Diabetic Neuropathy Collection: Treatment of Diabetic Neuropathy.
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ABSTRACT:
SUBMITTER: Alam U
PROVIDER: S-EPMC7136380 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
Publications
Diabetic Neuropathy Collection: Treatment of Diabetic Neuropathy.
Diabetes therapy : research, treatment and education of diabetes and related disorders 20200309 4
Video: Treatment of Diabetic Neuropathy podcast recording (MP4 61908 kb). ...[more]
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Project description:ObjectiveTo describe the natural history, clinical, neurophysiological, and histological features, and outcomes of diabetic patients presenting with acute painful neuropathy associated with glycemic control, also referred to as insulin neuritis.MethodsSixteen subjects presenting with acute painful neuropathy had neurological and retinal examinations, laboratory studies, autonomic testing, and pain assessments over 18 months. Eight subjects had skin biopsies for evaluation of intraepidermal nerve fiber density.ResultsAll subjects developed severe pain within 8 weeks of intensive glucose control. There was a high prevalence of autonomic cardiovascular, gastrointestinal, genitourinary, and sudomotor symptoms in all subjects. Orthostatic hypotension and parasympathetic dysfunction were seen in 69% of subjects. Retinopathy worsened in all subjects. Reduced intraepidermal nerve fiber density (IENFD) was seen in all tested subjects. After 18 months of glycemic control, there were substantial improvements in pain, autonomic symptoms, autonomic test results, and IENFD. Greater improvements were seen after 18 months in type 1 versus type 2 diabetic subjects in autonomic symptoms (cardiovascular p < 0.01; gastrointestinal p < 0.01; genitourinary p < 0.01) and autonomic function tests (p < 0.01, sympathetic and parasympathetic function tests).InterpretationTreatment-induced neuropathy is characterized by acute, severe pain, peripheral nerve degeneration, and autonomic dysfunction after intensive glycemic control. The neuropathy occurred in parallel with worsening diabetic retinopathy, suggesting a common underlying pathophysiological mechanism. Clinical features and objective measures of small myelinated and unmyelinated nerve fibers can improve in these diabetic patients despite a prolonged history of poor glucose control, with greater improvement seen in patients with type 1 diabetes.
| S-EPMC3057039 | biostudies-literature
Project description:Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNFα pathway activation and several other markers of neuroinflammation in the CNS. Chronic oral treatment with J147 protected the sciatic nerve from progressive diabetes-induced slowing of large myelinated fiber conduction velocity while single doses of J147 rapidly and transiently reversed established touch-evoked allodynia. Conduction slowing and allodynia are clinically relevant markers of early diabetic neuropathy and neuropathic pain, respectively. RNA expression profiling suggests that one of the pathways by which J147 imparts its protection against diabetic induced neuropathy may be through activation of the AMP kinase pathway. The diverse biological and therapeutic effects of J147 suggest it as an alternative to the polypharmaceutical approaches required to treat the multiple pathogenic mechanisms that contribute to diabetic neuropathy.
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Project description:Diabetic peripheral neuropathy (DPN) is a disabling common complication of diabetes mellitus (DM). Thrombin, a coagulation factor, is increased in DM and affects nerve function via its G-protein coupled protease activated receptor 1 (PAR1). A novel PAR1 modulator (PARIN5) was designed based on the thrombin PAR1 recognition site. Coagulation, motor and sensory function and small fiber loss were evaluated by employing the murine streptozotocin diabetes model. PARIN5 showed a safe coagulation profile and showed no significant effect on weight or glucose levels. Diabetic mice spent shorter time on the rotarod (p <0.001), and had hypoalgesia (p <0.05), slow conduction velocity (p <0.0001) and reduced skin innervation (p <0.0001). Treatment with PARIN5 significantly improved rotarod performance (p <0.05), normalized hypoalgesia (p <0.05), attenuated slowing of nerve conduction velocity (p <0.05) and improved skin innervation (p <0.0001). PARIN5 is a novel pharmacological approach for prevention of DPN development, via PAR1 pathway modulation.
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Project description:Diabetic Neuropathy (DN) is a common complication of diabetes. Currently, there is no drug treatment to prevent or slow the development of DN. Rosiglitazone (Rosi) is a potent insulin sensitizer and may also slow the development of DN by a mechanism independent of its effect on hyperglycemia. A two by two design was used to test the effect of Rosi treatment on the development of DN. Streptozotocin-induced diabetic DBA/2J mice were treated with Rosi. DN and oxidative stress were quantified, and gene expression was profiled using the Affymetrix Mouse Genome 430 2.0 microarray platform. An informatics approach identified key regulatory elements activated by Rosi. Diabetic DBA/2J mice developed severe hyperglycemia, DN and elevated oxidative stress. Rosi treatment did not affect hyperglycemia but did reduce oxidative stress and prevented development of thermal hypoalgesia. Two novel transcription factor binding modules were identified that may control genes correlated to changes in DN following Rosi treatment: SP1F_ZBPF and EGRF_EGRF. Rosi treatment reduced oxidative stress and DN independent of its insulin sensitizing effects. Gene expression profiling identified two novel targets activated by Rosi treatment. These targets may be useful in designing drugs with the same efficacy as Rosi in treating DN but with fewer undesirable effects. Keywords: disease and treatment analysis
2008-05-10 | GSE11343 | GEO
Project description:Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.
| S-EPMC7796340 | biostudies-literature
Project description:Diabetic neuropathy (DN) is a common complication of diabetes. Currently, there is no drug treatment to prevent or slow the development of DN. Rosiglitazone (Rosi) is a potent insulin sensitizer and may also slow the development of DN by a mechanism independent of its effect on hyperglycemia. A two by two design was used to test the effect of Rosi treatment on the development of DN. Streptozotocin-induced diabetic DBA/2J mice were treated with Rosi. DN and oxidative stress were quantified, and gene expression was profiled using the Affymetrix Mouse Genome 430 2.0 microarray platform. An informatics approach identified key regulatory elements activated by Rosi. Diabetic DBA/2J mice developed severe hyperglycemia, DN, and elevated oxidative stress. Rosi treatment did not affect hyperglycemia but did reduce oxidative stress and prevented the development of thermal hypoalgesia. Two novel transcription factor binding modules were identified that may control genes correlated to changes in DN after Rosi treatment: SP1F_ZBPF and EGRF_EGRF. These targets may be useful in designing drugs with the same efficacy as Rosi in treating DN but with fewer undesirable effects.
| S-EPMC2582925 | biostudies-literature
Project description:A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the ?(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ?2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.
| S-EPMC3413770 | biostudies-literature
Project description:Objective: To systematically evaluate the effects of different drugs for the treatment of painful diabetic peripheral neuropathy. Methods: All literature from PubMed, Embase, and Cochrane Central Register of Controlled Trials published over the past 12 years (from January 1, 2008 to June 1, 2020) was searched, and two reviewers independently assessed study eligibility, continuous data extraction, independent assessment of bias risk, and graded strength of evidence. The pain score was used as the main result, and 30 and 50% pain reduction and adverse events were used as secondary results. Results: A total of 37 studies were included. Pregabalin, duloxetine, tapentadol, lacosamide, mirogabalin, and capsaicin were all more effective than placebo in alleviating the pain associated with diabetic peripheral neuropathy, while ABT-894 and gabapentin showed no significant effect. In addition, the efficacy of buprenorphine, tanezumab, fulranumab and others could not be concluded due to insufficient studies. Conclusion: Pregabalin and duloxetine showed good therapeutic effects on painful DPN, but adverse events were also significant. The analgesic effects of ABT-894 and gabapentin need to be further studied with longer and larger RCTs. As an opioid drug, tapentadol has a good analgesic effect, but due to its addiction, it needs to be very cautious in clinical use. Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, the therapeutic effect is weaker than pregabalin. For the results of our meta-analysis, long-term studies are still needed to verify their efficacy and safety in the future. Systematic Review Registration: PROSPERO, identifier: CRD42020197397.
| S-EPMC8585758 | biostudies-literature