Progression Of Diabetic Neuropathy Research Articles

Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy.

Diabetic neuropathy (DN) is a neurodegenerative disorder that is primarily characterized by distal sensory loss, reduced mobility, and foot ulcers that may potentially lead to amputation. The multifaceted etiology of DN is linked to a range of inflammatory, vascular, metabolic, and other neurodegenerative factors. Chronic inflammation, endothelial dysfunction, and oxidative stress are the three basic biological changes that contribute to the development of DN. Although our understanding of the intricacies of DN has advanced significantly over the past decade, the distinctive mechanisms underlying the condition are still poorly understood, which may be the reason behind the lack of an effective treatment and cure for DN. The present study delivers a comprehensive understanding and highlights the potential role of the several pathways and molecular mechanisms underlying the etiopathogenesis of DN. Moreover, Schwann cells and satellite glial cells, as integral factors in the pathogenesis of DN, have been enlightened. This work will motivate allied research disciplines to gain a better understanding and analysis of the current state of the biomolecular mechanisms behind the pathogenesis of DN, which will be essential to effectively address every facet of DN, from prevention to treatment.

480-P: Synergistic Effects of Hyperglycemia and Dyslipidemia on Diabetic Neuropathy—High Glucose Aggravates Oxidized LDL-Induced Schwann Cell Death via Hyperactivation of TLR4

Diabetic neuropathy is a progressive complication of diabetes mellitus, with persistent pain and loss of sensory function. Oxidized LDL (oxLDL), an oxidized form of LDL, has been shown to play a significant role in the development of neuronal dysfunction. Circulating oxLDL is elevated in type 2 diabetes, leading to higher cardiovascular risk. However, the combined effects of hyperglycemia and oxLDL on the progression of diabetic neuropathy remain unknown. Here, we investigated the synergistic effects of high glucose on oxLDL-induced schwann cell death and its detailed mechanism. Immortalized adult mouse Schwann (IMS32) cells were treated with oxLDL (0, 150, 300 μg/mL) under normal glucose (NG, 5.5 mM) or high glucose (HG, 25 mM) conditions for 24 hours. Following treatment, we evaluated cell viability, gene, and protein expression of Toll-like receptor 4 (TLR4), a receptor for oxLDL. Under NG conditions, 300 μg/mL oxLDL, but not 150 μg/mL reduced the cell viability. Moreover, under HG conditions, both 150 μg/mL and 300 μg/mL oxLDL decreased the cell viability. Likewise, the gene and protein expression of TLR4 was synergistically upregulated by the combination of oxLDL and HG. We further evaluated the effects of TLR4 inhibition on the cell viability and apoptotic caspase-3 activity. The cells were pretreated with TAK-242, a TLR4 inhibitor, for 2 hours prior to 150 μg/mL of oxLDL treatment under NG or HG conditions. TAK-242 pretreatment attenuated the oxLDL-induced cell death in HG conditions. The caspase-3 activity was increased by oxLDL in HG conditions, but not in NG. Furthermore, the increased caspase-3 activity by oxLDL and HG was abolished by TAK-242. These results indicate that high glucose and oxLDL induce activation of TLR4, leading to exacerbated schwann cell apoptosis. The dysregulation of TLR4 signal in diabetes complicated with dyslipidemia may contribute to the pathogenesis of diabetic neuropathy. Disclosure W.Nihei: None. A.Kato: None. T.Himeno: None. M.Kondo: None. J.Nakamura: None. H.Kamiya: Research Support; Kissei Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Merck & Co., Inc., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Japan Tobacco Inc., Novo Nordisk, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Sanofi, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Daiichi Sankyo, Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Novartis Pharma K.K., Merck & Co., Inc., Sanwa Kagaku Kenkyusho, Otsuka Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Astellas Pharma Inc., Terumo Corporation, Fukuda Denshi, LifeScan Diabetes Institute, EA Pharma Co., Ltd, KAKEN PHARMACEUTICAL CO., LTD, AstraZeneca. K.Sango: None. K.Kato: None.

Protocolo de tratamiento de la nefropatía diabética

The early initiation of all known treatment strategies for halting the onset and slowing the progression of diabetic neuropathy (DN) is the principal objective in treating a diabetic patient. Prevention and a multidisciplinary approach are essential, given that they contribute to halting progression and decreasing cardiovascular events and the risk of mortality. In recent decades, DN progression rates have slowed, probably due to better control of diabetes and blood pressure (BP), the stabilization or decline in proteinuria favored by renin-angiotensin-aldosterone system (RAAS) inhibitors, and better lipid control. A reduction in the incidence and progression of DN will depend on all of these factors.

Antioxidant, Wound Healing Potential and In Silico Assessment of Naringin, Eicosane and Octacosane.

1. Diabetic chronic wounds, mainly foot ulcers, constitute one of the most common complications of poorly managed diabetes mellitus. The most typical reasons are insufficient glycemic management, latent neuropathy, peripheral vascular disease, and neglected foot care. In addition, it is a common cause of foot osteomyelitis and amputation of the lower extremities. Patients are admitted in larger numbers attributable to chronic wounds compared to any other diabetic disease. In the United States, diabetes is currently the most common cause of non-traumatic amputations. Approximately five percent of diabetics develop foot ulcers, and one percent require amputation. Therefore, it is necessary to identify sources of lead with wound-healing properties. Redox imbalance due to excessive oxidative stress is one of the causes for the development of diabetic wounds. Antioxidants have been shown to decrease the progression of diabetic neuropathy by scavenging ROS, regenerating endogenous and exogenous antioxidants, and reversing redox imbalance. Matrix metalloproteinases (MMPs) play vital roles in numerous phases of the wound healing process. Antioxidant and fibroblast cell migration activity of Marantodes pumilum (MP) crude extract has previously been reported. Through their antioxidant, epithelialization, collagen synthesis, and fibroblast migration activities, the authors hypothesise that naringin, eicosane and octacosane identified in the MP extract may have wound-healing properties. 2. The present study aims to identify the bioactive components present in the dichloromethane (DCM) extract of M. pumilum and evaluate their antioxidant and wound healing activity. Bioactive components were identified using LCMS, HPTLC and GCMS. Excision wound on STZ-induced diabetic rat model, human dermal fibroblast (HDF) cell line and colorimetric antioxidant assays were used to evaluate wound healing and antioxidant activities, respectively. Molecular docking and pkCMS software would be utilised to predict binding energy and affinity, as well as ADME parameters. 3. Naringin (NAR), eicosane (EIC), and octacosane (OCT) present in MP displayed antioxidant action and wound excision closure. Histological examination HDF cell line demonstrates epithelialization, collagen production, fibroblast migration, polymorphonuclear leukocyte migration (PNML), and fibroblast movement. The results of molecular docking indicate a substantial attraction and contact between MMPs. pkCMS prediction indicates inadequate blood-brain barrier permeability, low toxicity, and absence of hepatotoxicity. 4. Wound healing properties of (NEO) naringin, eicosane and octacosane may be the result of their antioxidant properties and possible interactions with MMP.

Neuroprotective Potential of 20(S)-Ginsenoside Rg3 Against the Progression of Diabetic Neuropathy: Experiments on Rat Sciatic Nerve

Neuroprotective Potential of 20(S)-Ginsenoside Rg3 Against the Progression of Diabetic Neuropathy: Experiments on Rat Sciatic Nerve

Diametrical Effects of Glucose Levels on Microvascular Permeability of Peripheral Nerves in Patients With Type 2 Diabetes With and Without Diabetic Neuropathy.

Clinical studies investigating the benefit of glucose control on the progression of diabetic neuropathy (DN) have come to controversial results in patients with type 2 diabetes (T2D). This study aimed to assess associations of HbA1c levels with parameters of nerve perfusion in patients with T2D with and without DN using dynamic contrast-enhanced magnetic resonance neurography (DCE-MRN) at 3 Tesla. A total of 58 patients with T2D (20 with DN and 38 without DN) took part in this cross-sectional single-center study. Groups were matched for age, BMI, HbA1c, duration of T2D, and renal function. All patients underwent DCE-MRN with subsequent electrophysiologic and serologic testing. The extended Tofts model was used to quantify the sciatic nerve's microvascular permeability (Ktrans), volume fraction of the extracapillary extracellular space, and volume fraction of the plasma space. As a main result, we found that Ktrans correlated positively with HbA1c in patients with DN, while a negative correlation between the two parameters was found in patients without DN. Our results indicate that the effect of glucose control on the capillary permeability of peripheral nerves differs between patients with T2D with and without DN.

Antidiabetic Effectiveness Test of Andaliman Fruit (Zanthoxylum acanthopodium) Extract on Histopathological Changes in Peripheral Nerves: An In Vivo Study

Background: Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood sugar levels, and the increase in sugar levels is triggered by low insulin production or the ineffective use of insulin by the body (relatively). Diabetic neuropathy is a complication that often attacks DM patients and is the highest complication of diabetes. This study aims to test the effectiveness of Andaliman fruit (Zanthoxylum acanthopodium) extract on the improved histopathology of Peripheral nerve in alloxan-induced Wistar rats (Rattus norvegicus).
 Methods: This study is an experimental study using 24 Wistar rats, which were grouped into 6 groups (1: normal, 2: negative control, 3: positive control, 4-6: DM + andaliman extract 150mg/kgBW, 250 mg/kgBW, 350 mg /kgBB). Data analysis used SPSS to determine differences in the histological conditions of peripheral nerves.
 Results: The administration of andaliman fruit extract at a dose of 350 mg/kgBW was most effective in inhibiting the proliferation of Schwann cells, which showed the potential of andaliman fruit extract in preventing the progression of diabetic neuropathy. The administration of andaliman fruit extract at a dose of 350 mg/kgBW also showed the most effective potential in inhibiting the inflammatory process in the peripheral nerves, which is believed to be responsible for peripheral nerve cell damage.
 Conclusion: Andaliman fruit (Zanthoxylum acanthopodium) extract is effective against improving the histopathology of peripheral nerves in alloxane-induced Wistar rats (Rattus norvegicus).

The Role of Angiotensin Receptor Blockers in the Personalized Management of Diabetic Neuropathy

Neuropathy is a frequent complication of diabetes mellitus (DM) and is associated with the increased risk ofamputation and vascular events. Tight glycemic control is an important component inthe prevention of diabetic neuropathy. However, accumulating data suggest that angiotensin receptor blockers (ARBs) might also be useful in this setting. We discuss the findings of both experimental and clinical studies that evaluated the effects of ARBs on indices of diabetic neuropathy. We also review the implicated mechanisms of the neuroprotective actions of these agents. Overall, it appears that ARBs might be a helpful tool for preventing and delaying the progression of diabetic neuropathy, but more data are needed to clarify their role in the management of this overlooked complication of DM.

Identification of independent risk factors for diabetic neuropathy progression in patients with type 2 diabetes mellitus.

ObjectiveTo identify independent risk factors for diabetic neuropathy (DN) in patients with type 2 diabetes mellitus (T2DM).MethodsWe retrospectively analyzed 376 patients with T2DM at the First Affiliated Hospital of Fujian Medical University, China between January 2013 and October 2016. Multivariate logistic regression was used to explore potential risk factors for progression of DN in patients with T2DM. Effect sizes were estimated using odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe prevalence of DN in patients with T2DM was 43.1%. Multivariate logistic regression indicated that retinopathy (OR: 2.755, 95% CI: 1.599–4.746); diabetic nephropathy (OR: 2.196, 95% CI: 1.279–3.772); longer duration of T2DM (OR: 1.081, 95% CI: 1.045–1.120); use of insulin (OR: 1.091, 95% CI: 1.018–1.170); longer history of alcohol consumption (OR: 1.034, 95% CI: 1.010–1.059); and higher blood urea nitrogen (OR: 1.081, 95% CI: 1.009–1.159) were associated with increased risk of DN in patients with T2DM.ConclusionsRetinopathy, diabetic nephropathy, longer duration of T2DM, use of insulin, longer history of alcohol consumption, and higher blood urea nitrogen were independent risk factors for DN. These findings should be verified in large-scale prospective studies.

Effect of caffeine on the possible amelioration of diabetic neuropathy: A spectroscopic study

ImportanceOne of the consequential and alarming complications of diabetes mellitus is diabetic neuropathy (DN). DN is assured to be caused chiefly by excess sorbitol levels in the body. The harmful consequences of DN alike peripheral nerve damage with extremity ulcers may be dodged with timely detection and treatment. The therapeutic methods for DN are scarce and expensive. Therefore economic and user friendly methodologies to prevent acquiring the disease need proper attention. ObjectiveThe present research has been conducted (1) to analyse the levels of sorbitol in diabetic blood samples and compare them with non-diabetic ones and (2) to study the reduction in sorbitol levels upon addition of an important biochemical compounds caffeine in both sample groups. Research design, setting, participants and methodSorbitol-caffeine interaction analysis of blood samples of 16 patients with type 2 diabetes from KPC Medical College, Kolkata, India was made. The spectroscopic analysis and their interpretations were compared with 16 healthy subjects. Main outcomes and measuresPresent work describes that caffeine can be helpful in reducing the sorbitol level in diabetics, so the chances of development and progression of diabetic neuropathy can be controlled with the introduction of caffeine. ResultsA total number of 32 blood samples of patients (aged 35–70 years); mean age ranges were 52.06 ± 2.68 and 53.50 ± 2.66 years for non-diabetic and diabetic ones respectively, glucose and sorbitol screening examination were done by enzymatic methodologies where concentrations were assessed by means of either absorption or fluorescence spectroscopy. The calibration range was 18.2–1119.3 mg/dL (Linear regression analysis r2 = 0.996). The sensitivity of this screening program in detecting DN with the healthy adults has been inquired and found efficient. Results of fasting insulin analyses have also been analysed for HOMA-IR (homeostasis model assessment – insulin resistance) and HOMA-B (homeostasis model assessment – pancreatic β cell function) values. Statistical significance of the results in non-diabetic and diabetic groups were performed and found to be statistically significant. ConclusionsWe have defined the relationship between blood glucose level, insulin level, sorbitol and caffeine in human body and utilized them in the plausible remediation of DN.

A Pilot Study Investigating the effect of Glycemic Control on Electrodiagnostic Parameters in Type II Diabetic Patients

Background: Diabetes is a chronic metabolic abnormality due to either decreased secretion of insulin or decreased tissue sensitivity of insulin resulting in elevated blood glucose. Most common complication of diabetes is peripheral neuropathy. In this research project, we will be conducting a pilot study to observe the effect of glycaemic control on physiological functioning of nerve with the help of neurophysiological parameters, independent of duration of diabetes.
 Objectives:
 
 To investigate relationship of quality of glycemic control & severity of neurological changes.
 To find out whether glycemic control acts as an independent risk factor for progression of diabetic neuropathy despite the duration of diabetes.
 To validate the HBA1C at 10 for future longitudinal study to understand the association between glycemic control & progression of neuropathy.
 
 Methodology: 60 type II diabetic patients visiting diabetic OPD (Medicine) will participate in the study. The patients will be divided in to 2 groups of Group number 1 with (30 subjects) HBA1C < 10 and Group number 2 having (30 subjects) HBA1C >10. Electrodiagnostic study will be conducted on motor (tibial nerve) and sensory (sural nerve) will be performed in Neurophysiology lab. Neurophysiological parameters data of two groups will be analysed and compared.
 Expected Results: The pilot study will help to find out whether glycaemic control acts as a separate risk factor for progression of diabetic neuropathy despite duration of diabetes.
 Conclusion: This pilot study will help to establish the association between quality of glycaemic control and severity of neurological changes. Also, this will help to validate the HBA1C at 10 for further longitudinal study to know whether poor diabetes control is an independent risk factor associated to the severity of neuropathy in type II diabetes.

Lipids and peripheral neuropathy.

Hyperlipidaemia is associated with the development of neuropathy. Indeed, a mechanistic link between altered lipid metabolism and peripheral nerve dysfunction has been demonstrated in a number of experimental and clinical studies. Furthermore, post hoc analyses of clinical trials of cholesterol and triglyceride-lowering pharmacotherapy have shown reduced rates of progression of diabetic neuropathy. Given, there are currently no FDA approved disease-modifying therapies for diabetic neuropathy, modulation of lipids may represent a key therapeutic target for the treatment of diabetic nerve damage. This review summarizes the current evidence base on the role of hyperlipidaemia and lipid lowering therapy on the development and progression of peripheral neuropathy. A body of literature supports a detrimental effect of dyslipidaemia on nerve fibres resulting in somatic and autonomic neuropathy. The case for an important modulating role of hypertriglyceridemia is stronger than for low-density lipoprotein cholesterol (LDL-C) in relation to peripheral neuropathy. This is reflected in the outcomes of clinical trials with the different therapeutic agents targeting hyperlipidaemia reporting beneficial or neutral effects with statins and fibrates. The potential concern with the association between proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy and cognitive decline raised the possibility that extreme LDL-C lowering may result in neurodegeneration. However, studies in murine models and data from small observational studies indicate an association between increased circulating PCSK9 levels and small nerve fibre damage with a protective effect of PCSK9i therapy against small fibre neuropathy. Additionally, weight loss with bariatric surgery leads to an improvement in peripheral neuropathy and regeneration of small nerve fibres measured with corneal confocal microscopy in people with obesity with or without type 2 diabetes. These improvements correlate inversely with changes in triglyceride levels. Hyperlipidaemia, particularly hypertriglyceridemia, is associated with the development and progression of neuropathy. Lipid modifying agents may represent a potential therapeutic option for peripheral neuropathy. Post hoc analyses indicate that lipid-lowering therapies may halt the progression of neuropathy or even lead to regeneration of nerve fibres. Well designed randomized controlled trials are needed to establish if intensive targeted lipid lowering therapy as a part of holistic metabolic control leads to nerve fibre regeneration and improvement in neuropathy symptoms.

421-P: Genetically Reduced Chondroitin Sulfate Prevents the Progression of Diabetic Neuropathy via Pericyte Functions

Background: The extracellular matrix is associated with diabetic complications; however, chondroitin sulfate (CS) role remains unclear. Herein, genetically engineered mice lacking the rate-limiting CS-synthesizing enzyme, CS N-acetylgalactosaminyltransferase-1 (T1), were used to clarify CS effects on diabetic neuropathy. Diabetes was induced by streptozotocin injection in 6-week-old male T1 knockout (T1KO) and wild-type (WT) mice. Results: Previously reported preliminary data at the former ADA meeting revealed that thermal nociception and the number of plantar peripheral nerve fibers were disrupted in diabetic WT mice, whereas in diabetic T1KO were preserved. Moreover, conduction velocity in the sciatic nerve was significantly declined in diabetic WT than in T1KO mice. [A1] Immunohistochemical data revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, whereas those neurons were protected in diabetic T1KO mice. Moreover, DRG gene expression analysis showed that caspase-3 and -9 were reduced in T1KO compared with WT mice. To investigate the mechanisms underlying these events, the role of pericytes, which are important CS-expressing components of the blood-nerve barrier (BNB), was explored. Assessment of the retinal vessels, which represent a good model to evaluate pericyte functions and easier to access than peripheral nerves, revealed a higher proportion of pericyte-deficient retina blood vessels in diabetic WT than in T1KO mice upon administration of a platelet-derived growth factor receptor (PDGFR) β antibody. Therefore, pericytes in T1KO mice were more resistant against PDGFRβ antibody than those of WT mice. Thus, it is possible that the BNB in T1KO mice may be more resistant against external stress, including diabetes. Conclusions: Reduced CS production may induce beneficial effects to prevent diabetic neuropathy by improving pericyte function. Disclosure H. Ishiguro: None. T. Ushiki: None. A. Honda: None. T. Mikami: None. H. Kitagawa: None. K. Sango: None. M. Masuko: None. M. Igarashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy.

The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN’s sensitivity and performance.

Genetic and Epigenomic Modifiers of Diabetic Neuropathy.

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.

Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy

Accurately quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. We have undertaken detailed neuropathy phenotyping to assess the longitudinal utility of different measures of neuropathy in patients with diabetes. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intra-epidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). Mean follow-up was 6.5 years. Glycated haemoglobin (p = 0.04), low-density lipoprotein-cholesterol (LDL-C) (p = 0.0009) and urinary albumin creatinine ratio (p < 0.0001) improved. Neuropathy symptom profile (p = 0.03), neuropathy disability score (p = 0.04), vibration perception threshold (p = 0.02), cold perception threshold (p = 0.006), CNFD (p = 0.03), CNBD (p < 0.0001), CNFL (p < 0.0001), IENFD (p = 0.04), sural (p = 0.02) and peroneal motor nerve conduction velocity (p = 0.03) deteriorated significantly. Change (∆) in CNFL correlated with ∆CPT (p = 0.006) and ∆Expiration/Inspiration ratio (p = 0.002) and ∆IENFD correlated with ∆CNFD (p = 0.005), ∆CNBD (p = 0.02) and ∆CNFL (p = 0.01). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy.

Effect of Pharmacist-Led Intervention on Progression of Diabetic Complications at Two Tertiary Care Hospitals of Malaysia.

Background and Objective:Diabetes mellitus is a chronic disease which can lead to different complications in patients if not treated properly. An appropriate intervention from health care providers is needed to stop and decrease the progression of diabetic complication in diabetic patients. This study aimed to measure the effect of pharmacist intervention on improvement in sign and symptoms and progression of diabetic complications in diabetic patients.Methodology:Diabetic patients were randomly selected and divided into two groups from two tertiary care hospitals. Control group contained those 200 patients who were receiving usual treatment from hospitals. In contrast, the intervention group included those 200 patients who were receiving conventional treatment from hospitals together with separate counselling sessions with pharmacists from Diabetes Medication Therapy Adherence Clinic departments. The study continued for 1 year and two follow-up visits for both groups. A prevalidated data collection form was used to measure the improvement in sign and symptoms and progression of diabetic complication in diabetic patients. Statistical Package for the Social Sciences (SPSS) version 24 was used to analyze the data.Results:The average hemoglobin A1c (HbA1c) values decreased up to 1.43% in the control group and 2.82% in the intervention group. The intervention group showed significant improvement in HbA1c between groups (P < 0.05). The results of univariate and multivariate regression analysis showed that a statistically significant (P < 0.001) improvement was observed in all the predictors of diabetic complications among in the intervention group when compared with the control group.Conclusion:Statistically significant reduction in the sign and symptoms of diabetic complications was observed in the intervention group at the end of 1 year. The progression of diabetic neuropathy was significantly reduced in the pharmacist intervention group.

Investigating the beneficial effect of aliskiren in attenuating neuropathic pain in diabetic Sprague-Dawley rats.

ObjectivesWorldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. The direct renin inhibitor aliskiren is recognized as a treatment for cardiovascular disease in diabetic patients, but little is known about its potential benefits in cases of diabetic neuropathy. Accordingly, we investigated the effects of aliskiren (ALIS) and gliclazide (GLZ) and their combination therapy on peripheral neuropathy in streptozotocin‐induced diabetic rats.MethodsIn total, 112 adult Sprague‐Dawley rats were used for this study. Diabetes was induced using streptozotocin (STZ), whereas the control group was treated with an equal volume of citrate buffer. The diabetic rats were divided randomly into six groups according to the proposed treatment regime: diabetic control (DC), gliclazide (GLZ), aliskiren (ALIS), ramipril (RAM), (GLZ + ALIS) and (GLZ + RAM). Behavioural responses to thermal (hot‐plate) and mechanical (tail‐pinch) pain were evaluated. After eight weeks of daily treatments, the animals were fasted and sacrificed. The blood samples were collected, with the serum separated and subjected to various biochemical and enzyme analyses so as to assess the effect of the treatments on diabetic peripheral neuropathy.ResultsAfter 8 weeks, aliskiren alone and in combination with gliclazide therapy had a significant effect (P < .001) in reducing blood glucose levels and showed increased hot‐plate and tail‐flick latencies compared with the diabetic control group. The threshold of mechanical hyperalgesia was also significantly elevated (P < .001).Conclusions/InterpretationsThese data suggest that either aliskerin alone or in combination with gliclazide can protect against the development and progression of diabetic neuropathy.

Clinical spectrum and diagnosis of diabetic neuropathies.

Neuropathy is the most prevalent microvascular complication of diabetes mellitus; it encompasses distal symmetric polyneuropathy, autonomic neuropathy, radiculoplexus neuropathy, mononeuropathy, and treatment-induced neuropathy. The prevalence rate of diabetic neuropathy in Korea was reported to be approximately 43%, which is similar to rates in other countries. However, the precise pathogenic mechanism underlying diabetic neuropathy is still obscure, and many clinical trials have failed to develop methods to prevent or reduce the progression of diabetic neuropathy. Nevertheless, early diagnosis and proper management of diabetic neuropathy are essential to alleviate disabling symptoms and to improve the quality of life of patients. This review discusses clinical manifestations and classification of diabetic neuropathies, bedside neurological examination, and electrophysiological tests.

Flavonoids as Potential Therapeutic Agents for the Management of Diabetic Neuropathy.

Flavonoids are secondary metabolites that are widely distributed in plants. These phenolic compounds are classified into various subgroups based on their structures: flavones, flavonols, isoflavones, flavanones, and anthocyanins. They are known to perform various pharmacological actions like antioxidant, anti-inflammatory, anticancer, antimicrobial, antidiabetic and antiallergic, etc. Diabetes is a chronic progressive metabolic disorder that affects several biochemical pathways and leads to secondary complications such as neuropathy, retinopathy, nephropathy, and cardiomyopathy. Among them, the management of diabetic neuropathy is one of the major challenges for physicians as well as the pharmaceutical industries. Naturally occurring flavonoids are extensively used for the treatment of diabetes and its related complications due to their antioxidant properties. Moreover, flavonoids inhibit various pathways that are involved in the progression of diabetic neuropathy like the reduction of oxidative stress, decrease in glycogenolysis, increase glucose utilization, decrease in the formation of advanced glycation end products, and inhibition of the α-glucosidase enzyme. This review entails current updates on the therapeutic perspectives of flavonoids in the treatment of neuropathic pain. This manuscript explains the pathological aspects of neuropathic pain, the chemistry of flavonoids, and their application in amelioration of neuropathic pain through preclinical studies either alone or in combination with other therapeutic agents.