Study on the effect and mechanism of Zhenzhu Tongluo pills in treating diabetic peripheral neuropathy injury.

BACKGROUND: As a traditional Mongolian medicine, Zhenzhu Tongluo pills has played a good neuroprotective function in clinic. However, the key mechanisms by which it works are poorly studied. OBJECTIVES: To study the effect and mechanism of Zhenzhu Tongluo pills in treating diabetic peripheral neuropathy injury. METHODS: Diabetic peripheral neuropathy model was established by injecting STZ into rats. Physiological, behavioral, morphological and functional analyses were used to evaluate that the overall therapeutic effect of rats, ELISA, qRT-PCR, Western blot, immunohistochemical staining, HE staining and TUNEL staining were used to further study the related mechanism. RESULTS: Zhenzhu Tongluo pills can significantly improve the physiological changes, behavioral abnormalities, structural and functional damage in diabetic peripheral neuropathy rats, which may be related to the anti-inflammatory and anti-apoptotic effects that realized by regulating PI3K/AKT, MAPK, NF-κB signaling pathways. CONCLUSIONS: Zhenzhu Tongluo pills has neuroprotective effect, and anti-inflammatory and anti-apoptosis may be the important way of its function.

Ginkgolide B can alleviate spinal cord glymphatic system dysfunction and provide neuroprotection in painful diabetic neuropathy rats by inhibiting matrix metalloproteinase-9.

The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. ß-Dystroglycan (ß-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated ß-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, ß-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased ß-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN.

Non-coding RNAs in diabetic peripheral neuropathy: their role and mechanisms underlying their effects.

Diabetic peripheral neuropathy (DPN) is a complication of diabetes with a high rate of disability. However, current clinical treatments for DPN are suboptimal. Non-coding RNAs (ncRNAs) are a type of RNAs that are not translated into proteins. NcRNAs perform functions that regulate epigenetic modifications, transcriptional or post-transcriptional regulators of proteins, and thus participate in the physiological and pathological processes of the body. NcRNAs play a role in the progress of DPN by affecting the processes of inflammation, oxidative stress, cellular autophagy or apoptosis. Therefore, ncRNAs treatment is regarded as a promising therapeutic approach for DPN. In addition, since some ncRNAs present stably in the blood of DPN patients, they are considered as potential biomarkers that contribute to early clinical diagnosis. In this paper, we review the studies on the role of ncRNAs in DPN in the last decade, and discuss the mechanisms of ncRNAs, aiming to provide a reference for the future research on the treatment and early diagnosis of DPN.

Long-term efficacy and safety of Huangqi ()-based Traditional Chinese Medicine in diabetic peripheral neuropathy: a Meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the long-term effectiveness of Huangqi (Radix Astragali Mongolici, HQ)-based Traditional Chinese Medicine (TCM) in the treatment of diabetic peripheral neuropathy (DPN). METHODS: Nine databases were searched to retrieve available randomized controlled trials that compared HQ-based TCM and Western Medicines in the treatment of DPN. The methodological quality of the included studies was assessed using the Cochrane bias risk tool, and RevMan 5.4 was used for data analysis. The effect estimates of interest were risk ratio (RR), mean difference (MD) or standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: The results from 48 available studies assessing 3759 patients demonstrated that cases administered HQ-based TCM [RR = 1.30, 95% CI (1.21, 1.40), P < 0.000 01] or HQ-based TCM combined with Western Medicines [RR = 1.25, 95% CI (1.19, 1.31), P < 0.000 01] exhibited higher total efficacy rates than individuals who received Western Medicine alone. The results showed that the HQ-based TCM group had decreased Toronto Clinical Scoring System scores [MD =－1.50, 95% CI (－1.83, －1.17), P < 0.000 01], and reduced serum interleukin 6 [SMD = －0.57, 95% CI (－0.87, －0.27), P = 0.0002] and tumor necrosis factors-α levels [SMD = －0.60, 95% CI (－0.95, －0.25), P = 0.0009]. In addition, both HQ-based TCM and HQ-based TCM combined with Western Medicine increased nerve conduction velocity and decreased glycaemia compared with Western Medicine alone. In terms of blood lipids, oxidative stress and adverse drug reactions, there were no significant differences between the HQ-based TCM groups and the Western Medicine control group. CONCLUSION: The current Meta-analysis revealed that HQ-based TCM yields higher efficacy and safety than Western Medicine alone for the treatment of DPN, although further well-designed RCTs are required to validate these findings.

A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Painful diabetic neuropathy: The role of ion channels.

Painful diabetic neuropathy (PDN) is a common chronic complication of diabetes that causes neuropathic pain and negatively affects the quality of life. The management of PDN is far from satisfactory. At present, interventions are primarily focused on symptomatic treatment. Ion channel disorders are a major cause of PDN, and a complete understanding of their roles and mechanisms may provide better options for the clinical treatment of PDN. Therefore, this review summarizes the important role of ion channels in PDN and the current drug development targeting these ion channels.

Research progress of traditional Chinese medicine monomer in treating diabetic peripheral neuropathy: A review.

Diabetes peripheral neuropathy is one of the most common complications of diabetes. Early symptoms are insidious, while late symptoms mainly include numbness, pain, swelling, and loss of sensation in the limbs, which can lead to disability, foot ulcers, amputation, and so on. At present, the pathogenesis is also complex and diverse, and it is not yet clear. Western medicine treatment mainly focuses on controlling blood sugar and nourishing nerves, but the effect is not ideal. In recent years, it has been found that many drug monomers have shown good therapeutic and prognostic effects in the prevention and treatment of diabetes peripheral neuropathy, and related research has become a hot topic. To understand the specific mechanism of action of traditional Chinese medicine monomers in treatment, this article provides a review of their mechanism research and key roles. It mainly includes flavonoids, phenols, terpenes, saponins, alkaloids, polysaccharides, etc. By nuclear factor-κB (NF-κB), the signaling pathways of adenosine monophosphate-activated protein kinase (AMPK), Nrf2/ARE, SIRT1/p53, etc, can play a role in lowering blood sugar, antioxidant, anti-inflammatory, inhibiting cell apoptosis, and autophagy, promoting sciatic nerve regeneration, and have great potential in the prevention and treatment of this disease. A systematic summary of its related mechanisms of action was conducted, providing ideas for in-depth research and exploration of richer traditional Chinese medicine components, and also providing a relatively complete theoretical reference for clinical research on diabetes peripheral neuropathy treatment.

Research progress of the effective active ingredients of Astragalus mongholicus in the treatment of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most prevalent consequences of diabetes, with a high incidence and disability rate. The DPN's pathogenesis is extremely complex and yet to be fully understood. Persistent high glucose metabolism, nerve growth factor deficiency, microvascular disease, oxidative stress, peripheral nerve cell apoptosis, immune factors, and other factors have been implicated in the pathogenesis of DPN. Astragalus mongholicus is a commonly used plant used to treat DPN in clinical settings. Its rich chemical components mainly include Astragalus polysaccharide, Astragalus saponins, Astragalus flavones, etc., which play a vital role in the treatment of DPN. This review aimed to summarize the pathogenesis of DPN and the studies on the mechanism of the effective components of Astragalus mongholicus in treating DPN. This is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.

Acetyllevocarnitine Hydrochloride for the Treatment of Diabetic Peripheral Neuropathy: A Phase 3 Randomized Clinical Trial in China.

Diabetic peripheral neuropathy (DPN) is a highly prevalent chronic complication in type 2 diabetes (T2D) for which no effective treatment is available. In this multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial in China, patients with T2D with DPN received acetyllevocarnitine hydrochloride (ALC; 1,500 mg/day; n = 231) or placebo (n = 227) for 24 weeks, during which antidiabetic therapy was maintained. A significantly greater reduction in modified Toronto clinical neuropathy score (mTCNS) as the primary end point occurred in the ALC group (-6.9 ± 5.3 points) compared with the placebo group (-4.7 ± 5.2 points; P < 0.001). Effect sizes (ALC 1.31 and placebo 0.85) represented a 0.65-fold improvement in ALC treatment efficacy. The mTCNS values for pain did not differ significantly between the two groups (P = 0.066), whereas the remaining 10 components of mTCNS showed significant improvement in the ALC group compared with the placebo group (P < 0.05 for all). Overall results of electrophysiological measurements were inconclusive, with significant improvement in individual measurements limited primarily to the ulnar and median nerves. Incidence of treatment-emergent adverse events was 51.2% in the ALC group, among which urinary tract infection (5.9%) and hyperlipidemia (7.9%) were most frequent.

Effect and Safety of Herbal Medicine Foot Baths in Patients with Diabetic Peripheral Neuropathy: A Multicenter Double-Blind Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect and safety of foot baths with Tangbi Waixi Decoction (TW) in treating patients with diabetic peripheral neuropathy (DPN). METHODS: It is a multicenter double-blinded randomized controlled trial. Participants with DPN were recruited between November 18, 2016 and May 30, 2018 from 8 hospitals in China. All patients received basic treatments for glycemic management. Patients received foot baths with TW herbal granules either 66.9 g (intervention group) or 6.69 g (control group) for 30 min once a day for 2 weeks and followed by a 2-week rest, as a therapeutic course. If the Toronto Clinical Scoring System total score (TCSS-TS) ⩾6 points, the patients received a total of 3 therapeutic courses (for 12 weeks) and were followed up for 12 weeks. The primary outcome was change in TCSS-TS score at 12 and 24 weeks. Secondary outcomes included changes in bilateral motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the median and common peroneal nerve. Safety was also assessed. RESULTS: Totally 632 patients were enrolled, and 317 and 315 were randomized to the intervention and control groups, respectively. After the 12-week intervention, patients in both groups showed significant declines in TCSSTS scores, and significant increases in MNCV and SNCV of the median and common peroneal nerves compared with pre-treatment (P<0.05). The reduction of TCSS-TS score at 12 weeks and the increase of SNCV of median nerve at 24 weeks in the control group were greater than those in the intervention group (P<0.05). The number of adverse events did not differ significantly between groups (P>0.05), and no serious adverse event was related with treatment. CONCLUSION: Treatment of TW foot baths was safe and significantly benefitted patients with DPN. A low dose of TW appeared to be more effective than a high dose. (Registry No. ChiCTR-IOR-16009331).

A gluco-mindful approach to diabetic gastroparesis.

Diabetes gastroparesis is a common manifestation of autonomic neuropathy in persons with long-standing, uncontrolled diabetes. Most discussion about its management revolves around the mitigation of symptoms. Here, we share tips on choosing the right glucose-lowering medication, based upon predominant symptomatology of gastroparesis. We highlight about insulin preparations, and their timing of administration, can be tailored according to need. We also emphasize the need to choose oral glucose lowering drugs with care.

Exploring the molecular mechanism of Xuebifang in the treatment of diabetic peripheral neuropathy based on bioinformatics and network pharmacology.

Background: Xuebifang (XBF), a potent Chinese herbal formula, has been employed in managing diabetic peripheral neuropathy (DPN). Nevertheless, the precise mechanism of its action remains enigmatic. Purpose: The primary objective of this investigation is to employ a bioinformatics-driven approach combined with network pharmacology to comprehensively explore the therapeutic mechanism of XBF in the context of DPN. Study design and Methods: The active chemicals and their respective targets of XBF were sourced from the TCMSP and BATMAN databases. Differentially expressed genes (DEGs) related to DPN were obtained from the GEO database. The targets associated with DPN were compiled from the OMIM, GeneCards, and DrugBank databases. The analysis of GO, KEGG pathway enrichment, as well as immuno-infiltration analysis, was conducted using the R language. The investigation focused on the distribution of therapeutic targets of XBF within human organs or cells. Subsequently, molecular docking was employed to evaluate the interactions between potential targets and active compounds of XBF concerning the treatment of DPN. Results: The study successfully identified a total of 122 active compounds and 272 targets associated with XBF. 5 core targets of XBF for DPN were discovered by building PPI network. According to GO and KEGG pathway enrichment analysis, the mechanisms of XBF for DPN could be related to inflammation, immune regulation, and pivotal signalling pathways such as the TNF, TLR, CLR, and NOD-like receptor signalling pathways. These findings were further supported by immune infiltration analysis and localization of immune organs and cells. Moreover, the molecular docking simulations demonstrated a strong binding affinity between the active chemicals and the carefully selected targets. Conclusion: In summary, this study proposes a novel treatment model for XBF in DPN, and it also offers a new perspective for exploring the principles of traditional Chinese medicine (TCM) in the clinical management of DPN.

Disease-modifying therapies for diabetic peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Alpha-lipoic acid, epalrestat, and mecobalamin are widely used as monotherapies for diabetic peripheral neuropathy. However, whether a triple-combination therapy with these three drugs is superior to monotherapy or dual therapy remains debatable. METHODS: Nine randomized controlled trials were identified through a search on electronic databases such as PubMed, Web of Science, and Cochrane Library. The trial participants (N = 1153) were divided into the experimental group who received the triple-combination therapy and the control group who received conventional or dual therapy with the aforementioned drugs. RESULTS: Therapeutic outcomes were better in the experimental group than in the control group (odds ratio: 3.74; 95 % confidence interval: 2.57-5.45; I2 = 0 %; p < 0.00001). No statistic difference was noted in adverse effects. Compared with the control group, the experimental group exhibited significant improvements in median motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV, and vibration perception thresholds (VPT) in the left and right lower limbs. In the control group, a subgroup analysis by treatment strategy revealed similar improvements in total efficacy, MNCV, and SNCV. CONCLUSIONS: For diabetic peripheral neuropathy, the triple-combination therapy may be more effective than monotherapy or dual therapy.

Alpha-lipoic acid for diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN. Although alpha-lipoic acid (ALA, also known as thioctic acid) is widely used, there is no consensus about its benefits and harms. OBJECTIVES: To assess the effects of alpha-lipoic acid as a disease-modifying agent in people with diabetic peripheral neuropathy. SEARCH METHODS: On 11 September 2022, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two clinical trials registers. We also searched the reference lists of the included studies and relevant review articles for additional references not identified by the electronic searches. SELECTION CRITERIA: We included randomised clinical trials (RCTs) that compared ALA with placebo in adults (aged 18 years or older) and that applied the study interventions for at least six months. There were no language restrictions. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was change in neuropathy symptoms expressed as changes in the Total Symptom Score (TSS) at six months after randomisation. Secondary outcomes were change in neuropathy symptoms at six to 12 months and at 12 to 24 months, change in impairment, change in any validated quality of life total score, complications of DPN, and adverse events. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Our analysis incorporated three trials involving 816 participants. Two studies included people with type 1 or type 2 diabetes, while one study included only people with type 2 diabetes. The duration of treatment was between six months and 48 months. We judged all studies at high risk of overall bias due to attrition. ALA compared with placebo probably has little or no effect on neuropathy symptoms measured by TSS (lower score is better) after six months (mean difference (MD) -0.16 points, 95% confidence interval (CI) -0.83 to 0.51; 1 study, 330 participants; moderate-certainty evidence). The CI of this effect estimate did not contain the minimal clinically important difference (MCID) of 0.97 points. ALA compared with placebo may have little or no effect on impairment measured by the Neuropathy Impairment Score-Lower Limbs (NIS-LL; lower score is better) after six months (MD -1.02 points, 95% CI -2.93 to 0.89; 1 study, 245 participants; low-certainty evidence). However, we cannot rule out a significant benefit, because the lower limit of the CI surpassed the MCID of 2 points. There is probably little or no difference between ALA and placebo in terms of adverse events leading to cessation of treatment within six months (risk ratio (RR) 1.48, 95% CI 0.50 to 4.35; 3 studies, 1090 participants; moderate-certainty evidence). No studies reported quality of life or complications associated with DPN. AUTHORS' CONCLUSIONS: Our analysis suggests that ALA probably has little or no effect on neuropathy symptoms or adverse events at six months, and may have little or no effect on impairment at six months. All the studies were at high risk of attrition bias. Therefore, future RCTs should ensure complete follow-up and transparent reporting of any participants missing from the analyses.

Aldose reductase is a potential therapeutic target for neurodegeneration.

Neurodegeneration is a complex process involving various inflammatory mediators and cellular responses. Aldose reductase (AR) is a key enzyme in the polyol pathway, which converts glucose to sorbitol. Beyond its metabolic role, AR has also been found to play a significant role in modulating neuroinflammation. This review aims to provide an overview of the current knowledge regarding the involvement of AR inhibition in attenuating neuroinflammation and complications from diabetic neuropathies. Here, we review the literature regarding AR and neuropathy/neurodegeneration. We discuss the mechanisms underlying the influence of AR inhibitors on ocular inflammation, beta-amyloid-induced neurodegeneration, and optic nerve degeneration. Furthermore, potential therapeutic strategies targeting AR in neurodegeneration are explored. The understanding of AR's role in neurodegeneration may lead to the development of novel therapeutic interventions for other neuroinflammatory disorders.

A neuroprotective effect of pentoxifylline in rats with diabetic neuropathy: Mitigation of inflammatory and vascular alterations.

BACKGROUND: Treatment of diabetic neuropathic pain does not change the natural history of neuropathy. Improved glycemic control is the recommended treatment in these cases, given that no specific treatment for the underlying nerve damage is available, so far. In the present study, the potential neuroprotective effect of pentoxifylline in streptozotocin (50 mg/kg) induced diabetic neuropathy in rats was investigated. METHODS: Pentoxifylline was administered at doses equivalent to 50, 100 & 200 mg/kg, in drinking water, starting one week after streptozotocin injection and for 7 weeks. Mechanical allodynia, body weight and blood glucose level were assessed weekly. Epidermal thickness of the footpad skin, and neuroinflammation and vascular alterations markers were assessed. RESULTS: Tactile allodynia was less in rats that received pentoxifylline at doses of 100 and 200 mg/kg (60 % mechanical threshold increased by 48 % and 60 %, respectively). The decrease in epidermal thickness of footpad skin was almost completely prevented by the same doses. This was associated with a decrease in spinal tumor necrosis factor alpha (TNFα) and nuclear factor kappa B levels and a decrease in microglial ionized calcium binding adaptor molecule 1 immunoreactivity, compared to the control diabetic group. In sciatic nerve, there was decrease in TNF-α and vascular endothelial growth factor levels and intercellular adhesion molecule immunoreactivity. CONCLUSION: Pentoxifylline showed a neuroprotective effect in streptozotocin-induced diabetic neuropathy, which was associated with a suppression of both the inflammatory and vascular pathogenic pathways that was not associated with a hypoglycemic effect. Thus, it may represent a potential neuroprotective drug for diabetics.

Protective effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve of rats with diabetic peripheral neuropathy.

Dyslipidemia has been considered a risk factor for diabetic peripheral neuropathy. Proprotein convertase subtilisin-like/Kexin 9 inhibitor (PCSK9) inhibitors are a new type of lipid-lowering drug currently in clinical use. The role of PCSK9 in diabetic peripheral neuropathy is still unclear. In this study, the effect of alirocumab, a PCSK9 inhibitor, on the sciatic nerve in rats with diabetic peripheral neuropathy and its underlying mechanisms were investigated. The diabetic peripheral neuropathy rat model was established by using a high-fat diet combined with streptozotocin injection, and experimental subjects were divided into normal, diabetic peripheral neuropathy, and alirocumab groups. The results showed that Alirocumab improved nerve conduction, morphological changes, and small fiber deficits in rats with DPN, possibly related to its amelioration of oxidative stress and the inflammatory response.

Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. METHODS: Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). RESULTS: There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p<0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). CONCLUSIONS/INTERPRETATION: This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure.

Clinical and preclinical evidence that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent diabetic peripheral neuropathy.

Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni's test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and ß-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM.

NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice.

Abnormal NAD+ signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD+ precursors could alleviate DPN symptoms through increasing the NAD+ levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD+, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD+ levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.