Treatment Of Diabetic Peripheral Neuropathy Research Articles

Efficacy and safety of Buyang Huanwu decoction for diabetic peripheral neuropathy: a systematic review and Metaanalysis.

To evaluate the efficacy and safety of Buyang Huanwu decoction (BYHWD) in treating diabetic peripheral neuropathy (DPN). Eight electronic databases, including China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, Chinese Biomedical Literature Database, Cochrane Library, Embase, Web of Science, and PubMed, were searched for randomized controlled trials (RCTs) of BYHWD to treat DPN. We identified all RCTs related to BYHWD and those on the treatment of DPN with the combination of mecobalamin. RevMan software was used for the statistical analysis. Twentyone RCTs with a total of 1945 patients were included. The methodological quality of the literature included was low. Metaanalysis showed that the efficacy of the treatment group was significantly better than that of the control group in the treatment of DPN with BYHWD [risk ratio () = 0.33, 95% (0.27, 0.40), 11.25, 0.000 01]. The median nerve of median motor nerve conduction velocity (MNCV) [mean difference () = 4.16, 95% (1.35, 6.98)] and median sensory NCV (SNCV) [(= 3.28, 95% (2.35, 4.22)] were improved in the treatment group. The MNCV in the common peroneal nerve [(= 1.63, 95% (0.39, 2.87)] and SNCV [(= 4.56, 95% (3.16, 5.97)] were significantly higher than those in the control group ( 0.01). Plasma viscosity [(= －0.15, 95% (－0.20, －0.09), 5.17, 0.01)], whole blood high shear [(= 0.83, 95% (1.56, －0.11), 2.26, 0.02)]and whole blood low shear [(= 1.61, 95% (2.28, 0.94), 4.68, 0.01)] decreased significantly after treatment. There was no significant difference in fasting blood glucose [(= 0.42, 95% ( 0.89, 0.05), 1.76, 0.08)] between the treatment and control groups; postprandial blood glucose [(= 0.62, 95% ( 1.19, 0.05), 2.12, 0.03)] decreased significantly. No significant difference was found in the blood lipid levels between the treatment and control groups, including triglycerides [(= 0.21, 95% (0.52, 0.10), 1.34, 0.18)] and cholesterol [(= 0.13, 95% ( 0.27, 0.00), 1.92, 0.06)]. Of the 21 RCTs, only five reported adverse reactions, and four studies reported the length of followup. No serious adverse events were reported. None of the studies reported the quality of life and economic conditions. Our study suggests that BYHWD has a significant therapeutic effect on DPN. Highquality, largescale RCTs are needed to provide more reliable evidence.

Digital Nerve Care Forum: Innovative Healthcare Professionals Education on Neuropathy.

Neuropathy is a common complication of diabetes, rarely detected on time, often deprioritized by treating physicians, and hence rarely managed in time, leading to avoidable complications which can be limb and life-threatening. Despite introducing new diagnostic tests, novel potential bio parameters, and a series of relatively small intervention studies utilizing detailed phenotypic profiling, the management of diabetic neuropathy (DN) and painful DN has remained unchanged due to misdiagnosis. The diagnostic complexity of diabetic peripheral neuropathy (DPN), variation in patient response to treatment, and regulatory pressures to meet data-driven quality metrics for diabetes management all likely contributes to the underdiagnosis and treatment of DPN in clinical practice. Educating the primary healthcare providers and diabetic trainers would help improve the number of diagnosed DPN cases as these practitioners lead public health literacy. The digital nerve care forum (NCF) is an educational initiative created by clinical experts and Procter and Gamble (P&G) health academy. Its primary aim is to generate awareness amongst healthcare practitioners (HCPs) about early diagnosis and timely management of DPN. Since its inception in October 2020, NCF has conducted 143 engagements; 39 neuropathy case puzzles, four interactive case-based discussions, two diagnostic workshops, four mentor-mentee nerve talk shows, two intercountry nerve talk shows, two global neuropathy awareness week initiatives, three nerves of steel (Women's Day special engagements), and 17 NCF times (Newsletters). This online forum is hosted on a global HCP education and upskilling platform, MediSage, which offers these educational resources to HCPs worldwide for free. It has helped create a community of 254, 714 HCPs from 86 countries across six continents supported by 30 neuropathy experts from seven countries. With a repeated viewership of 53% of HCPs engaging continuously, NCF empowers this community to improve diabetic patient care. Activities that increase disease awareness and highlight the importance of diabetic nerve health have been the key objectives behind the several educational programs on NCF. To drive this continuum, these digital programs are now becoming more phygital and impactful than ever. Therefore, earlier detection of DPN in at-risk individuals and those with prediabetes or type 2 diabetes is recommended for better management through optimal intervention and lifestyle changes and to prevent future complications of untreated DPN. How to cite this article: Kalra S, Tiwaskar M, Shrestha D, et al. Digital Nerve Care Forum: Innovative Healthcare Professionals Education on Neuropathy. J Assoc Physicians India 2023;71(10):89-92.

Formate Might Be a Novel Potential Serum Metabolic Biomarker for Type 2 Diabetic Peripheral Neuropathy.

As one of the most frequent complications of type 2 diabetes mellitus (T2DM), diabetic peripheral neuropathy (DPN) shows a profound impact on 50% of patients with symptoms of neuropathic pain, numbness and other paresthesia. No valid serum biomarkers for the prediction of DPN have been identified in the clinic so far. This study is to investigate the potential serum biomarkers for DPN firstly based on 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomics technique. Thirty-six patients enrolled in this study were divided into two groups: 18 T2DM patients without DPN (T2DM group) and 18 T2DM patients with DPN (DPN group). Serum metabolites were measured via 1H-NMR spectroscopy. Bioinformatic approaches including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), independent sample t-test, Fisher's test, Pearson and Spearman correlation analysis, Stepwise multiple linear regression analysis and receiver operating characteristic (ROC) curve analysis were used to identify the potential altered serum biomarkers. A total of 20 metabolites were obtained and further analyzed. Formate was identified as the only potential biomarker that decreased in the DPN group with statistical significance after multiple comparisons (p<0.05). Formate also displayed a negative relationship with some elevated clinical markers in DPN. ROC curve analysis showed a good discriminative ability for formate in DPN with an area under the curve (AUC) value of 0.981. Formate could be considered a potential serum metabolic biomarker for DPN. The reduced level of formate in DPN may be associated with mitochondrial dysfunction and gut microbiota alteration. Monitoring the level of serum formate would be an important strategy for the early diagnosis of DPN and a supplement of formate may be a promising treatment for DPN in the future.

Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. The lifetime prevalence of DPN is thought to be >50%, and 15%-25% of patients with diabetes experience neuropathic pain, referred to as "painful DPN." Appropriate treatment of painful DPN is important because this pain contributes to a poor quality of life by causing sleep disturbance, anxiety, and depression. The basic principle for the management of painful DPN is to control hyperglycemia and other modifiable risk factors, but these may be insufficient for preventing or improving DPN. Because there is no promising diseasemodifying medication for DPN, the pain itself needs to be managed when treating painful DPN. Drugs for neuropathic pain, such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, alpha-lipoic acid, sodium channel blockers, and topical capsaicin, are used for the management of painful DPN. The U.S. Food and Drug Administration (FDA) has approved pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch as drugs for the treatment of painful DPN. Recently, spinal cord stimulation using electrical stimulation is approved by the FDA for the treatment for painful DPN. This review describes the currently available pharmacological and nonpharmacological treatments for painful DPN.

Açaí berry ameliorates cognitive impairment by inhibiting NLRP3/ASC/CASP axis in STZ-induced diabetic neuropathy in mice.

Diabetes complications such as diabetic peripheral neuropathy (DPN) are linked to morbidity and mortality. Peripheral nerve damages in DPN are accompanied by discomfort, weakness, and sensory loss. Some drugs may demonstrate their therapeutic promise by reducing neuroinflammation, but they have side effects. Based on these considerations, the objective of this study was to examine the beneficial properties of açaí berry in a mouse model of DPN generated by injection of streptozotocin (STZ). Açaí berry was given orally to diabetic and control mice every day beginning 2 wk after STZ injection. The animals were euthanized after 16 wk, and tissues from the spinal cord and sciatic nerve and urine were taken. Our findings showed that daily treatment of açaí berry at a dose of 500 mg/kg was able to prevent behavioral changes as well as mast cell activation and nerve deterioration via NOD-like receptor family pyrin-domain-containing-3 (NLRP3)/apoptosis-associated speck-like protein containing a card (ASC)/caspase (CASP) regulation after diabetes induction.NEW & NOTEWORTHY Our research shows that açaí berry reduces mast cells degranulation and histological damage in diabetic neuropathy, improves physiological defense against reactive oxygen species, modulates the NLRP3/ASC/CASP axis, and ameliorates inflammation and oxidative stress. Diet could help treatment for diabetic peripheral neuropathy.

Honokiol attenuates high glucose-induced peripheral neuropathy via inhibiting ferroptosis and activating AMPK/SIRT1/PGC-1ɑ pathway in Schwann cells.

Schwann cells injury induced by high glucose (HG) contributes to the development of diabetic peripheral neuropathy (DPN). Honokiol has been reported to regulate glucose metabolism, however, its effect on DPN and the precise molecular mechanisms remain unclear. This study aimed to investigate the role of AMPK/SIRT1/PGC-1α axis in the protective effects of honokiol on DPN. The biochemical assay and JC-1 staining results demonstrated that honokiol reduced HG-induced oxidative stress and ferroptosis as well as mitochondrial dysfunction in Schwann cells. RT-qPCR and western blotting were utilized to investigate the mechanism of action of honokiol, and the results showed that HG-induced inhibition of AMPK/SIRT1/PGC-1α axis and changes of downstream gene expression profile were restored by honokiol. Moreover, silencing of Sirt1 by siRNA delivery markedly diminished the changes of gene expression profile induced by honokiol in HG-induced Schwann cells. More importantly, we found that administration of honokiol remarkably attenuated DPN via improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity in streptozotocin-induced diabetic rats. Collectively, these results demonstrate that honokiol can attenuate HG-induced Schwann cells injury and peripheral nerve dysfunction, suggesting a novel potential strategy for treatment of DPN.

Effect of 10.6 μm laser moxibustion on inflammation in diabetic peripheral neuropathy rats.

Diabetic peripheral neuropathy (DPN) is the main cause of disability in diabetes patients but the efficacy of available drugs is poor. Moxibustion is an adjunctive treatment for DPN that can reduce symptoms. The peak value of the far infrared wavelength of 10.6 μm laser moxibustion is close to the infrared radiation spectrum of traditional moxibustion. Its effect is similar to that of moxibustion and does not cause pain, infection or produce irritating smoke. Twenty-four male SD rats were divided into control (Con), DPN, laser moxibustion (LM), and pyrrolidine dithiocarbamate (PDTC) groups (n=6/group). The DPN, LM and PDTC group rats were intraperitoneally injected with 1% streptozotocin (STZ) to induce a model of DPN. LM group rats were irradiated with a laser at bilateral ST36 acupoints for 15min, once every other day, for 14 days. PDTC group rats were intraperitoneally injected with PDTC once a day. Body weight, blood glucose, and paw withdrawal mechanical threshold (PWMT) were measured and laser speckle imaging (LSI) performed before and after modeling and at 1 and 2 weeks after intervention. Two weeks after intervention, changes in serum interleukin 1β (IL1β), interleukin 6 (IL6), tumor necrosis factor α (TNFα) and nerve growth factor (NGF) were analyzed, and the abundance of NF-κB and IκB-α proteins and levels of NF-κB and IκB-α mRNAs in the sciatic nerve were observed. The results showed that 10.6 μm laser moxibustion can relieve pain, improve microcirculation, and alleviate inflammation in DPN rats, possibly via the NF-κB inflammatory pathway.

Effect of Traditional Chinese Medicine collapse stains combined with ultrasound drug penetration therapy in the treatment of diabetic peripheral neuropathy in the elderly

Effect of Traditional Chinese Medicine collapse stains combined with ultrasound drug penetration therapy in the treatment of diabetic peripheral neuropathy in the elderly

Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy is a common complication of diabetes mellitus. Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies. However, existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research. Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy, it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods. This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods. Various metabolic mechanisms (e.g., polyol, hexosamine, protein kinase C pathway) are associated with diabetic peripheral neuropathy, and researchers are looking for more effective treatments through these pathways.

105-OR: Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy—Is the Source Important?

Introduction: We have shown that omega-3 polyunsaturated fatty acids (PUFA) derived from fish oil (FO) was an effective treatment for diabetes vascular and neural complications. However, is FO the best source of omega-3 PUFA for treating diabetic peripheral neuropathy (DPN)? Methods: To address this question we used a rat model of type 2 diabetes and a late intervention protocol. After 10 weeks of hyperglycemia, diabetic rats were treated for 12 weeks via diet with omega-3 PUFA derived from a variety of sources including menhaden (fish) oil (MO), krill oil (KO), oils derived from algae that produce primarily eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or combination of EPA and DHA, or commercial ethyl esters of EPA, DHA or combination of EPA and DHA. Primary endpoints were motor (MNCV) and sensory (SNCV) nerve conduction velocity, intraepidermal and cornea nerve fiber density, thermal and cornea sensitivity, and vascular reactivity of epineurial arterioles that provide circulation to the sciatic nerve. The omega-3 index, and serum fatty acid levels were also determined. Results: The dose of each omega-3 PUFA supplement was customized to create a healthy omega-3 index. Defined as the sum of EPA and DHA as a percentage of total fatty acids in red blood cells, range for healthy level 8 - 12%. Following 22 weeks of untreated diabetes neural and vascular endpoints were significantly impaired compared to control rats. Treatment with MO provided the greatest improvement for all neural endpoints followed by KO and algal oils or ethyl esters containing a combination of EPA and DHA. Algal oil or ethyl ester of EPA alone was the least effective. The greatest improvement in vascular reactivity of epineurial arterioles to acetylcholine was realized following treatment with MO with less benefit from the other omega-3 PUFA sources. Conclusion: These pre-clinical studies suggest that in a clinical trial for DPN the best outcome may be obtained by using FO as the source for omega-3 PUFA. Disclosure M.A.Yorek: Consultant; Novo Nordisk. Funding U.S. Department of Veterans Affairs (RX003826-01)

106-OR: Degludec-Like Insulin Analog Improves Peripheral Neuropathy More than Control Insulin Independent of Glycemic Control in a Rat Model of Type 2 Diabetes

Current treatments for type 2 diabetes fail to prevent the development of peripheral neuropathy. To examine insulin degludec’s effect on peripheral neuropathy in rats, we tested insulin 700, an analog identical to insulin degludec with the same pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, but with the absence of the terminal threonine on the B-chain. Rats were fed a high fat diet for 8 weeks and then treated with a low dose of streptozotocin to induce hyperglycemia. After 2 weeks, diabetic rats were treated with I700 or a control basal insulin (IC) with similar PK twice daily for 18 weeks. A healthy reference group fed a chow diet and not subjected to streptozotocin treatment was also included. The endpoints evaluated included sensory and motor nerve conduction velocity, allodynia using von Frey’s test, thermal sensitivity using Hargreaves test and corneal sensitivity. We evaluated innervation of sensory nerves using corneal confocal microscopy and, in the skin, using histological methods. We also tested vascular reactivity of epineurial arterioles using pressure myography. The insulin analogues were equally effective at correcting hyperglycemia as determined by HbA1C levels of 4.1±0.1 and 4.1±0.1% for I700 and IC, respectively. Both insulin analogues improved all neuropathy related parameters. However, I700 was more effective in that by the end of the treatment period there was no difference in thermal sensitivity, corneal sensitivity, corneal nerve fiber length and sensory and motor nerve conduction velocity between the group treated with I700 and the healthy reference rats. Interestingly, vascular relaxation to acetylcholine improved more with IC treatment. In conclusion, this study demonstrates that I700 (a degludec-like insulin analog) is a more effective treatment for diabetic peripheral neuropathy than a comparable control insulin, independent of glycemic control. Disclosure T.C.A.Åkerström: Employee; Novo Nordisk. L.Andreasen: Employee; Novo Nordisk. E.Nishimura: Employee; Novo Nordisk A/S. M.A.Yorek: Consultant; Novo Nordisk.

493-P: SCS for the Treatment of Painful DPN—Consistent Outcomes from Multiple RCTs

Pain associated with diabetic peripheral neuropathy (DPN) is treated medically with gabapentin/pregabalin, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors1 which are often not satisfactory long-term. Spinal Cord Stimulation (SCS) is an effective alternative per 3 randomized controlled trials (RCTs)2,3,4. We reviewed and compared 3 published RCTs2,3,4 comparing SCS to conventional treatments for painful DPN in subjects with mostly type 2 diabetes (Table 1). Study outcome measures included a composite primary endpoint where patients could be identified as treatment responders by reduction in pain diary scores or Patient Global Impression of Change, ≥50% reduction in VAS measurement for pain, and a compound primary endpoint of ≥50% reduction in pain score and no neurologic decline. EQ5D questionnaires were used to assess Quality of Life. The difference in treatment success between SCS and control for the primary endpoint in the Intention-to-Treat populations ranged from 52 - 58%. Improvement in EQ5D index scores at 6 months ranged from 0.124 - 0.380. The similarity of outcomes in 3 RCTs2,3,4 demonstrate that SCS is an effective treatment modality for DPN pain compared with conventional medical approaches. Patients from 1 study4 have been followed-up to 18 months8 and patients in another2 up to 10 years9 with similar outcomes, demonstrating long-term benefits of SCS for patients with painful DPN. Disclosure B.W.Bode: Advisory Panel; Ascensia Diabetes Care, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Research Support; Abbott Diabetes, Abvance Therapeutics, Better Therapeutics, Inc, Dexcom, Inc., Diasome, Dompé, Insulet Corporation, Lilly Diabetes, Medtronic, Novo Nordisk, Sanvita Medical, Senseonics, Provention Bio, Inc., REMD Biotherapeutics, ViaCyte, Inc., Xeris Pharmaceuticals, Inc., vTv Therapeutics, Speaker's Bureau; Abbott Diabetes, American Diabetes Association, Boehringer Ingelheim and Eli Lilly Alliance, Insulet Corporation, Lilly Diabetes, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; Glytec, LLC. G.Grunberger: Advisory Panel; CeQur SA, Nevro Corp., LifeScan Diabetes Institute, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. M.Fishman: Consultant; Abbott, Biotronik, Medtronic, Nevro Corp., Other Relationship; Medtronic, Abbott, Research Support; Abbott, Boston Scientific Corporation, Medtronic, Nalu, SGX Medical, Thermaquil, Biotronik, Stock/Shareholder; Celeri Health, Thermaquil. M.Murphy: Consultant; Medtronic, Relievant. R.A.Vigersky: Employee; Medtronic. L.Johanek: Employee; Medtronic. M.Larue: Employee; Medtronic. Funding Medtronic

Analysis of lncRNA and mRNA expression profiles in diabetic peripheral neuropathy based on weighted gene co-expression network analysis

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. Recent studies have explored the involvement of long non-coding RNA (lncRNA) in diabetes, but its specific role in DPN development remains unclear. To investigate the association between lncRNAs and DPN, we conducted comprehensive bioinformatics analyses. We obtained gene expression data from the sciatic nerve of 8-week-old and 24-week-old diabetic mice from the Gene Expression Omnibus database (GEO). Weighted gene co-expression network analysis (WGCNA) was performed to identify co-expression modules and hub differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and other bioinformatics methods were used to establish the biological processes and functions of the differentially expressed RNAs related to DPN. The identified hub genes were validated using an animal model of DPN and quantitative real-time polymerase chain reaction. Two lncRNAs (DIO3OS and A530053G22Rik) and three mRNAs (FGF18, DUSP3, and DUSP9) were identified as potential DPN-related genes, potentially affecting DPN through the MAPK pathway. Five hub genes were identified as potential biomarkers for the diagnosis and treatment of DPN, based on the GEO database.

Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy.

Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).

ID: 211861 Painful DPN and SCS: Using the Product Surveillance Registry (PSR) to Collect Real World Evidence

Painful Diabetic Peripheral Neuropathy (DPN) is the most common neuropathic syndrome seen in persons with diabetes and is accompanied by pain in the feet and lower legs by the typical ‘glove and stocking’ pattern of distribution. Patients can experience a variety of symptoms, including prickling or tingling, burning, shooting, or stabbing pain or unusual sensations, which can interfere with sleep and quality of Life (QoL) leading to reduced activity levels, depression and social isolation1. Literature has demonstrated that conventional Spinal Cord Stimulation (SCS) is an effective treatment for painful DPN of the lower extremities, showing significant benefits of pain relief and improved QoL2,3,4. New stimulation paradigms may offer additional options for DPN patients. The purpose of this study is collecting real-world data on pain, QoL, stimulation paradigms, sleep, and activity.

ID: 215433 The History of Spinal Cord Stimulation to Treat Painful Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is the most common neuropathic syndrome seen in patients with diabetes. Roughly 30% of the diabetes patient population1 experience painful DPN symptoms including bilateral stabbing or burning pain in addition to numbness in the feet and lower legs. Traditionally painful DPN symptoms have been treated with conventional medical management (CMM) including glycemic control, general risk factor management, as well as pharmaceutical agents. These treatment approaches are often unsuccessful in the long-term1. Spinal cord stimulation (SCS) has been demonstrated as an effective treatment for painful DPN of the lower extremities with multiple publications dating back to 1996 showing benefits of SCS for pain relief and improved Quality of Life (QoL) in DPN patients (Figure 1)2-18.

Clinical Pathobiochemistry of Vitamin B12 Deficiency: Improving Our Understanding by Exploring Novel Mechanisms with a Focus on Diabetic Neuropathy.

Vitamin B12 (B12) is an essential cofactor of two important biochemical pathways, the degradation of methylmalonic acid and the synthesis of methionine from homocysteine. Methionine is an important donor of methyl groups for numerous biochemical reactions, including DNA synthesis and gene regulation. Besides hematological abnormalities (megaloblastic anemia or even pancytopenia), a deficiency in B12 may cause neurological symptoms, including symptoms resembling diabetic neuropathy. Although extensively studied, the underlining molecular mechanism for the development of diabetic peripheral neuropathy (DPN) is still unclear. Most studies have found a contribution of oxidative stress in the development of DPN. Detailed immunohistochemical investigations in sural nerve biopsies obtained from diabetic patients with DPN point to an activation of inflammatory pathways induced via elevated advanced glycation end products (AGE), ultimately resulting in increased oxidative stress. Similar results have been found in patients with B12 deficiency, indicating that the observed neural changes in patients with DPN might be caused by cellular B12 deficiency. Since novel results show that B12 exerts intrinsic antioxidative activity in vitro and in vivo, B12 may act as an intracellular, particularly as an intramitochondrial, antioxidant, independent from its classical, well-known cofactor function. These novel findings may provide a rationale for the use of B12 for the treatment of DPN, even in subclinical early states.

A Review of Recent Pharmacological Advances in the Management of Diabetes-Associated Peripheral Neuropathy.

Diabetic peripheral neuropathy is a common complication of longstanding diabetes mellitus. These neuropathies can present in various forms, and with the increasing prevalence of diabetes mellitus, a subsequent increase in peripheral neuropathy cases has been noted. Peripheral neuropathy has a significant societal and economic burden, with patients requiring concomitant medication and often experiencing a decline in their quality of life. There is currently a wide variety of pharmacological interventions, including serotonin norepinephrine reuptake inhibitors, gapentanoids, sodium channel blockers, and tricyclic antidepressants. These medications will be discussed, as well as their respective efficacies. Recent advances in the treatment of diabetes mellitus with incretin system-modulating drugs, specifically glucagon-like peptide-1 agonists, have been promising, and their potential implication in the treatment of peripheral diabetic neuropathy is discussed in this review.

Three genes expressed in relation to lipid metabolism considered as potential biomarkers for the diagnosis and treatment of diabetic peripheral neuropathy

Diabetic neuropathy is one of the most common chronic complications and is present in approximately 50% of diabetic patients. A bioinformatic approach was used to analyze candidate genes involved in diabetic distal symmetric polyneuropathy and their potential mechanisms. GSE95849 was downloaded from the Gene Expression Omnibus database for differential analysis, together with the identified diabetic peripheral neuropathy-associated genes and the three major metabolism-associated genes in the CTD database to obtain overlapping Differentially Expressed Genes (DEGs). Gene Set Enrichment Analysis and Functional Enrichment Analysis were performed. Protein–Protein Interaction and hub gene networks were constructed using the STRING database and Cytoscape software. The expression levels of target genes were evaluated using GSE24290 samples, followed by Receiver operating characteristic, curve analysis. And Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the target genes. Finally, mRNA-miRNA networks were constructed. A total of 442 co-expressed DEGs were obtained through differential analysis, of which 353 expressed up-regulated genes and 89 expressed down-regulated genes. The up-regulated DEGs were involved in 742 GOs and 10 KEGG enrichment results, mainly associated with lipid metabolism-related pathways, TGF-β receptor signaling pathway, lipid transport, and PPAR signaling pathway. A total of 4 target genes (CREBBP, EP300, ME1, CD36) were identified. Analysis of subject operating characteristic curves indicated that CREBBP (AUC = 1), EP300 (AUC = 0.917), ME1 (AUC = 0.944) and CD36 (AUC = 1) may be candidate serum biomarkers for DPN. Conclusion: Diabetic peripheral neuropathy pathogenesis and progression is caused by multiple pathways, which also provides clinicians with potential therapeutic tools.

Early Diagnosis through Estimation of Inflammatory Biomarkers and the Neuroprotective Role of Metformin in Diabetic Peripheral Neuropathy

Purpose: Diabetic peripheral neuropathy (DPN), a chronic neurological complication of type 2 diabetes mellitus (T2DM) with signs and symptoms of peripheral nerve dysfunction such as numbness, tingling or burning sensation, paresthesias etc. Several lacunae exist in relation to the cause and effect of DPN. Therefore diagnosis, as well as treatment of DPN remains unsatisfactory. The involvement of chronic low-grade inflammation in DPN is a rapidly emerging concept and therefore the present study adds weight to it. We estimated some of the biomarkers of inflammation which may be the early markers of DPN. This study is the earliest of its kind to correlate the biomarker levels with metformin, a drug less reported in terms of its anti-inflammatory and neuroprotective activity. &#x0D; Methods: After approval from the institutional human ethical committee, 90 patients attending the outpatient ward of a tertiary care hospital were included in the study. They were divided into two groups: M- group (patients on non metformin) and M+ group (patients on metformin). 5ml serum sample from each patient was processed for estimation of IL-1, IL-6, IL-8, TNF- α, INF- α, GMCSF and MCP-1 according to the manufacturer’s instructions on the commercially available ELISA kit. Metformin levels in the serum were estimated by HPLC. Data was put into statistical analysis. &#x0D; Results: Results showed that IL-1, IL-2, IL-6 and TNF- α were significantly higher in the M- group. The difference was statistically significant between the two groups. The level of biomarkers showed a negative correlation with drug levels in the initial 2m treatment with the drug but was not statistically significant. However, after 6m treatment with metformin the correlation was found to be of statistical significance.&#x0D; Conclusion: we conclude that these biomarkers can be work tested for their clinical utility to be used as diagnostic tools for early detection of DPN and short-term metformin treatment greatly benefits DPN patients. Longitudinal studies may be more insightful as to the long term neuroprotective action of metformin.