The design process involved of calculating and optimizing the orthotic insole thickness which has a direct effect on the performance of the shoe. Elasticity theory is applied and the optimum insole thickness is determined based on the critical properties of resilience and compressive stiffness. Furthermore, a SOLIDWORKS static simulation is done and demonstrated that the calculated insole thickness can be effectively used in the production of the shoe. Finally, a case study is done by selecting a 27-year-old study subject with diabetic foot problems and producing a shoe that matches her. Results: Under the assumption of a constant maximum compressive force, a rigorous theoretical analysis showed that the diabetic shoe should be constructed from an insole material with a minimum thickness of 6.66mm. A SOLIDWORKS static simulation showed that, under the application of a maximum compressive force, the maximum compression of the insole material is about 0.211mm. This proves that the insole material has the right resilience and compressive stiffness for the thickness computed. This study proved that the produced shoe is indeed comfortable and effective for peoples with diabetics.

Streptozotocin (STZ) induced neurotoxicity causes development of diabetic neuropathy in rodent models and oxidative stress is the main culprit in development of diabetic neuropathy. In the present study we aimed to evaluate the neuroprotective and antioxidant role of Pregabalin in STZ induced neurotoxicity. After 8 weeks, STZ induced diabetic rats showed sciatic nerve damage which was evident from hyperalgesia, allodynia, motor deficits and Transmission Electron Microscopic studies of sciatic nerves. Pregabalin treatment at a daily dose of 15 mg/kg for 7 weeks ameliorated hyperalgesia, allodynia, motor deficits and prevented the structural abnormalities in sciatic nerves of diabetic rats. STZ neurotoxicity reduced antioxidant enzyme levels in sciatic nerves. Pregabalin treatment significantly ameliorated the decrease in antioxidant defence in diabetic rats. These results demonstrated neuroprotective effect of Pregabalin, which is mediated through attenuation of oxidative stress. The...

Electrophysiological testing remains an important efficacy parameter in clinical neuropathy trials. The quality of nerve conduction studies in reported trials varies greatly, and may be responsible for negative results. We report the utilization of an expert core lab for electrophysiological testing. With the core lab, the variability of repeat testing is comparable to that of a single, excellent laboratory. Motor conduction velocities demonstrated a coefficient of variation of 3% and sensory conduction velocities 4% across 60 study sites. The distal motor evoked potential amplitudes varied by 13% at the ankle, and 10% at the wrist. The sensory potential amplitudes varied by 16% at the ankle, and 11% at the wrist in 60 sites. The overall monitoring rate in all submitted nerve conduction tracings was 36.6%. Our results show that an expert core lab can improve the electrophysiological quality of clinical trial data with the potential to show small changes in nerve conduction velocities and in both motor and sensory potential amplitudes.

OBJECTIVE—The primary purpose of this investigation was to determine whether AS-3201, a new aldose reductase inhibitor, penetrates the sural nerve and inhibits sorbitol and fructose accumulation in patients with diabetic sensorimotor polyneuropathy (DSP). An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy. RESEARCH DESIGN AND METHODS—Patients with mild to moderate DSP based on nerve conduction studies were randomized into one of three treatment groups in a double-blind fashion: placebo or AS-3201 at 5 or 20 mg/day. After 12 weeks of administration, the sural nerve was biopsied for measurement of sorbitol, fructose, and AS-3201. RESULTS—At baseline, no important clinical, electrophysiological, or laboratory differences were found between the three groups. The nerve sorbitol concentration of 3.14 × 10−2 nmol/mg wet nerve in patients in the placebo group was inhibited by 65 and 84% in patients on AS-3201 at 5 and 20 mg/day, resp...

Diabetes mellitus (DM) is a disease of increasing incidence and prevalence. Arterial baroreceptors are stretch-sensitive receptors, which in a reflex manner are involved in the homeostatic control of arterial blood pressure. Diabetic subjects have depressed baroreflex sensitivity (BRS), although the exact pathomechanisms are unclear. In this review, we discuss the features, clinical and prognostic implications of reduced BRS for diabetic patients and the potential involvement of cardiovascular autonomic neuropathy and atherosclerosis. Finally, we demonstrate evidence on interventions (e.g. pioglitazone, alpha-lipoic acid, leptin, fluvastatin, physical training etc.) which could improve BRS and ameliorate cardiovascular autonomic dysfunction in diabetic patients.

Diabetes mellitus (DM) is a disease of increasing incidence and prevalence. Arterial baroreceptors are stretch-sensitive receptors, which in a reflex manner are involved in the homeostatic control of arterial blood pressure. Diabetic subjects have depressed baroreflex sensitivity (BRS), although the exact pathomechanisms are unclear. In this review, we discuss the features, clinical and prognostic implications of reduced BRS for diabetic patients and the potential involvement of cardiovascular autonomic neuropathy and atherosclerosis. Finally, we demonstrate evidence on interventions (e.g. pioglitazone, alpha-lipoic acid, leptin, fluvastatin, physical training etc.) which could improve BRS and ameliorate cardiovascular autonomic dysfunction in diabetic patients.

Purpose: To investigate the relationship between distal symmetric peripheral neuropathy and early stages of autonomic bladder dysfunction in type 2 diabetic women. A total of 137 diabetic women with minimal coexisting confounders of voiding dysfunction followed at a diabetes clinic were subject to the following evaluations: current perception threshold (CPT) tests on myelinated and unmyelinated nerves at the big toe for peroneal nerve and middle finger for median nerve, uroflowmetry, post-void residual urine volume, and overactive bladder (OAB) symptom score questionnaire. Patients presenting with voiding difficulty also underwent urodynamic studies and intravesical CPT tests. Results: Based on the OAB symptom score and urodynamic studies, 19% of diabetic women had the OAB syndrome while 24.8% had unrecognized urodynamic bladder dysfunction (UBD). The OAB group had a significantly greater mean 5 Hz CPT test value at the big toe by comparison to those without OAB. When compared to diabetic women without UBD, those with UBD showed greater mean 5 Hz CPT test values at the middle finger and big toe. The diabetic women categorized as C-fiber hyposensitivity at the middle finger or big toe by using CPT test also had higher odds ratios of UBD. Among diabetic women with UBD, the 5 Hz CPT test values at the big toe and middle finger were significantly associated with intravesical 5 Hz CPT test values. Using electrophysiological evidence, our study revealed that hyposensitivity of unmyelinated C fiber afferents at the distal extremities is an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women. The C fiber dysfunction at the distal extremities seems concurrent with vesical C-fiber neuropathy and may be a sentinel for developing early diabetic bladder dysfunction among female patients.

OBJECTIVE -To evaluate the effects of a 14-day intensive insulin therapy and short-term improvement of glycemic control on serum levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in NIDDM patients with poor glycemic control. A total of 16 NIDDM patients were compared with 23 healthy subjects (control group) and investigated before and after intensive insulin treatment. RESULTS -On day 0, sE-selectin and sVCAM-1 levels were significantly higher in NIDDM patients than in nondiabetic control subjects (median 87, range 63-115; median 544, range 408-797 vs. 58, 43-80; 443, 395-573 ng/ml, respectively) (P < 0.008 in both cases). On day 15, the fall in sE-selectin levels was significant (P < 0.0001) and at a lesser extent in sVCAM-1 levels (64, 48-85; 506, 417-678 ng/ml, respectively); these levels reached values that no longer differed from those of control subjects (P = 0.23 and 0.15, respectively). Moreover, the fall in sE-selectin was positively associated with the change in LDL cholesterol and the improvement of glycemia. CONCLUSIONS -In poorly controlled NIDDM patients, sE-selectin levels are increased and significantly fall to normal after short-term improvement of glycemic control. This suggests that assaying sE-selectin makes it possible to detect endothelium activation and to follow its reversal with euglycemia.

Objective: The most commonly used technique for diagnosis of diabetic neuropathy (DN) is nervous conduction (NC). Our hypothesis is that the use of the thermal threshold (TT) technique to evaluate small fiber damage, which precedes large fiber damage, could enable earlier diagnosis and diminish false negatives. Research Design and Methods: The study involved 70 asymptomatic patients with type 2 diabetes mellitus (T2DM) all being treated with oral hypoglycemic medication, and having negative metabolic control levels with glycosylated hemoglobin A1c greater than 7% and less than 8%. Diabetic neuropathy was their only evident complication. All other complications or other causes of neuropathy were discarded. Their time of evolution was 1 to 48 months since date of diagnosis of diabetes. Both thermal threshold and sensory and motor nervous conduction were determined in upper and lower limbs. Results: Nervous conduction was found normal in 81% and altered in 19% of patients (large fiber ...

Type 1 diabetes mellitus (T1DM) is a serious autoimmune condition that arises from the destruction of insulin-producing beta cells in the pancreas. It is a prevalent chronic disease among children if left untreated with lifelong insulin therapy, it can be fatal. Despite advancements in treatment, a definitive way to prevent or cure the disease remains elusive. Recent studies from Iraq have shown a rise in T1DM cases among children, which has been attributed to environmental and economic changes in the country. Furthermore, genetic factors are believed to significantly contribute to the development of T1DM. The current study aimed to determine if there was any association between T1DM and polymorphisms in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene in Iraqi children.

Background Diabetic kidney disease is a major microvascular complication of diabetes mellitus and is the leading cause of end-stage renal disease all over the world. The general recommendation for the subjects with DM is to perform kidney function as screening: in T1DM, 5 years after diagnosis, and in type 2, at the time of diagnosis. The early diagnosis of diabetic kidney disease depends on the albumin excretion ratio; however, the albumin excretion ratio (AER) does not correlate with the severity and progression of the disease. Methods The subjects in this study included thirty patients with type 1 diabetes mellitus and thirty patients with type 2 diabetes mellitus who were recruited from the outpatient clinic and inpatient in the Internal Medicine Department at Benha University Hospitals in the endocrinology unit from January 2022 to January 2023 as cases who were subground according to albuminuria into two groups (normoalbuminuria less than 30 mg/24 h urinary collection) and albuminuric group more than 30 mg/24 h urinary collection; all patients were subjected to thorough history including baseline characteristics, examination, and related laboratory investigations. Results Serum cystatin C level at a cutoff value of 82 was associated with sensitivity (81.4) and specificity (82.4), and it was negatively significantly correlated with BMI, duration of diabetes mellitus, albuminuria, blood urea, and serum creatinine, and it was positively significantly correlated with e-GFR creatinine. Conclusion Serum cystatin C can be used as an early marker of diabetic kidney disease in both type I and type II diabetic patients better than AER and serum creatinine.

Streptozotocin (STZ)-induced type 1 diabetes in rats leads to the development of peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia at early stages (4th week) followed by hypoalgesia after 8 weeks of diabetes development. Here we found that 6-7 week STZ-diabetic rats developed either thermal hyper-(18%), hypo-(25%) or normalgesic (57%) types of PDN. These developmentally similar diabetic rats were studied in order to analyze mechanisms potentially underlying different thermal nociception. The proportion of IB4positive capsaicin-sensitive small DRG neurons, strongly involved in thermal nociception, was not altered under different types of PDN implying differential changes at cellular and molecular level. We further focused on properties of T-type calcium and TRPV1 channels, which are known to be involved in Ca 2+ signaling and pathological nociception. Indeed, TRPV1-mediated signaling in these neurons was downregulated under hypo-and normalgesia and upregulated under hyperalgesia. A complex interplay between diabetes-induced changes in functional expression of Cav3.2 T-type calcium channels and depolarizing shift of their steady-state inactivation resulted in upregulation of these channels under hyper-and normalgesia and their downregulation under hypoalgesia. As a result, T-type window current was increased by several times under hyperalgesia partially underlying the increased resting [Ca 2+ ] i observed in the hyperalgesic rats. At the same time Cav3.2-dependent Ca 2+ signaling was upregulated in all types of PDN. These findings indicate that alterations in functioning of Cav3.2 T-type and TRPV1 channels, specific for each type of PDN, may underlie the variety of pain syndromes induced by type 1 diabetes.

Streptozotocin (STZ)-induced type 1 diabetes in rats leads to the development of peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia at early stages (4th week) followed by hypoalgesia after 8 weeks of diabetes development. Here we found that 6-7 week STZ-diabetic rats developed either thermal hyper-(18%), hypo-(25%) or normalgesic (57%) types of PDN. These developmentally similar diabetic rats were studied in order to analyze mechanisms potentially underlying different thermal nociception. The proportion of IB4positive capsaicin-sensitive small DRG neurons, strongly involved in thermal nociception, was not altered under different types of PDN implying differential changes at cellular and molecular level. We further focused on properties of T-type calcium and TRPV1 channels, which are known to be involved in Ca 2+ signaling and pathological nociception. Indeed, TRPV1-mediated signaling in these neurons was downregulated under hypo-and normalgesia and upregulated under hyperalgesia. A complex interplay between diabetes-induced changes in functional expression of Cav3.2 T-type calcium channels and depolarizing shift of their steady-state inactivation resulted in upregulation of these channels under hyper-and normalgesia and their downregulation under hypoalgesia. As a result, T-type window current was increased by several times under hyperalgesia partially underlying the increased resting [Ca 2+ ] i observed in the hyperalgesic rats. At the same time Cav3.2-dependent Ca 2+ signaling was upregulated in all types of PDN. These findings indicate that alterations in functioning of Cav3.2 T-type and TRPV1 channels, specific for each type of PDN, may underlie the variety of pain syndromes induced by type 1 diabetes.

T-type Ca 2+ channels are known as important participants of nociception and their remodeling contributes to diabetes-induced alterations of pain sensation. In this work we have established that about 30% of rat nonpeptidergic thermal C-type nociceptive (NTCN) neurons of segments L4-L6 express a slow T-type Ca 2+ current (T-current) while a fast T-current is expressed in the other 70% of these neurons. Streptozotocin-induced diabetes in young rats resulted in thermal hyperalgesia, hypoalgesia, or normalgesia 5-6 weeks after the induction. Our results show that NTCN neurons obtained from hyperalgesic animals do not express the slow Tcurrent. Meanwhile, the fraction of neurons expressing the slow T-current did not significantly change in the hypo-and normalgesic diabetic groups. Moreover, the peak current density of fast T-current was significantly increased only in the neurons of hyperalgesic group. In contrast, the peak current density of slow T-current was significantly decreased in the hypo-and normalgesic groups. Experimental diabetes also resulted in a depolarizing shift of steady-state inactivation of fast T-current in the hyperalgesic group and slow T-current in the hypo-and normalgesic groups. We suggest that the observed changes may contribute to expression of different types of peripheral diabetic neuropathy occurring during the development of diabetes mellitus.

Background: Diabetes mellitus (DM) is a growing problem all over the world, including Africa. This disorder accounts for high morbidity and mortality due to microvascular complications especially in type 1 diabetics. This study was conducted to assess prevalence of microvascular complications as well as associated risk factors among adolescents aged 10-19 years obtaining care in Kigali city, in Rwanda. Methods: This cross-sectional study was conducted in 261 adolescents with type 1 DM attending care in a Rwandan Diabetic clinic in Kigali city. Participants were examined for microvascular complications and possible risk factors. Results: Thirteen of 261 participants had diabetic nephropathy (5%), 12 had diabetic retinopathy (4.6%), and 9 had diabetic neuropathy (3.4%). Risk factors for development of a microvascular complication included place of residence as well as previous hypoglycemia or hospitalization. In addition, 232 patients (88.9%) had poor levels of glycemic control. Conclusion: Microvascular complications seem to be common in adolescents with type 1 DM in our study setting. They appear to be associated with other morbid diabetic complications, which are indicative of poor diabetic disease control. Actions should therefore be directed towards glycemic control to prevent these complications.

Prolonged corrected QT (QTc) has been identified as a risk factor for malignant arrhythmias and sudden cardiac death. Caucasian studies have shown a definite relationship between QTc prolongation and Cardiac Autonomic Neuropathy (CAN) in diabetic subjects. To determine the prevalence of prolonged QTc in Black diabetic individuals with CAN and to ascertain how prolonged QTc correlated with the severity of CAN among these patients. A total of 176 adult diabetic subjects were studied, 87 males and 89 females. There was a control group of non-diabetic individuals. Cardiac autonomic function was assessed using five cardiovascular autonomic function tests. CAN was diagnosed if 2 or more of these tests were abnormal. Severity of CAN was determined according to the number of abnormal tests. QTc &gt; 0.440 was regarded as prolonged. Fifty-one out of the 176 diabetic subjects (29%) had CAN. The prevalence of prolonged QTc in diabetic subjects with CAN was 12%. QTc was prolonged in 1.6% and 0....

Aims/hypothesis Cerebrovascular disease may be causal or a vulnerability factor in late-onset depression and may explain the high rate of depression in older adults with diabetes. We explored a wide range of potential explanatory variables of depression in a longitudinal study of older diabetic subjects to investigate the vascular depression hypothesis in these patients. Methods We recruited 207 subjects with diabetes selected for potential cognitive deficits from an existing observational cohort study (average age 75.7±4.6 years, 52.2% men) for an assessment of depression using a standardised diagnostic instrument (Cambridge Examination for Mental Disorders of the Elderly -Revised). All subjects underwent a detailed clinical assessment at baseline and at follow-up (after 7.5± 1.1 years). Results Major depression was present in 45 subjects (21.7%) and minor depression in ten (4.8%). A positive history of strokes and the presence of peripheral arterial disease were significantly associated with depression at the time of diagnosis. In a subsample of 93 cases who underwent structural neuroimaging, the presence of cerebral infarcts was also significantly associated with depression. Treatment with glucose-lowering therapy, higher serum cholesterol levels and difficulties with activities of daily living at baseline were significant predictors of depression at follow-up. Conclusions/interpretation A history of cerebrovascular disease was strongly associated with depression and cerebrovascular risk factors were significant predictors of depression in older diabetic patients. Our findings are consistent with the hypothesis that the excess risk of depression in older diabetic patients is related to underlying cerebrovascular disease.

Peripheral neuropathy is one of the most common complications of diabetes mellitus. Using a mouse model of diabetic peripheral neuropathy, we tested the hypothesis that thymosin β 4 (Tβ4) ameliorates diabetes-induced neurovascular dysfunction in the sciatic nerve and promotes recovery of neurological function from diabetic peripheral neuropathy. Tβ4 treatment of diabetic mice increased functional vascular density and regional blood flow in the sciatic nerve, and improved nerve function. Tβ4 upregulated angiopoietin-1 (Ang1) expression, but suppressed Ang2 expression in endothelial and Schwann cells in the diabetic sciatic nerve. In vitro, incubation of Human Umbilical Vein Endothelial Cells (HUVECs) with Tβ4 under high glucose condition completely abolished high glucose-downregulated Ang1 expression and high glucose-reduced capillary-like tube formation. Moreover, incubation of HUVECs under high glucose with conditioned medium collected from Human Schwann cells (HSCs) treated with Tβ4 significantly reversed high glucose-decreased capillary-like tube formation. PI3K/Akt signaling pathway is involved in Tβ4-regulated Ang1 expression on endothelial and Schwann cells. These data indicate that Tβ4 likely acts on endothelial cells and Schwann cells to preserve and/or restore vascular function in the sciatic nerve which facilitates improvement of peripheral nerve function under diabetic neuropathy. Thus, Tβ4 has potential for the treatment of diabetic peripheral neuropathy.

To compare the nerve conduction studies in clinically undetectable and detectable sensorimotor polyneuropathy in type 2 diabetics. Diagnosed diabetics (n = 60) were divided in two groups. Group 1 (n1 = 30) with clinically undetectable and group 2 (n2 = 30) with clinically detectable Diabetic Polyneuropathy. Detection of the sensorimotor neuropathy was done according to Diabetic Neuropathy Symptom Score and Diabetic Neuropathy Examination scores. The simplified nerve conduction studies protocol was followed in recording amplitudes, velocities and latencies of minimum two (Sural, Peroneal) and maximum six i.e. three sensory (Sural, Ulnar, Median) and three motor (Peroneal, Ulnar, Tibial) nerves. The comparisons were done between different parameters of nerve conduction studies with the neurological scores in undetectable and detectable groups using Pearson&#39;s chi square test. The amplitudes, velocities, latencies, outcome and grading of neuropathy in nerve conduction studies when c...

To check the reliability of the commonly used neurological scoring systems taking the nerve conduction studies as the reference. Diagnosed diabetics (n=60) were selected by purposive sampi ng Detection and grading of neuropathy were done according to Diabetic Neuropathy Symptom Score (DrNS), modified Neuropathy Symptom Score (NSS), Diabetic Neuropathy Examination (DNE) and modified Neuropathy Disability Score (NDS). For the nerve conduction studies, amplitudes, velocities and latencies of minimum two (Sural, Peroneal) and maximum six, i.e., three sensory (Sural, Ulnar, Median) and three motor (Peroneal, Ulnar, Tibial) nerves were checked. If the patient had 2 or more than two abnormal findings in any of the nerve he was labeled to have peripheral sensorimotor neuropathy. Later the sensitivity, specificity and diagnostic efficacy of each neurological score was checked taking nerve conduction studies as the gold standard. Taking the NCS as gold standard DNS, DNE, NSS and NDS had 64.1%...

Diabetic amyotrophy is a distinctive form of diabetic neuropathy. It is characterised by a weakness and wasting of proximal muscles of the lower limbs with associated pain. We report a case of an elderly patient with unusual presentation of diabetic amyotrophy. He presented with myoclonic jerks and recurrent falls. Examination findings and electrophysiological studies were consistent with a diagnosis of diabetic amyotrophy. He responded well to steroids with marked improvement in strength of the lower limb muscles and complete resolution of myoclonic jerks. Diabetic amyotrophy presenting as myoclonic jerks has been rarely reported before.

The treatment of painful diabetic polyneuropathy (DPN) is often inadequate and frequently limited by the systemic adverse effects of medications, necessitating the evaluation of novel treatments. Objective: To evaluate the effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in painful diabetic polyneuropathy.

Identificou-se que pais vivenciam o Método Canguru com realização e prazer. Ademais, apresentaram dificuldades, medo e insegurança que podem estar associados ao funcionamento e a dispositivos de apoio à vida, utilizados para garantir a sobrevida de prematuros no cuidado relacionado ao distanciamento da figura paterna com neonato. Conclusão: a figura paterna, atualmente, apresenta-se mais participativa e consciente acerca do papel no âmbito familiar e nos cuidados inerentes ao filho prematuro. No entanto, pais se sentem despreparados, mas orgulhosos e esperançosos com evolução clínica de bebês, ao vivenciar o Método Canguru.

The purpose of this study was to explore communication barriers as independent predictors and potential mediators of variation in clinical recognition of diabetic peripheral neuropathy (DPN). In this cross-sectional analysis, we estimated the likelihood of having a DPN diagnosis among 4,436 patients with DPN symptoms. We controlled for symptom frequency, demographic and clinical characteristics, and visit frequency using a modified Poisson regression model. We then evaluated 4 communication barriers as independent predictors of clinical documentation and as possible mediators of racial/ethnic differences: difficulty speaking English, not talking to one&#39;s doctor about pain, limited health literacy, and reports of suboptimal patient-provider communication. Difficulty speaking English and not talking with one&#39;s doctor about pain were independently associated with not having a diagnosis, though limited health literacy and suboptimal patient-provider communication were not. Limit...

Background: The incidence of peripheral neuropathy among chronic diabetic patients is escalating, with a notable rise observed in Pakistan. This trend has been partly attributed to the predominant reliance on pharmacotherapy, while the role of physical exercise in management remains underutilized. Aerobic exercise is widely recommended in clinical guidelines for the treatment and prevention of diabetic complications, and it is hypothesized that the addition of strength training could yield even more benefits. Objective: This study aimed to evaluate the effects of combined aerobic and strength training exercises on neuropathic symptoms in patients with diabetic peripheral neuropathy. Methods: In this randomized clinical trial, 40 patients with diabetic peripheral neuropathy were equally divided into two groups: Group A underwent a combined regimen of aerobic and strength training exercises, whereas Group B engaged in aerobic exercises alone. The effectiveness of these interventions was assessed using the Michigan Neuropathy Screening Instrument (MNSI), Numeric Pain Rating Scale (NPRS), and Clinical Global Impression of Change (CGIC). Data were analyzed using SPSS version 20.0, employing independent t-tests, repeated measures ANOVA, and descriptive statistics for in-depth analysis. Results: Group A demonstrated a significant reduction in MNSI scores with a mean difference of 1.700 and a p-value < 0.001, indicating a substantial improvement in neuropathic symptoms compared to Group B. While both groups showed significant improvements in NPRS and CGIC scores, the differences were not statistically significant, with p-values of 0.599 and 0.330, respectively, and mean differences of 0.1500 and 0.2500 for NPRS and CGIC. The overall statistical analysis revealed a high significance level (p < 0.001) within both groups in all measured outcomes, suggesting considerable improvements post-intervention. Conclusion: The addition of strength training to aerobic exercises significantly enhances the reduction of neuropathic symptoms in diabetic patients. However, for pain relief and overall clinical improvement, both treatment approaches-combined aerobic and strength training or aerobic exercise alone-were equally effective.

Introduction: One of the common syndromes that affect humanity is neuropathic pain (NP), yet poorly understood with no efficient treatment till now. Consequently, it is extremely crucial to seek further evidence for accurate diagnosis and optimum treatment. The aim of this work is to summarize the findings related to neuropathic pain in terms of etiology, types, diagnosis, current and future management prospective, and identify the gaps in neuropathic pain therapy. Methods: A literature investigation was carried out by analyzing classical peer reviewed papers and textbooks, taking into consideration worldwide well established scientific databases mainly PUBMED and SCOPUS to retrieve accessible published literature. The selection of phytotherapies was based upon their potentials in relieving NP in pre-clinical or clinical models. Results: One of the most critical points in this research is that recommendations of the future plans should be focused on the engagement of phytotherapy in the treatment regimen aiming at improving patients' quality of life and reaching optimum efficacy and minimum toxicity. Phytotherapies offer relatively low-risk options to NP patients and have an increasing evidence to be the future of neuropathic pain management. Patients suffering from neuropathy are depending increasingly on phytotherapies; however, they need more clinical trials in order to fully understand their mechanism of actions. Conclusion: Health-care specialists should be regularly informed about neuropathic pain current therapies and promising future phytotherapies, bearing in mind the risk/benefit profile of the utilization of these therapies in the amelioration of NP.

Diabetes mellitus is a metabolic disorder arising from deficiency of insulin by the pancreas or by the ineffectiveness of the insulin produced in the target cells. It is characterized by high levels of glucose in blood, which in turn damages many of the body systems particularly the blood vessels and nerves. This review explores the metabolic complications accompanying diabetes mellitus. It also provides a discussion of the pathogenesis of the complications of the disease.

Peripheral neuropathy, the most prevalent chronic complication of diabetes, critically contributes to increased pain and risk of amputations, lower physical functioning and daily living burden, reduced quality of life, increased health care costs, and high mortality risk. Although intensive glucose control was shown to delay the onset and progression of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes, similar evidence is not available for most patients who have type 2 diabetes (T2D). In addition, despite continuous research, a disease-modifying therapy to reverse human DPN is still not available. The mechanisms involved in DPN are complex, including but not limited to non-enzymatic glycation, polyol pathway activation, and oxidative and inflammatory stress. This makes finding a successful treatment extremely difficult.

Peripheral neuropathy, the most prevalent chronic complication of diabetes, critically contributes to increased pain and risk of amputations, lower physical functioning and daily living burden, reduced quality of life, increased health care costs, and high mortality risk. Although intensive glucose control was shown to delay the onset and progression of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes, similar evidence is not available for most patients who have type 2 diabetes (T2D). In addition, despite continuous research, a disease-modifying therapy to reverse human DPN is still not available. The mechanisms involved in DPN are complex, including but not limited to non-enzymatic glycation, polyol pathway activation, and oxidative and inflammatory stress. This makes finding a successful treatment extremely difficult.

Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. We sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. NP patients showed a widespread reduction of connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. We also found a generalized reduction of the length of functional connections in the NP group: in all the examined networks, the Euclidian distance between connected voxels was significantly shorter in patients vs. controls. In sum, our work showed that in diabetic NP pain a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, we conclude that chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self monitoring, pain processing and salience detection.

In this paper we explored thalamocortical functional connectivity in a group of eight patients suffering from peripheral neuropathic pain (diabetic pain), and compared it with that of a group of healthy subjects. We hypothesized that functional interconnections between the thalamus and cortex can be altered after years of ongoing chronic neuropathic pain. Results: Functional connectivity was studied through a resting state functional magnetic resonance imaging (fMRI) paradigm: temporal correlations between predefined regions of interest (primary somatosensory cortex, ventral posterior lateral thalamic nucleus, medial dorsal thalamic nucleus) and the rest of the brain were systematically investigated. The patient group showed decreased resting state functional connectivity between the thalamus and the cortex. This supports the idea that chronic pain can alter thalamocortical connections causing a disruption of thalamic feedback, and the view of chronic pain as a thalamocortical dysrhythmia.

Background There is a need for a non-pharmacological approach to reduce pain and plantar pressure in diabetic peripheral neuropathy (DPN). Matrix Rhythm Therapy (MaRhyThe®) is a therapeutic modality that works on the principle of physiologic rhythmic oscillations of the body cells. This study aimed to evaluate the effect of MaRhyThe® on neuropathic pain and maximum plantar pressure distribution among type 2 diabetes mellitus patients with peripheral neuropathy. Materials and methods A total of 33 participants with DPN were recruited for the study based on inclusion criteria. Maximum plantar pressure was recorded using Win-Track 11K005, and the pain score was obtained using a visual analogue scale. Ten sessions of MaRhyThe® were given to all the participants. Outcome measures were evaluated at the baseline and after 10th session. Paired t-test was performed to analyze the changes in outcome measures. Results Participants of DPN were recruited with the average age of 64 ± 9 years, and...

E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolera...

ERVE GROWTH FACTOR (NGF) is a protein that plays a major role in the development and maintenance of the peripheral nervous system. Nerve growth factor selectively promotes the survival of small fiber sensory neurons that mediate pain, temperature sensation, and sympathetic neurons. 1 Nerve growth factor is expressed in target tissues innervated by responsive neurons, where it binds to specific high-affinity receptors and is retrogradely transported back to the neuronal cell body. Recent data suggest that reduced availability of NGF may play a significant role in the pathogenesis of diabetic polyneuropathy. In animals with diabetes mellitus, retrograde axonal transport of NGF is impaired, 3-5 and lev-els of NGF messenger RNA are reduced in neuronal target tissues. In patients with diabetes mellitus, levels of NGF are reduced in skin biopsy specimens. Furthermore, the diminished lev-Author Affiliations and a List of the Members of the rhNGF Investigator Group are listed at the end of this article.

Rationale: Diabetic autonomic neuropathy (DAN), a major complication of diabetes mellitus, is characterized, in part, by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K + current, I KAch , via a (GIRK1) 2 /(GIRK4) 2 K + channel. Sterol regulatory element binding protein-1 (SREBP-1) is a lipid-sensitive transcription factor. Objective: We describe a unique SREBP-1–dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for DAN. Methods and Results: Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2 Akita type I diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in the duration of bradycardia, a 52±8% decrease in atrial expression of GIRK1 ( P &lt;0.01), and a 31.3±2.1% decrease in SREBP-1 ( P &lt;0.05). Whole-cell patch-clamp studies of atri...

Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element–binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3β (GSK3β) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K+ (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K+ channel (IKACh), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a do...

Obecnie dysponujemy coraz obszerniejszą wiedzą na temat leczenia krótkowzroczności. Najważniejsze są jednak profilaktyka i zapobieganie szybkiemu postępowi wady refrakcji. Wyniki niektórych badań wskazują, że jedną z najskuteczniejszych metod hamujących lub zmniejszających postęp krótkowzroczności jest ortokorekcja wraz z zastosowaniem leczenia farmakologicznego. Ważną rolę w profilaktyce odgrywają także: codzienna higiena wzrokowa, czyli czas trwania pracy wzrokowej z bliska i jej jakość (czytanie, praca z komputerem), stosowanie ćwiczeń ortoptycznych, dobrze dobrana korekcja wady, odpowiednie nasłonecznienie (ruch na świeżym powietrzu), dieta i styl życia. Coraz częściej pojawiają się także doniesienia o możliwości zastosowania komórek macierzystych. Wyniki badań oceniających metody powstrzymywania lub zmniejszenia postępu krótkowzroczności u dzieci wykazały, że jedną z najskuteczniejszych metod jest ortokorekcja. Ta metoda polega na nocnym noszeniu specjalnie skonstruowanych, twardych, wysoko gazoprzepuszczalnych soczewek kontaktowych o odwrotnej czterokrzywiznowej geometrii (1, 2). Zasada działania ortosoczewek jest znana już od 1960 roku. Niemniej jednak dopiero skonstruowanie w latach 80. minionego stulecia nowej generacji wysoko gazoprzepuszczalnych soczewek kontaktowych o odwrotnej czterokrzywiznowej geometrii oraz zastosowanie komputerowej topografii rogówki pozwoliły na dokładną i przewidywalną korekcję krótkowzroczności. Ta szczególna konstrukcja soczewki powoduje zmiany kształtu powierzchni Krótkowzroczność. Część II -profilaktyka i leczenie według najnowszych wytycznych Myopia. Part II -prevention and treatment of the latest guidelines

Diabetic neuropathy is associated with functional and morphological changes of the neuromuscular junction (NMJ) associated with muscle weakness. This study examines the effect of type 1 diabetes on NMJ function. Swiss Webster mice were made diabetic with three interdaily ip injections of streptozotocin (STZ). Mice were severely hyperglycemic within 7 days after the STZ treatment began. Whereas performance of mice on a rotating rod remained normal, the twitch tension response of the isolated extensor digitorum longus to nerve stimulation was reduced significantly at 4 wk after the onset of STZ-induced hyperglycemia. This mechanical alteration was associated with increased amplitude and prolonged duration of miniature end-plate currents (mEPCs). Prolongation of mEPCs was not due to expression of the embryonic acetylcholine receptor but to reduced muscle expression of acetylcholine esterase (AChE). Greater sensitivity of mEPC decay time to the selective butyrylcholinesterase (BChE) inh...

Abstract. Vascular endothelial growth factor (VEGF) is a cytokine that potently stimulates angiogenesis, microvascular hyperpermeability, and endothelium-dependent vasodilation, effects that are largely mediated by endothelial nitric oxide synthase (eNOS). The expression of VEGF is pronounced in glomerular visceral epithelial cells, but its function in renal physiology and pathophysiology is unknown. VEGF expression is upregulated by high ambient glucose concentrations in several cell types in vitro and in glomeruli of diabetic rats. To assess the role of VEGF in the pathophysiology of early renal dysfunction in diabetes, monoclonal anti-VEGF antibodies (Ab) were administered to control and streptozotocin-induced diabetic rats for 6 wk after induction of diabetes. Based on in vitro binding studies, an adequate serum VEGF inhibitory activity was achieved during the entire course of anti-VEGF

Surgical decompression at the site of anatomic narrowing has been promoted as an alternative treatment for patients with symptomatic diabetic neuropathy. Systematic review of the literature revealed only Class IV studies concerning the utility of this therapeutic approach. Given the current evidence available, this treatment alternative should be considered unproven (Level U). Prospective randomized controlled trials with standard definitions and outcome measures are necessary to determine the value of this therapeutic intervention.