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Biomarkers and Novel Therapies of Diabetic Neuropathy: An Updated Review
Abstract
Diabetic neuropathy is a persistent consequence of the biochemical condition known as diabetes mellitus. As of now, the identification and management of diabetic neuropathy continue to be problematic due to problems related to the safety and efficacy of existing therapies. This study examines biomarkers, molecular and cellular events associated with the advancement of diabetic neuropathy, as well as the existing pharmacological and non-pharmacological treatments employed. Furthermore, a holistic and mechanism-centric drug repurposing approach, antioxidant therapy, Gene and Cell therapies, Capsaicin and other spinal cord stimulators and lifestyle interventions are pursued for the identification, treatment and management of diabetic neuropathy. An extensive literature survey was done on databases like PubMed, Elsevier, Science Direct and Springer using the keywords “Diabetic Neuropathy”, “Biomarkers”, “Cellular and Molecular Mechanisms”, and “Novel Therapeutic Targets”.Thus, we may conclude that non-pharmacological therapies along with palliative treatment, may prove to be crucial in halting the onset of neuropathic symptoms and in lessening those symptoms once they have occurred.
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Pulsed electromagnetic fields (PEMFs) are recognized for their potential in regenerative medicine, offering a non-invasive avenue for tissue rejuvenation. While prior research has mainly focused on their effects on bone and dermo-epidermal tissues, the impact of PEMFs on nervous tissue, particularly in the context of neuropathy associated with the diabetic foot, remains relatively unexplored. Addressing this gap, our preliminary in vitro study investigates the effects of complex magnetic fields (CMFs) on glial-like cells derived from mesenchymal cell differentiation, serving as a model for neuropathy of the diabetic foot. Through assessments of cellular proliferation, hemocompatibility, mutagenicity, and mitochondrial membrane potential, we have established the safety profile of the system. Furthermore, the analysis of microRNAs (miRNAs) suggests that CMFs may exert beneficial effects on cell cycle regulation, as evidenced by the upregulation of the miRNAs within the 121, 127, and 142 families, which are known to be associated with mitochondrial function and cell cycle control. This exploration holds promise for potential applications in mitigating neuropathic complications in diabetic foot conditions.
Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto‐Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated.
Diabetes mellitus, a complex metabolic disorder, presents a growing global health challenge. In 2021, there were 529 million diabetics worldwide. At the super-regional level, Oceania, the Middle East, and North Africa had the highest age-standardized rates. The majority of cases of diabetes in 2021 (>90.0%) were type 2 diabetes, which is largely indicative of the prevalence of diabetes in general, particularly in older adults (K. L. Ong, et al., Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021, Lancet, 2023, 402(10397), 203–234). Nowadays, slowing the progression of diabetic complications is the only effective way to manage diabetes with the available therapeutic options. However, novel biomarkers and treatments are urgently needed to control cytokine secretion, advanced glycation end products (AGEs) production, vascular inflammatory effects, and cellular death. Emerging research has highlighted the intricate interplay between reactive oxygen species (ROS) and protein aggregation in the pathogenesis of diabetes. In this scenario, the main aim of this paper is to provide a comprehensive review of the current understanding of the molecular mechanisms underlying ROS-induced cellular damage and protein aggregation, specifically focusing on their contribution to diabetes development. The role of ROS as key mediators of oxidative stress in diabetes is discussed, emphasizing their impact on cellular components and signaling. Additionally, the involvement of protein aggregation in impairing cellular function and insulin signaling is explored. The synergistic effects of ROS and protein aggregation in promoting β-cell dysfunction and insulin resistance are examined, shedding light on potential targets for therapeutic intervention.
Diabetic nephropathy (DN), a severe complication of diabetes, is widely recognized as a primary contributor to end-stage renal disease. Recent studies indicate that the inflammation triggered by Toll-like receptor 4 (TLR4) is of paramount importance in the onset and progression of DN. TLR4 can bind to various ligands, including exogenous ligands such as proteins and polysaccharides from bacteria or viruses, as well as endogenous ligands such as biglycan, fibrinogen, and hyaluronan. In DN, the expression or release of TLR4-related ligands is significantly elevated, resulting in excessive TLR4 activation and increased production of proinflammatory cytokines through downstream signaling pathways. This process is closely associated with the progression of DN. Natural compounds are biologically active products derived from natural sources that have advantages in the treatment of certain diseases. Various types of natural compounds, including alkaloids, flavonoids, polyphenols, terpenoids, glycosides, and polysaccharides, have demonstrated their ability to improve DN by affecting the TLR4 signaling pathway. In this review, we summarize the mechanism of action of TLR4 in DN and the natural compounds that can ameliorate DN by modulating the TLR4 signaling pathway. We specifically highlight the potential of compounds such as curcumin, paclitaxel, berberine, and ursolic acid to inhibit the TLR4 signaling pathway, which provides an important direction of research for the treatment of DN.
Repurposing is one of the key opportunities to address the unmet rare diseases therapeutic need. Based on cases of drug repurposing in small population conditions, and previous work in drug repurposing, we analyzed the most important lessons learned, such as the sharing of clinical observations, reaching out to regulatory scientific advice at an early stage, and public-private collaboration. In addition, current upcoming trends in the field of drug repurposing in rare diseases were analyzed, including the role these trends could play in the rare diseases’ ecosystem. Specifically, we cover the opportunities of innovation platforms, the use of real-world data, the use of artificial intelligence, regulatory initiatives in repurposing, and patient engagement throughout the repurposing project. The outcomes from these emerging activities will help progress the field of drug repurposing for the benefit of patients, public health and medicines development.
Diabetic peripheral neuropathy (DPN) refers to the development of peripheral nerve dysfunction in patients with diabetes when other causes are excluded. Diabetic distal symmetric polyneuropathy (DSPN) is the most representative form of DPN. As one of the most common complications of diabetes, its prevalence increases with the duration of diabetes. 10-15% of newly diagnosed T2DM patients have DSPN, and the prevalence can exceed 50% in patients with diabetes for more than 10 years. Bilateral limb pain, numbness, and paresthesia are the most common clinical manifestations in patients with DPN, and in severe cases, foot ulcers can occur, even leading to amputation. The etiology and pathogenesis of diabetic neuropathy are not yet completely clarified, but hyperglycemia, disorders of lipid metabolism, and abnormalities in insulin signaling pathways are currently considered to be the initiating factors for a range of pathophysiological changes in DPN. In the presence of abnormal metabolic factors, the normal structure and function of the entire peripheral nervous system are disrupted, including myelinated and unmyelinated nerve axons, perikaryon, neurovascular, and glial cells. In addition, abnormalities in the insulin signaling pathway will inhibit neural axon repair and promote apoptosis of damaged cells. Here, we will discuss recent advances in the study of DPN mechanisms, including oxidative stress pathways, mechanisms of microvascular damage, mechanisms of damage to insulin receptor signaling pathways, and other potential mechanisms associated with neuroinflammation, mitochondrial dysfunction, and cellular oxidative damage. Identifying the contributions from each pathway to neuropathy and the associations between them may help us to further explore more targeted screening and treatment interventions.
Capsaicin, which is abundant in chili peppers, exerts antioxidative, antitumor, antiulcer and analgesic effects and it has demonstrated potential as a treatment for cardiovascular, gastrointestinal, oncological and dermatological conditions. Unique among natural irritants, capsaicin initially excites neurons but then ‘calms’ them into long-lasting non-responsiveness. Capsaicin can also promote weight loss, making it potentially useful for treating obesity. Several mechanisms have been proposed to explain the therapeutic effects of capsaicin, including antioxidation, analgesia and promotion of apoptosis. Some of the mechanisms are proposed to be mediated by the capsaicin receptor (transient receptor potential cation channel subfamily V member 1), but some are proposed to be independent of that receptor. The clinical usefulness of capsaicin is limited by its short half-life. The present review provided an overview of what is known about the therapeutic effects of capsaicin and the mechanisms involved and certain studies arguing against its clinical use were mentioned.
Statins are widely used to prevent cardiovascular disease events. Cardiovascular diseases and type 2 diabetes are tightly connected since type 2 diabetes is a major risk factor for cardiovascular diseases. Additionally, cardiovascular diseases often precede the development of type 2 diabetes. These two diseases have common genetic and environmental antecedents. Statins are effective in the lowering of cardiovascular disease events. However, they have also important side effects, including an increased risk of type 2 diabetes. The first study reporting an association of statin treatment with the risk of type 2 diabetes was the WOSCOPS trial (West of Scotland Coronary Prevention Study) in 2001. Other primary and secondary cardiovascular disease prevention studies as well as population-based studies have confirmed original findings. The purpose of our review is to examine and summarize the most important findings of these studies as well as to describe the mechanisms how statins increase the risk of type 2 diabetes.
Background
One of the largest problems for global public health is diabetes mellitus (DM) and its micro and macrovascular consequences. Although prevention, diagnosis, and treatment have generally improved, its incidence is predicted to keep rising over the coming years. Due to the intricacy of the molecular mechanisms, which include inflammation, oxidative stress, and angiogenesis, among others, discovering treatments to stop or slow the course of diabetic complications is still a current unmet need.
Methods
The pathogenesis and development of diabetic neuropathies may be explained by a wide variety of molecular pathways, hexosamine pathways, such as MAPK pathway, PARP pathway, oxidative stress pathway polyol (sorbitol) pathway, cyclooxygenase pathway, and lipoxygenase pathway. Although diabetic neuropathies can be treated symptomatically, there are limited options for treating the underlying cause.
Result
Various pathways and screening models involved in diabetic neuropathies are discussed, along with their possible outcomes. Moreover, both medicinal and non-medical approaches to therapy are also explored.
Conclusion
This study highlights the probable involvement of several processes and pathways in the establishment of diabetic neuropathies and presents in-depth knowledge of new therapeutic approaches intended to stop, delay, or reverse different types of diabetic complications.
Type 2 diabetes mellitus (T2DM) is considered a chronic metabolic disease in which oxidative stress plays a vital part in the pathogenesis of diabetes. Essentially, hyperglycemia instigates the auto-oxidation of glucose to free radicals. The free radicals overwhelm endogenous antioxidant defense in macrovascular and microvascular dysfunctions. The antioxidants (such as vitamin C and α-lipoic acid) effectively reduce diabetic complications; they are used to treat and decrease the complication of diabetes mellitus. Supplementations with antioxidants and medicinal plants that possess antioxidant activity have been investigated for hypoglycemic effects. This review article sums up the role and mechanism of antioxidants in the prevention of T2DM and its complications.
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.
Background:
peripheral arterial disease (PAD) is identified late in diabetic patients because, in the majority of cases, it is associated with diabetic peripheral neuropathy, resulting in little or no symptoms, or symptoms that are completely neglected.
Methods:
In this study were enrolled all patients over 18 years of age, with diabetes mellitus type II for more than a year with poor glycemic control, diagnosed with diabetic polyneuropathy admitted to the Diabetology Department, Emergency County Hospital of Targu Mures, Romania between January 2020 and March 2023. We divided the patients into two groups, based on the presence or absence of subclinical atherosclerosis in the lower limb, named "SA" and "non-SA".
Results:
Patients in the SA group were older (p = 0.01) and had a higher incidence of IHD (p = 0.03), history of MI (p = 0.02), and diabetic nephropathy (p = 0.01). Moreover, patients with subclinical atherosclerosis had a higher BMI (p < 0.0001) and a longer duration of diabetes (p < 0.0001). Among all patients, the systemic inflammatory markers, MLR (r = 0.331, p < 0.001), NLR (r = 0.517, p < 0.001), PLR (r = 0.296, p < 0.001), SII (r = 0.413, p < 0.001), as well as BMI (r = 0.241, p < 0.001) and HbA1C (r = 0.489, p < 0.001), demonstrated a strong positive correlation with the diabetes duration. The multivariate logistic regression analysis showed that older patients (OR: 2.58, p < 0.001), the male gender (OR: 2.30, p = 0.006), a higher baseline levels of BMI (OR: 7.71, p < 0.001), and the duration of diabetes (OR: 8.65, p < 0.001) are predictors of subclinical atherosclerosis in DN patients. Additionally, the high baseline levels of all systemic inflammatory markers (for all: p < 0.001) and poor diabetes management (OR: 10.4, p < 0.001 for HbA1C; OR: 10.78, p < 0.001 for admission glucose) are independent predictors of SA.
Conclusions:
the inflammatory markers, NLR, MLR, PLR, and SII, being cheap and easy to collect in routine medical practice from the standard blood tests, could be an important step in predicting vascular outcomes in diabetic patients and the disease's progression, playing a key role in follow-up visits in type-2 diabetic patients and PAD patients.
Diabetes mellitus poses a substantial global health challenge, necessitating innovative approaches to improve patient outcomes. Conventional one-size-fits-all treatment strategies have shown limitations in addressing the diverse nature of the disease. In recent years, personalized medicine has emerged as a transformative solution, tailoring treatment plans based on individual genetic makeup, lifestyle factors, and health characteristics. This review highlights the role of genetic screening in predicting diabetes susceptibility and response to treatment, as well as the potential of pharmacogenomics in optimizing medication choices. Moreover, it discusses the incorporation of lifestyle modifications and behavioral interventions to empower patients in their health journey. Telemedicine and remote patient monitoring are also examined for their role in enhancing accessibility and adherence. Ethical considerations and challenges in implementing personalized medicine are addressed. The review envisions a future where personalized medicine becomes a cornerstone in diabetes management, ensuring improved patient outcomes and fostering more effective and patient-centric care on a global scale.
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is involved in numerous physiological functions and plays a key role in pain modulation including neuropathic pain. Diabetic neuropathy is a common complication of diabetes mellitus often accompanied by chronic neuropathic pain. Animal models of diabetes offer relevant tools for studying the pathophysiological mechanisms and pharmacological sensitivity of diabetic neuropathic pain and for identifying new therapeutic targets. In this review, we report data from preclinical work published over the last 15 years on the analgesic activity of drugs acting on the serotonergic system, such as serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants, and on the involvement of certain serotonin receptors-in particular 5-HT1A, 5-HT2A/2c and 5-HT6 receptors-in rodent models of painful diabetic neuropathy.
Aims
Previous studies showed conflicting relationship between hyperlipidemia, lipid-lowering therapy and diabetic peripheral neuropathy (DPN). As most of these works emerges from the Western and Australian countries, our study aims to investigate whether hyperlipidemia or lipid-lowering therapy (LLT) is associated with DPN in Taiwanese patients with type 2 diabetes (T2D).
Methods
A cross-sectional, hospital-based observation study in adults with T2D was conducted from January to October 2013. DPN was screened using the Michigan Neuropathy Screening Instrument. Data were obtained at the time of enrollment, including medication usage, anthropometric measurements and laboratory examinations.
Results
2,448 participants were enrolled, 524 (21.4%) of whom had DPN. Patients with DPN had significantly lower plasma total cholesterol (185.6 ± 38.6 vs 193.4 ± 42.3 mg/dL) and low-density lipoprotein cholesterol levels (114.6 ± 32.7 vs 119 ± 30.8 mg/dL). Multivariate analysis demonstrated that neither hyperlipidemia (adjusted OR (aOR), 0.81; 95% confidence interval (CI), 0.49–1.34) nor LLT (aOR, 1.10; 95% CI, 0.58–2.09) was associated with DPN. Subgroup analysis revealed that neither total cholesterol (aOR, 0.72; 95% CI, 0.2–2.62), low-density lipoprotein cholesterol levels (aOR, 0.75; 95% CI, 0.2–2.79), statin (aOR, 1.09; 95% CI, 0.59–2.03) nor fibrate (aOR, 1.73; 95% CI, 0.33–1.61) was associated with DPN.
Conclusion
Our results suggest that neither hyperlipidemia nor lipid-lowering medication was associated with DPN in adults with T2D. DPN is a multifactorial disease, and our findings indicate that lipid metabolism may play a minor role in its pathogenesis.
Introduction
Intensive lifestyle intervention (ILI) has significantly reduced incidence of diabetes and improved many cardiovascular disease risk factors. We evaluated long-term effects of ILI on cardiometabolic risk factors, and microvascular and macrovascular complications among patients with diabetes in real-world clinical practice.
Research design and methods
We evaluated 129 patients with diabetes and obesity enrolled in a 12-week translational model of ILI. At 1 year, we divided participants into group A, who maintained <7% weight loss (n=61, 47.7%), and group B, who maintained ≥7% weight loss (n=67, 52.3%). We continued to follow them for 10 years.
Results
The total cohort lost an average of 10.8±4.6 kg (−9.7%) at 12 weeks and maintained an average weight loss of 7.7±10 kg (−6.9%) at 10 years. Group A maintained 4.3±9.5 kg (−4.3%) and group B maintained 10.8±9.3 kg (−9.3%) of weight loss at 10 years (p<0.001 between groups). In group A, A1c decreased from 7.5±1.3% to 6.7±0.9% at 12 weeks but rebounded to 7.7±1.4% at 1 year and 8.0±1.9% at 10 years. In group B, A1c decreased from 7.4±1.2% to 6.4±0.9% at 12 weeks then increased to 6.8±1.2% at 1 year and 7.3±1.5% at 10 years (p<0.05 between groups). Maintenance of ≥7% weight loss at 1 year was associated with a 68% lower risk of developing nephropathy for up to 10 years compared with maintenance of <7% weight loss (adjusted HR for group B: 0.32, 95% CI 0.11, 0.9, p=0.007).
Conclusions
Weight reduction in patients with diabetes can be maintained for up to 10 years in real-world clinical practice. Sustained weight loss is associated with significantly lower A1c at 10 years and improvement in lipid profile. Maintenance of ≥7% weight loss at 1 year is associated with decreased incidence of diabetic nephropathy at 10 years.
Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. While several treatment options are available, they often have limited efficacy and are associated with adverse effects. In recent years, gels have emerged as a promising option for the treatment of neuropathic pain. Inclusion of various nanocarriers, such as cubosomes and niosomes, into gels results in pharmaceutical forms with higher drug stability and increased drug penetration into tissues compared to products currently marketed for the treatment of neuropathic pain. Furthermore, these compounds usually provide sustained drug release and are biocompatible and biodegradable, which makes them a safe option for drug delivery. The purpose of this narrative review was to provide a comprehensive analysis of the current state of the field and identify potential directions for future research in the development of effective and safe gels for the treatment of neuropathic pain, ultimately improving the quality of life for patients suffering from neuropathic pain.
Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.
Objective
To evaluate the clinical efficacy of a new antioxidant therapy for the treatment of complex neuroischaemic diabetic foot ulcers (DFUs).
Method
A prospective case series study has been conducted in patients with complex neuroischaemic DFUs after transmetatarsal amputation. DFUs were locally treated with an antioxidant dressing twice a week for the first two weeks, and then once a week until the end of the study or complete wound closure. Patients were followed-up for eight weeks and assessed weekly to analyse wound outcome. Primary outcomes were the wound closure ratio and percentage of granulation tissue; secondary outcomes were parameters related to wound management, namely, presence of non-viable tissue in the wound bed, levels of maceration and exudates, presence of erythema and pain.
Results
A total of 20 patients were included with a mean baseline wound area of 20.4cm². At 8 weeks, the mean reduction in wound area was 88.1% (p<0.0001) and complete closure was observed in 33% of cases. In addition, there was a mean increase of 94.7% in granulation tissue in the wound bed (p<0.0001). Furthermore, the therapy was associated with a significant percentage reduction in wounds with non-viable tissue, good exudate management, and the maintenance of low levels of maceration, erythema and pain.
Conclusion
The new antioxidant therapy was associated with good clinical outcomes in large hard-to-heal neuroischaemic DFUs, with significant wound area reduction and granulation tissue formation. The therapy was also found to be safe and perform well from a practical perspective.
Introduction:
Painful diabetic polyneuropathy (P-DPN) occurs in 20% - 30% of diabetic patients. Currently, therapeutic strategies include lifestyle modifications, good glycemic control, and neuropathic pain drugs. Spinal cord stimulation (SCS) has been shown to be successful in patients who have not responded to other treatments. The American Diabetes Association strongly recommends early screening and diagnosis for this condition through clinical tests and nerve conduction study (NCS). In recent years, high-resolution ultrasonography (HRUS) with the analysis of cross-sectional area (CSA) has shown an increasingly important role in detecting changes in the nervous structures, blood vessels, echo, and mobility of the nerve. Cross-sectional area is frequently enlarged in these patients, even those with normal NCS. We aimed to use SCS with fast-acting sub-perception therapy (FAST) modality to treat P-DPN. We also evaluated the CSA of the involved nerves before and after treatment.
Case presentation:
A 58-year-old female patient was referred to our hospital in 2020 (Civitavecchia, Italy). She suffered from P-DPN for 3 years and did not respond to conventional medical treatments. Preoperative electromyography (EMG) was negative for radiculopathy, while electroneurography (ENG) showed a reduction in sensory conduction velocity (SCV) in the sural nerve (SN) bilaterally. Clinical tests on perceived pain and quality of life showed high severity. The report was confirmed by HRUS with enlargement of the CSA of the posterior tibial nerve (PTN), external popliteal nerve (EPN), and SN. The patient was successfully subjected to all-in-one SCS implantation in the FAST modality. She obtained immediate pain relief that remained unaltered at the 3-month follow-up. The patient completely discontinued drug therapy. One month after implantation, ENG highlighted an increased SN SCV, and the HRUS of PTN EPN and SN showed a significant reduction in CSA in all 3 nerves involved.
Conclusions:
Early diagnosis and treatment are crucial in improving the clinical outcome of P-DPN, but there is still no gold standard therapy. Spinal cord stimulation in the new FAST modality was effective in this clinical case. The pain relief was supported by a significant reduction in the CSA of the studied nerves observed on HRUS 1 month after SCS implantation. The results and the improvement of a pathological nervous pattern, albeit with a short follow-up of only 3 months, could suggest not only a symptomatic but perhaps also a therapeutic role of SCS in P-DPN.
Diabetic neuropathy is a major complication of diabetes mellitus that occurs during the early stages of the disease. Many pathogenic mechanisms are related and induced by hyperglycemia. However, even if these factors improve, diabetic neuropathy cannot go into remission and progresses slowly. Furthermore, diabetic neuropathy often progresses even with proper glycemic control. Recently, bone marrow-derived cells (BMDCs) were reported to be involved in the pathogenesis of diabetic neuropathy. BMDCs expressing proinsulin and TNFα migrate to the dorsal root ganglion and fuse with neurons, and this neuronal-hematopoietic cell fusion induces neuronal dysfunction and apoptosis. The CD106-positive lineage-sca1+c-kit+ (LSK) stem cell fraction in the bone marrow is strongly involved in cell fusion with neurons, leading to diabetic neuropathy. Surprisingly, when CD106-positive LSK stem cells obtained from diabetic mice were transplanted into nondiabetic mice, they fused with dorsal root ganglion neurons and induced neuropathy in non-hyperglycemic normal mice. The transplanted CD106-positive LSK fraction inherited the trait even after transplantation; this "progeny effect" may explain the irreversibility of diabetic neuropathy and is a significant finding for determining the target of radical treatments and provides new directions for developing therapeutic methods for diabetic neuropathy.
Impaired cognition is the primary symptom of dementia, which can lead to functional disability and reduced quality of life among an increasingly ageing population. Ageing is associated with increased oxidative stress, chronic low-grade systemic inflammation, and endothelial dysfunction, which reduces cerebrovascular function leading to cognitive decline. Chronic low-grade systemic inflammatory conditions, such as obesity, exacerbate this decline beyond normal ageing and predispose individuals to neurodegenerative diseases, such as dementia. Capsaicin, the major pungent molecule of chilli, has recently demonstrated improvements in cognition in animal models via activation of the transient receptor potential vanilloid channel 1 (TRPV1). Capsaicin-induced TRPV1 activation reduces adiposity, chronic low-grade systemic inflammation, and oxidative stress, as well as improves endothelial function, all of which are associated with cerebrovascular function and cognition. This review examines the current literature on capsaicin and Capsimax, a capsaicin supplement associated with reduced gastrointestinal irritation compared to capsaicin. Acute and chronic capsaicin treatment can improve cognition in animals. However, studies adequately assessing the effects of capsaicin on cerebrovascular function, and cognition in humans do not exist. Capsi-max may be a potentially safe therapeutic intervention for future clinical trials testing the effects of capsaicin on cerebrovascular function and cognition.
Diabetic neuropathy (DN) is one of the main microvascular complications of both type 1 and type 2 diabetes mellitus. Sometimes, this could already be present at the time of diagnosis for type 2 diabetes mellitus (T2DM), while it appears in subjects with type 1 diabetes mellitus (T1DM) almost 10 years after the onset of the disease. The impairment can involve both somatic fibers of the peripheral nervous system, with sensory-motor manifestations, as well as the autonomic system, with neurovegetative multiorgan manifestations through an impairment of sympathetic/parasympathetic conduction. It seems that, both indirectly and directly, the hyperglycemic state and oxygen delivery reduction through the vasa nervorum can determine inflammatory damage, which in turn is responsible for the alteration of the activity of the nerves. The symptoms and signs are therefore various, although symmetrical painful somatic neuropathy at the level of the lower limbs seems the most frequent manifestation. The pathophysiological aspects underlying the onset and progression of DN are not entirely clear. The purpose of this review is to shed light on the most recent discoveries in the pathophysiological and diagnostic fields concerning this complex and frequent complication of diabetes mellitus.
To evaluate safety and efficacy of Gabapentin and Duloxetine in patients with painful diabetic neuropathy.
This is a prospective randomized double blinded parallel group study done for a period of 12 weeks. Total of 60 patients were enrolled and randomly allocated to two groups with 30 patients each, group A received Duloxetine 30 mg twice daily and group B received Gabapentin 300mg twice daily and followed every 2 weeks. Patients of age 35 to 60 years with painful diabetic peripheral polyneuropathy are included in the study. Primary objective is improvement in pain assessed by NPRS; Secondary objective is improvement in sleep and clinical condition of the patient, assessed by Sleep Interference Score and Clinical Global Impression of Change (CGIC). Assessment was done at beginning and at four, eight and twelve weeks. Data was analysed using SPSS 12.0 version.
Numerical pain rating scores and daily sleep interference scores were reduced significantly with course of treatment within both groups (p = <0.05 in both groups), but there was no significant difference observed between two groups at baseline, 4th week, 8th week and 12th week. There is significant reduction in CGIC severity scores with course of treatment within both groups (p = <0.05 in both groups), but there was no significant difference observed between groups at baseline and at end of treatment. Common adverse events seen are nausea, dry mouth, dizziness, somnolence and constipation in both groups. There is high incidence of nausea and dry mouth with Duloxetine when compared to Gabapentin.
Monotherapy with either Duloxetine or Gabapentin was equally effective at 12 weeks treatment with minor side effects. In addition, Gabapentin showed fewer side effects. It can be concluded that for preventing side effects, Gabapentin can be used. Further large head to- head comparator and combination trials are required.
Diabetic polyneuropathy (DPN) is the most frequent, although neglected, complication of long-term diabetes. Nearly 30% of hospitalized and 20% of community-dwelling patients with diabetes suffer from DPN; the incidence rate is approximately 2% annually. To date, there has been no curable therapy for DPN. Under these circumstances, cell therapy may be a vital candidate for the treatment of DPN. The epidemiology, classification, and treatment options for DPN are disclosed in the current review. Cell-based therapies using bone marrow-derived cells, embryonic stem cells, pluripotent stem cells, endothelial progenitor cells, mesenchymal stem cells, or dental pulp stem cells are our primary concern, which may be a useful treatment option to ease or to stop the progression of DPN. The importance of cryotherapies for treating DPN has been observed in several studies. These findings may help for the future researchers to establish more focused, accurate, effective, alternative, and safe therapy to reduce DPN. Cell-based therapy might be a permanent solution in the treatment and management of diabetes-induced neuropathy.
Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic (n = 5) and other hereditary (n = 9) to acquired (n = 2) myopathies and myotonia syndromes (n = 22). Under carbamazepine (daily dose 254 ± 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale (−1.9 ± 1.8, p < 0.001). Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of Aδ-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects (n = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement (n = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional Aδ-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.
Background and objective:
Painful diabetic peripheral neuropathy (DPN) affects approximately 6-34% of all patients with diabetes. DPN-induced pain reduces the quality of life and makes daily activities difficult. Distal symmetric polyneuropathy (DSPN) is the most common type of DPN. Here we review the pathophysiology, diagnosis, and treatment of DPN.
Methods:
A MEDLINE database (PubMed) search was conducted for English-language articles dealing with the effect of DPN that were published until April 1, 2022. To identify potentially relevant articles, the following key search phrases were combined: 'diabetes mellitus', 'diabetes', 'neuropathy', 'polyneuropathy', 'diabetic neuropathies', 'peripheral neuropathy', 'diabetic polyneuropathy', 'pathophysiology', 'diagnosis', and 'treatment'.
Key content and findings:
In a biopsy study of the su; ral nerve, damage to C and Aδ fibers were seen in patients who had recent onset of pain in their feet consisting of tingling, burning, and prickling, followed by initial demyelination/remyelination of large fibers. DPN is characterized by a pattern of distal-to-proximal axonal loss with symptoms. Hyperglycemia and dyslipidemia are the primary causes of DPN in patients with type 1 and 2 diabetes, respectively. The pattern of pain from DPN is described as "glove and stocking". DPN-induced pain is described as burning, electric, sharp, and dull aching with various pain intensities. DPN is a diagnosis of exclusion; diagnosis is made with a thorough medical history, physical examination, and clinical testing to rule out other causes of pain. Anticonvulsants (pregabalin and gabapentin), antidepressants (duloxetine, venlafaxine, and amitriptyline), opioids (tramadol, tapentadol, and oxycodone), and topical capsaicin are commonly administered to treat DPN. The combination of two or three of these pharmacological agents better resolves pain at lower doses and with fewer side effects.
Conclusions:
Clinicians should have sufficient knowledge of DPN to ensure its accurate diagnosis and appropriate treatment. This review provides clinicians with the necessary knowledge of the pathophysiology, diagnosis, and treatment of painful DPN.
The global prevalence of diabetes continues to increase partly due to rapid urbanization and an increase in the aging population. Consequently, this is associated with a parallel increase in the prevalence of diabetic vascular complications which significantly worsen the burden of diabetes. For these diabetic vascular complications, there is still an unmet need for safe and effective alternative/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic options to come from natural products such as plants. Hyperglycemia-induced oxidative stress is central to the development of diabetes and diabetic complications. Furthermore, oxidative stress-induced inflammation and insulin resistance are central to endothelial damage and the progression of diabetic complications. Human and animal studies have shown that polyphenols could reduce oxidative stress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols is attributed to their modulatory effect on endogenous antioxidant systems. This review attempts to summarize the established effects of polyphenols on endogenous antioxidant systems from the literature. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenols for diabetic vascular complications are also discussed.
Data obtained from observational studies have shown that patients with untreated hypertension display an increased incidence of type 2 diabetes mellitus compared with the normotensive state. They have also shown that this phenomenon is made worse when thiazide diuretics or beta-blockers are administered chronically. Pathophysiological mechanisms recognize in inflammation and impaired insulin sensitivity the principal factors responsible for the new-onset diabetes in hypertensive subjects in particular when affected by concomitant presence of obesity, metabolic syndrome, and heart failure. Patients at high cardiovascular risk needing far a primary and/or secondary prevention with statins have also shown that the use of these drugs are associated with development of new-onset diabetes or worsening of glycemic profile. This could be attributed to the pathophysiological mechanisms of statins that induce an impaired insulin sensitivity and an inflammatory status. This paper will review the above data and discuss their clinical implications for protection of patients from hypertension or dyslipidemia based on current treatment of these conditions.
Background:
Gabapentin is a recommended first-line agent for treating neuropathic pain; however, its efficacy rate is reportedly low, and the risk of adverse events is high. A plausible explanation for this lies with its wide range of actions, the entirety of which have yet to be fully elucidated.
Methods:
A review of the literature was conducted on gabapentin's known and proposed analgesic mechanisms of action, as well as potentially opposing or detrimental actions.
Results:
Gabapentin's classical analgesic mechanisms involve direct attenuation of excitatory neurotransmission in the spinal cord via inhibition of neuronal ion channels, while indirect mechanisms include descending inhibition and block of injury-evoked synaptogenesis. Glial effects have also been reported; however, whether they are neuroprotective or detrimental is unknown. Furthermore, data from animal models do not reflect clinical outcomes.
Conclusions:
Gabapentin's clinical use should be reconsidered according to the net effects of its numerous assumed actions, including the tripartite synapse and oligodendrocyte effects. Whether it is doing more harm than good, especially in the scenarios of incomplete or loss of response, warrants consideration when prescribing gabapentin.
Diabetic neuropathy is a chronic complication to metabolic disorder, diabetes mellitus. Till date, diagnosis and treatment of diabetic neuropathy remain elusive with challenges associated with the efficacy and safety of the current therapeutics. Considering, the hurdles associated with discovery of de novo drugs, repurposing of old drugs for new therapeutic modalities sounds promising. This review, focuses on a molecular pathways involved in the progression of diabetic neuropathy, and the current pharmacological and non-pharmacological therapies implemented. Furthermore, a holistic and mechanism centric drug repurposing approach is pursued for identification of existing drugs as novel therapy in the treatment of diabetic neuropathy. The global status of ongoing clinical research on diabetic neuropathy is also highlighted. In conclusion, the barriers associated with drug repurposing is identified to stimulate the curiosity of the researchers to overcome them and rapidly translate the drugs to the patients suffering from diabetic neuropathy.
Background: Diabetes stands among the top ten contributors to worldwide mortality, with diabetics facing 2 to 3 times greater susceptibility to all-encompassing mortality. The adipose tissue has garnered growing recognition as a vigorously dynamic endocrine organ, discharging an array of biologically impactful molecules, among which is adiponectin. We investigated the influence of serum adiponectin levels and their correlation with oxidative stress in individuals with type 2 diabetes mellitus (T2DM) in the province Anbar of Iraq. Methodology: A case-control research was carried out at Al-Ramadi Hospitals located in Anbar province, Iraq. The study encompassed a total of 84 individuals, comprising 42 patients diagnosed with T2DM, and 42 individuals enrolled as healthy controls (HCs). Venous blood samples were collected and each sample was divided into four, to obtain the serum. Serum levels of adiponectin and oxidative stress were assessed through the utilization of enzyme-linked immunosorbent assays (ELISA). Results: The study findings revealed that there was no significant impact on the lipid profile among patients when compared to the control group, as evidenced by statistically insignificant differences (P > 0.05). However, a noteworthy increase in glucose levels was observed in patients compared to healthy individuals, demonstrating a significant difference (P < 0.05). Furthermore, the average levels of malondialdehyde (MDA) displayed a significant rise in patients in comparison to the healthy cohort (P < 0.05). In a similar vein, superoxide dismutase (SOD) levels demonstrated a notable contrast, showcasing higher values in the healthy group in contrast to the patients (P < 0.05). The adiponectin levels exhibited remarkable divergence, with notably elevated values in the T2DM group relative to the healthy group, achieving statistical significance (P < 0.05). The data indicated positive associations between serum adiponectin levels and MDA, as well as fasting serum glucose (FSG), triglycerides (TGs), and very-low-density lipoprotein (VLDL). Nevertheless, no significant correlations were identified between adiponectin and SOD, as well as the other variables. Conclusion The findings of the study indicated that reduced adiponectin levels are associated with elevated oxidative stress among T2DM patients. Abbreviations: FSG - fasting serum glucose; MDA - malondialdehyde; SOD - superoxide dismutase; TGs - Triglycerides; T2DM - type 2 diabetes mellitus; VLDL - Very-low-density lipoprotein Key words: Adiponectin; SOD; Oxidative Stress; Diabetes Mellitus Citation: Al-Dulaimy AHH, Abdul Ghafoor KF. Evaluation of adiponectin serum levels and their association with oxidative stress in individuals with type 2 diabetes mellitus in Iraq. Anaesth. pain intensive care 2024;28(3):553−557; DOI: 10.35975/apic.v28i3.2475 Received: October 23, 2023; Revised: January 19, 2024; Accepted: April 02, 2024
Background
Type 2 diabetes mellitus (T2DM) is frequently referred to as a "lifestyle illness". In 2000, India (31.7 million) had the greatest global prevalence of diabetes mellitus, followed by China (20.8 million), the United States (17.7 million), and other countries. In recent years, the treatment of gene therapy (T2DM) has attracted intensive interest.
Objective
We aimed to critically review the literature on the various techniques and methods, which may be a possible novel approach through the gene therapy CRISPR Cas9 and some other gene editing techniques for T2DM. Interventional and pharmacological approaches for the treatment of T2DM were also included to identify novel therapies for its treatment.
Method
An extensive literature survey was done on databases like PubMed, Elsevier, Science Direct and Springer.
Conclusion
It can be concluded from the study that recent advancements in gene-editing technologies, such as CRISPR Cas9, have opened new avenues for the development of novel therapeutic approaches for T2DM. CRISPR Cas9 is a powerful tool that enables precise and targeted modifications of the genome.
Diabetic neuropathy (DN) is a painful, chronic ailment that affects a large segment of diabetic population worldwide. Current medications such as pregabalin or duloxetine treat only the pain symptom associated with DN, but not the underlying nerve damage. DDD-028 (1) is a small molecule that displays potent pain-relieving activity in streptozotocin (STZ)-induced rodent model of DN. Combined with other studies indicating that DDD-028 suppresses astrogliosis and nerve damage induced by the anti-cancer drug, paclitaxel, the present study suggests that DDD-028 would be useful as a disease modifying therapeutic in the treatment of DN. The 3-dimensional structure of DDD-028 was confirmed by single crystal X-ray crystallography.
Spinal cord stimulation (SCS) is a last resort treatment for pain relief in painful diabetic peripheral neuropathy (PDPN) patients. However, the effectivity of SCS in PDPN is limited. New SCS paradigms such as high frequency (HF) and differential target multiplexed (DTM) might improve responder rates and efficacy of SCS-induced analgesia in PDPN patients, and are suggested to modulate the inflammatory balance and glial response in the spinal dorsal horn. The aim of this study was to research the effects of Con-, HF- and DTM-SCS on pain behavior and the spinal inflammatory balance in an animal model of PDPN. Streptozotocin-induced PDPN animals were stimulated for 48 hours with either Con-SCS (50Hz), HF-SCS (1200Hz) or DTM-SCS (combination of Con- and HF-SCS). Mechanical hypersensitivity was assessed using Von Frey (VF) test and the motivational aspects of pain were assessed using the mechanical conflict avoidance system (MCAS). The inflammatory balance and glial response were analyzed in the dorsal spinal cord based on RNA expression of pro- and anti-inflammatory cytokines (Tnf-α, Il-1ß, Il-4, Il-10), a microglia marker (Itgam), an astrocyte marker (Gfap), a T-cell marker (Cd3d), microglia proliferation markers (Irf8, Adgre1) and P2X4, p13-MAPK, BDNF signaling markers (P2x4, Mapk14, Bdnf). The results show that Con-, HF-, and DTM-SCS significantly decreased hypersensitivity after 48 hours of stimulation compared to Sham-SCS in PDPN animals, but at the same time did not affect escape latency in the MCAS. At the molecular level, Con-SCS resulted in a significant increase in spinal pro-inflammatory cytokine Tnf-α after 48 hours compared to DTM-SCS and Sham-SCS. In summary, Con-SCS showed a shift of the inflammatory balance towards a pro-inflammatory state whilst HF- and DTM-SCS shifted the balance towards an anti-inflammatory state. These findings suggest that the underlying mechanism of Con-SCS induced pain relief in PDPN differs from that induced by HF- and DTM-SCS.
Aim: To investigate the potential benefit of topical capsaicin formulations. Materials & methods: A narrative systematic review was employed. Results: About 8% Capsaicin patches were found to significantly reduce symptoms of diabetic peripheral neuropathy. Capsaicin was found to improve sleep quality (p = 0.02). Capsaicin patch exposure for 60 min showed significant reduction in symptoms (-32.8%). Capsaicin cream significantly reduced pain at weeks 2 and 6 (p = 0.003 and p = 0.03, respectively), but not at week 8 in comparative studies. 0.025% Capsaicin gel had an insignificant reduction in pain compared with placebo (p = 0.53), however 0.075% was found to be significant (p = 0.038). Capsaicin cream did not have superior improvement of pain as compared with clonidine gel (p = 0.931). The most common adverse events included application site discomfort, erythema and burning. Conclusion: Topical capsaicin treatments are a potentially beneficial peripherally acting medication. Further research is needed to determine the best means of ameliorating the side effects of treatments.
Diabetic peripheral neuropathy (DPN) is an extremely common chronic complication of diabetes, and also the one with the most complex and partially understood pathogenesis. In contrast to retinopathy or nephropathy, the risk of neuropathy does not follow closely the degree of glycemic control achieved by patients, and other factors seem to play a larger role in its appearance and progression. Lipid and lipoprotein metabolism is one among such factors. Epidemiological evidence indicates a higher incidence of DPN among patients with diabetes and dyslipidemia, while patients in the active group of clinical trials of statins and fibrates have a reduced incidence. From a biological standpoint, lipid mediators are involved in multiple pathways that lead to nerve cell damage. For these reasons, several interventions that impact lipid metabolism like statins, fibrates, alpha-lipoic acid, gamma-linolenic acid, and coenzyme Q10 (ubiquinone) have been tested as therapies for DPN, with varying results. In this chapter, we summarize the mechanisms by which lipid metabolism relates to DPN, the evidence supporting this hypothesis, and relevant ongoing clinical trials in the field.KeywordsDiabetesNeuropathyLipidsComplicationsPain
Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral neuropathy (DPN), the most common microvascular complication, is length-dependent damage to peripheral nerves. DPN pathogenesis is complex, but, at its core, it can be viewed as a state of impaired metabolism and bioenergetics failure operating against the backdrop of long peripheral nerve axons supported by glia. This unique peripheral nerve anatomy and the injury consequent to T2D underpins the distal-to-proximal symptomatology of DPN. Earlier work focused on the impact of hyperglycemia on nerve damage and bioenergetics failure, but recent evidence additionally implicates contributions from obesity and dyslipidemia. This review will cover peripheral nerve anatomy, bioenergetics, and glia-axon interactions, building the framework for understanding how hyperglycemia and dyslipidemia induce bioenergetics failure in DPN. DPN and painful DPN still lack disease-modifying therapies, and research on novel mechanism-based approaches is also covered.
Over the past few decades, substantial advances have been made in neuropathic pain clinical research. An updated definition and classification have been agreed. Validated questionnaires have improved the detection and assessment of acute and chronic neuropathic pain; and newer neuropathic pain syndromes associated with COVID-19 have been described. The management of neuropathic pain has moved from empirical to evidence-based medicine. However, appropriately targeting current medications and the successful clinical development of drugs acting on new targets remain challenging. Innovative approaches to improving therapeutic strategies are required. These mainly encompass rational combination therapy, drug repurposing, non-pharmacological approaches (such as neurostimulation techniques), and personalised therapeutic management. This narrative review reports historical and current perspectives regarding the definitions, classification, assessment, and management of neuropathic pain and explores potential avenues for future research.
As common complication of prediabetes, type I and type II diabetes, diabetic peripheral neuropathy (DPN) includes a series of sensory and motor changes associated with slow nerve conduction, nerve degeneration, gate disturbances, pain, and loss of sensation. Although proper glycemic control can prevent DPN progression, these complications remain difficult to clinically treat. Current pharmacological medications have limited effectiveness, creating the need for additional clinical options. Lifestyle interventions hold great promise as the broad spectrum of improvements derived from certain lifestyle changes appears promising to improve diabetes management and DPN. In this chapter, we highlight research that illustrates the consequences of poor diet on DPN and discuss the benefits of lifestyle changes associated with dietary change and/or exercise. Reversal of dietary changes appears to have positive impact on DPN, and we highlight new studies in which a low-carbohydrate/high-fat diet has been used to prevent and/or reverse DPN. In addition, a growing number of basic and clinical studies are revealing how exercise can improve symptoms of DPN. These interventions affect a broad range of cellular and metabolic changes that can lead to improvements in DPN symptoms. These interventions likely involve overlapping cellular pathways but could also improve DPN through unique mechanisms. As approaches using personalized medicine increase, clinical treatments for DPN will need to determine the most impactful interventions that are relevant to specific symptoms in patients suffering from DPN. Lifestyle and dietary interventions should play an important role in these treatment plans and the convergence of shared mechanisms should be a focus of preclinical and clinical research.KeywordsDiabetesKetogenic dietMediterranean dietExercisePhysical activity
The most common of painful diabetic neuropathies is painful polyneuropathy, affecting up to 50% of patients with polyneuropathy. The risk factors for developing neuropathic pain in those with diabetic polyneuropathy are largely unknown. Increasing evidence point toward an association between pain and neuropathy severity, but studies also suggest that other risk factors, such as female sex and high HbA1c, are also involved. The symptoms of painful diabetic polyneuropathy can be a shooting, squeezing, or burning pain in the feet, often together with other abnormal sensations, such as numbness or pins and needles. The diagnosis of painful diabetic neuropathy is primarily clinical, consisting of evaluation of symptoms and signs, and can be confirmed with abnormal nerve conduction studies or intraepidermal nerve fiber density. The management of painful diabetic polyneuropathy consists of symptomatic pain treatment including nonpharmacological treatment, such as pain education, physiotherapy, and psychological treatment and pharmacological treatment to improve quality of life. According to guideline recommendations, pregabalin and gabapentin, tricyclic antidepressants, and serotonin noradrenaline reuptake inhibitors are recommended as a first-line therapy with a strong recommendation and moderate to high quality of evidence. Effect sizes are moderate and not all patients experience an effect in tolerated doses and often combination treatment and a multidisciplinary approach to treatment is needed.KeywordsDiabetic neuropathyNeuropathic painTricyclic antidepressantsSerotonin noradrenaline reuptake inhibitorsGabapentinPregabalin
Diabetes is associated with devastating microvascular complications including neuropathy, retinopathy, and nephropathy. Hypertension is common in patients with diabetes. The impact of blood pressure lowering to slow and prevent progression of these microvascular complications has been well studied. The optimal blood pressure target in patients with diabetes is subject to debate with many guidelines now recommending a target BP < 130/80. The benefits of intensive blood pressure control must be balanced against the increased risk of orthostatic hypotension particularly in elderly patients and those with autonomic neuropathies. RAAS inhibitors are the first line antihypertensive medications in diabetic patients with kidney disease. They also likely have beneficial impacts on patients with diabetic neuropathy and retinopathy independent of their blood pressure lowering impacts. Future studies are needed to identify those patients most at risk for developing microvascular disease from diabetes and to develop additional treatments to prevent the onset of these devastating complications.
Significance:
Diabetic peripheral neuropathy (DPN), a complication of metabolic syndrome, type I, and type II diabetes, leads to sensory changes that include slow nerve conduction, nerve degeneration, loss of sensation, pain, and gate disturbances. These complications remain largely untreatable, although tight glycemic control can prevent neuropathy progression. Nonpharmacological approaches remain the most impactful to date, but additional advances in treatment approaches are needed.
Recent advances:
This review highlights several emerging interventions, including a focus on dietary interventions and physical activity that continue to show promise for treating DPN. We provide an overview of our current understanding of how exercise can improve aspects of DPN. We also highlight new studies in which a ketogenic diet has been used as an intervention to prevent and reverse DPN.
Critical issues:
Both exercise and consuming a ketogenic diet induce systemic and cellular changes that collectively improve complications associated with DPN. Both interventions may involve similar signaling pathways and benefits but also impact DPN through unique mechanisms.
Future directions:
These lifestyle interventions are critically important as personalized medicine approaches will likely be needed to identify specific subsets of neuropathy symptoms and deficits in patients and determine the most impactful treatment. Overall, these two interventions have the potential to provide meaningful relief for patients with DPN and provide new avenues to identify new therapeutic targets.