Early Stage Of Diabetic Neuropathy Research Articles

Sudomotor dysfunction diagnostic test for early detection of diabetic neuropathy

Sudomotor dysfunction may appear in early stages of diabetic neuropathy. To evaluate the diagnostic capacity of the Neuropad test, based on the detection of sudomotor dysfunction, as an early indicator of diabetic neuropathy. In Forty-two type 2 diabetic patients, the Neuropad test was compared with the 10 g monofilament test (proposed in the technical orientation of diabetic foot of the Ministry of Health of Chile), deep and thermal sensitivity. The surface sensitivity assessed with a brush had a sensitivity and specificity of 18.8 and 100% respectively when compared with the 10 g monofilament. When compared with the Neuropad, the figures were 9 and 100%, respectively. Pain perception sensitivity and specificity were 13 and 100% respectively when compared with the 10 g monofilament. The figures were 6 and 100%, when compared with the Neuropad. Thermal discrimination had a sensitivity and specificity of 88 and 33% respectively when compared with the 10 g monofilament. The figures were 75 and 25% respectively when compared with the Neuropad. The deep sensitivity evaluated with a 128 Hz tuning fork had a sensitivity and specificity of 31 and 100% respectively when compared with the 10 g monofilament. The figures were 16 and 31% respectively when compared with the Neuropad. The Neuropad had a sensitivity and specificity of 94 and 29% respectively were compared with the 10 g monofilament. Neuropad had a good diagnostic yield for the early detection of sudomotor dysfunction.

Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy.

AimsType 1 diabetes can be complicated with neuropathy that involves immune‐mediated and inflammatory pathways. Glucagon‐like peptide‐1 receptor agonists such as liraglutide, have shown anti‐inflammatory properties, and thus we hypothesized that long‐term treatment with liraglutide induced diminished inflammation and thus improved neuronal function.MethodsThe study was a randomized, double‐blinded, placebo‐controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2–1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing.ResultsThirty‐nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin‐6 (−22.6%; 95% confidence interval [CI]: −38.1, −3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with −3.38 kg (95% CI: −5.29, −1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (−40.2%; 95% CI: −60.6, −9.5; P = .02).ConclusionHitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

Central Corneal Thickness can be Related to Diabetic Peripheral Neuropathy in Children with Type 1 Diabetes.

Diabetic eye disease with its various manifestations as well as diabetic neuropathy may occur in patients with type 1 diabetes (T1D) after several years of diabetes duration. Pachymetry is a promising method evaluating central corneal thickness (CCT) in diabetic patients. The aim of the study was to evaluate the CCT values in children with T1D and its relationship to neurophysiological markers of diabetic neuropathy. The study groups included 119 T1D children with average 5.3 years of diabetes duration and 38 age-matched controls. CCT index was measured with pachymeter in all subjects and in 19/119 of T1D patients the CCT values were referred to the ENG-EMG-SSR study results. In T1D patients the higher CCT values were observed as compared to healthy controls (p=0.037). Correlations between CCT values and both distal latency of the motor fibers of the median nerve (R=0.51; p=0.044) and conduction velocity of this nerve (R=-0.55; p=0.027) were noted. A conduction velocity of the sensory fibers of sural nerve correlated negatively with CCT index (R=-0.50; p=0.045) in the T1D patients. CCT measurement may be helpful in the referral of the asymptomatic pediatric T1D patients to assess an early stage of diabetic neuropathy.

Quantitative sensory testing in type 1 diabetic patients with mild to severe diabetic neuropathy

Background: Small nerve fibre damage has been shown to precede large fibre damage and represents the early stage for diabetic neuropathy (DPN). Aims: To assess small nerve fibre deficit in patients with mild to severe DPN using quantitative sensory testing (QST) and to correlate QST findings with other neuropathy assessment measures in patients with DPN. Materials and Methods: Seventy-nine diabetic patients (49 with and 30 without diabetic neuropathy) and 35 healthy volunteers underwent neuropathy assessment. The evaluation comprised neuropathy symptoms profile, modified neuropathy disability score (NDS), quantitative sensory testing (QST) in form of cold and warm thresholds, vibration pressure threshold (VPT), nerve conduction studies (NCS), deep breathing heart rate variability (DB-HRV), and Neuropad staining scores. Patients were also stratified by their NDS scores into mild, moderate and severe DPN. Measures of QST were compared among various grades of DPN severity and correlated with other clinical and neurophysiological tests. Results: Patients with DPN demonstrated higher vibration perception (P<0.001) and warm (P<0.001) thresholds and lower cold threshold (P<0.001) and these QST abnormalities related directly to the grade of DPN severity. Measures of QST also correlated with those of nerve conduction studies (r range 0.54-0.68) and autonomic function assessment(r range 0.33-0.48). Conclusion: Quantitative sensory testing can identify small nerve fibres impairment which could represent the early stage of diabetic neuropathy and hence the optimal period for intervention.

Hydroxytyrosol Attenuates Peripheral Neuropathy in Streptozotocin-Induced Diabetes in Rats

Peripheral neuropathy is one of the most frequent and severe complications of diabetes. Hydroxytyrosol (HT), the major antioxidant polyphenolic compound of olive oil, has been investigated as a new potential treatment to counteract the progression of peripheral diabetic neuropathy in rats. An established model of streptozotocin-induced diabetes has been used. After confirmation of hyperglycemia, diabetic and nondiabetic animals were randomized to receive either a low dose or a high dose of HT, or the corresponding vehicle, for 6 weeks. At the end of the 6-week period of treatment, HT blunted plasma thiobarbituric acid-reactive substances increase (p < 0.05) and significantly reduced nerve conduction velocity (p < 0.05) and thermal nociception impairment in diabetic rats (p < 0.05). Sciatic nerve Na(+), K(+)-ATPase activity reduction was also abolished by HT (p < 0.05). The present study provides evidence of the therapeutic potential of the natural substance hydroxytyrosol in the early stage of diabetic neuropathy.

Feasibility of contact heat evoked potentials for detection of diabetic neuropathy

The involvement of small myelinated fibers in the early stages of diabetic neuropathy (DN) has been suggested, but few objective methods can identify minimal neuropathy. The purpose of this study was to determine whether there are differences in contact heat evoked potential (CHEP) parameters between healthy adults and diabetics with and without lower limb symptoms. CHEP was recorded at the midline channels. A peak stimulating temperature of 51°C was applied to the dorsum of the foot and at a point 10 cm proximal to the lateral malleolus. There was a significant difference in N1-P1 amplitude in the three groups after stimulation of the dorsum of the foot (P = 0.028) and the point 10 cm proximal to the lateral malleolus (P = 0.006). CHEP can help to detect early A-delta fiber damage in diabetic patients with minimal neuropathy.

Sensitized peripheral nociception in experimental diabetes of the rat

Painful neuropathy is a common complication of diabetes. Particularly in the early stage of diabetic neuropathy, patients are characterized by burning feet, hyperalgesia to heat, and mechanical stimuli, as if residual nociceptors were sensitized. Such symptoms are barely explained by common pathophysiological concepts of diabetic neuropathy. Diabetes was induced in Wistar rats by streptozotocin (STZ). After 4weeks behavioral testing (Plantar test, Randall–Selitto) was conducted. Basal and stimulated release of calcitonin gene-related peptide (CGRP), Substance P (SP) and prostaglandin E2 (PGE2) from isolated skin and sciatic nerve were assessed by enzyme immunoassays. Electrophysiological properties of identified nociceptors under hyperglycemic, hypoxic, and acidotic conditions were investigated using the skin-nerve preparation. The diabetic rats showed hyperalgesia to heat and pressure stimulation. The basal CGRP/SP release was reduced, but chemical stimulation with bradykinin induced greater release of SP, CGRP and PGE2 than in control animals. In contrast, capsaicin-stimulated CGRP release was reduced in sciatic nerves. Hypoxia per se lowered von Frey thresholds of most C-nociceptors to half. Hyperglycemic hypoxia induced ongoing discharge in all diabetic but not control C-fibers which was further enhanced under acidosis. Sensory and neurosecretory nociceptor functions are sensitized in diabetes. Diabetic C-fibers show exaggerated sensitivity to hyperglycemic hypoxia with and without additional acidosis, conditions that are thought to mimic ischemic episodes in diabetic nerves. Ongoing C-fiber discharge is known to induce spinal sensitization. Together with altered receptor and ion channel expressions this may contribute to painful episodes in diabetic neuropathy.

Evaluation of sudomotor function in diabetes using the dynamic sweat test

The study of sudomotor function represents a useful tool to evaluate autonomic disorders. Currently available tests allow either the measurement of sweat output from the whole body or selected small skin locations over time, or quantification of the number and size of sweat drops at a fixed time after stimulation. We devised a dynamic sweat test (DST) that measures at the same time sweat gland density, distribution of active glands, and sweat rate, and applied it to the evaluation of sudomotor function in diabetes. The DST was used to evaluate sweating in the forearm of 14 asymptomatic diabetic subjects and 14 age- and sex-matched healthy controls. Distal leg was also tested in 7 patients and 7 controls. The formation of the imprint of pilocarpine-induced sweating was recorded by a digital video camera through a cornstarch-powdered transparent tape used as a contrast-enhancing device. Mean sweat output per gland and per skin area and sweat gland density per cm(2) were evaluated. We observed a significant reduction of sweating in diabetic subjects as compared to controls; sweat gland density per cm(2) (59.7 +/- 18.6 vs 83.7 +/- 17.3; p < 0.05) and mean sweat output (nL/min) per gland (4.7 +/- 0.7 vs 8.3 +/- 2.7; p = 0.01) and per skin area (261 +/- 100 vs 645 +/- 296; p = 0.01) were reduced in the lower limb. Values for the forearm were not significantly different from controls. Dynamic sweat test is an easy-to-perform, informative method to study sudomotor function. It provides the ability to detect subtle functional changes occurring in the early stages of diabetic neuropathy.

Lowered response threshold and increased responsiveness to mechanical stimulation of cutaneous nociceptive fibers in streptozotocin-diabetic rat skin in vitro--correlates of mechanical allodynia and hyperalgesia observed in the early stage of diabetes.

Rats rendered diabetic by streptozotocin (STZ) show allodynia and hyperalgesia and thus, have been offered as a model of pain in diabetic neuropathy. However, recent electrophysiological studies on these rats found that C-fiber nociceptors were not consistently hyperexcitable to mechanical stimulations by von Frey hairs and that there was no change in their response thresholds. In the present study, we used rat skin-saphenous nerve in vitro preparations, in which the receptive fields of identified single C-polymodal receptors (CPRs) can be accurately stimulated with a servo-controlled mechanical stimulator. Single fiber recordings from CPRs were performed in diabetic rats with an increased behavioral nociceptive response 7-19 days after STZ injection. The proportion of units with spontaneous activity and the magnitude of this activity increased in the diabetic preparations. The response thresholds of CPRs were significantly decreased with ramp-pressure stimulation and their response magnitude to the suprathreshold stimulation was significantly increased in diabetic rats. In addition, the response pattern to mechanical stimulation was also changed to a non-adapting type. These findings suggest that changes in CPRs contribute to the enhanced nociception observed in the early stage of diabetic neuropathy.

Activation of IL-1 signaling pathway in Schwann cells during diabetic neuropathy.

Our results show activation of the IL-1 signaling pathway in Schwann cells (SC), prior to and during early stages of diabetic neuropathy, thus suggesting its role in the initiation of SC-axonal miscommunication.

Abnormal axonal inward rectifier in streptozocin-induced experimental diabetic neuropathy.

In order to explore the pathophysiology of diabetic neuropathy, we studied serial changes of axonal excitability in 20 adult Wistar rats with streptozocin-induced diabetes using the technique of threshold electrotonus (TE). After persistent hyperglycaemia had developed, rats were divided into two groups: nine were fed a diet containing aldose reductase inhibitor (Epalrestat 30 mg/kg/day) (ARI(+) group) and 11 were fed a diet without the inhibitor (ARI(-) group). Eight normal control rats of similar age (NC group) were also studied. We monitored membrane properties of motor axons in the tail for 3 months using TE to measure the changes in excitability induced by subthreshold polarizing currents while recording compound muscle action potentials (CMAPs) in the tail muscle. The ARI(-) group showed a significant increase in CMAP latency 1 month after streptozocin injection, and by 3 months there was significantly lower excitability after hyperpolarization for 100 ms compared with the NC group. A similar change in TE was reproduced by injection of caesium chloride, an inhibitor of inward rectification. By contrast, the ARI(+) group exhibited no significant change in TE or latency at 3 months, although they showed significant body weight loss and hyperglycaemia. These findings indicate that inward rectification is reduced in an experimental model, as in human diabetes, and that blocking the polyol pathway with an ARI prevents this reduction. Reduced inward rectification potentiates conduction block caused by activity-dependent hyperpolarization and may underlie the decreased vibratory sensation seen in the early stage of diabetic neuropathy.

Subclinical diabetic polyneuropathy: early detection of involvement of different nerve fibre types.

Nerve conduction studies, tests of autonomic function and terminal nerve branches, and soleus muscle H reflexes were applied to 60 patients with insulin dependent diabetes mellitus who had no clinical symptoms but abnormal vibratory or temperature perception thresholds indicating subclinical neuropathy. In most patients neurophysiological examination yielded a broad spectrum of neural dysfunction. The perception threshold for cold stimuli was sometimes selectively impaired and abnormal pupillometry results were common, suggesting that small fibres are vulnerable in the early stage of diabetic neuropathy. The arms were less frequently and less severely affected than the legs, an effect that may be related to nerve length. The neurophysiological test results did not change in 30 patients followed up for one year.

Ganglioside treatment and improved axonal regeneration capacity in experimental diabetic neuropathy.

The efficacy of gangliosides in enhancing axonal regeneration and maturation in the early stages of diabetic neuropathy was assessed by quantitative analysis of immunostained serial sections of the sciatic nerve. Sprague-Dawley rats were made diabetic with a single injection of alloxan (100 mg/kg). One week later they were injected daily intraperitoneally with either a highly purified ganglioside mixture (10 mg/kg) or sterile saline for 4 wk. At the end of the treatment, sciatic nerves were crushed and allowed to regenerate for 1 wk without ganglioside treatment. The animals were then killed, and the nerves were frozen and processed for immunohistochemistry and electron microscopy. The number of regrowing axons was counted with a computerized image-analysis system on cross sections taken at predefined distances along the regenerating stump and stained with monoclonal antibody iC8 specific for the 145,000-Mr subunit of the neurofilaments. In untreated diabetic animals the number of axons able to regenerate and sustain elongation for greater than or equal to 13 mm from the crush point was reduced by 40% with respect to control rats. Ganglioside treatment was effective in compensating almost completely for this dramatic reduction. Electron microscopy confirmed that the immunofluorescence counts corresponded to regenerating axons containing neurofilaments. These results suggest that gangliosides are able to compensate for the derangements of axonal transport of cytoskeletal proteins reported in experimental diabetic neuropathy.

NEUROPATHY OF DIABETES MELLITUS.

This experiences of the internist, the neurosurgeon, and the neuropathologist. It demonstrates some of the clinical symptoms and signs which diabetes mellitus may assume. To a certain degree, diabetic neuropathy is a diagnosis of exclusion. When a neuropathy exists in a patient with diabetes, a cause-and-effect relationship to the diabetes should be considered first. However, the patient should have as careful an evaluation of the central and peripheral nervous system as the nondiabetic patient. The converse is also true—a neurological problem, particularly of the peripheral variety, might be the first indication of diabetes, and appropriate investigations should be done. There have been few postmortem examinations in early stages of diabetic neuropathy; therefore most of the reports are concerned with severe forms of the disease. Fraser and Bruce (1895) 1 found segmental degeneration of the myelin, but preservation of the continuity of the axons. Woltman and Wilder (1929) 2 described diffuse