-
BMJ Open Diabetes Research & Care Nov 2023Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose...
INTRODUCTION
Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose using Mendelian randomization studies to explore shared and distinct risk factors for diabetic lower extremity complications.
RESEARCH DESIGN AND METHODS
We selected uncorrelated genetic variants associated with 85 phenotypes in five categories at the genome-wide significance level as instrumental variables. Genetic associations with DFU, diabetic polyneuropathy (DPN), and diabetic peripheral artery disease (DPAD) were obtained from the FinnGen and UK Biobank studies.
RESULTS
Body mass index (BMI) emerged as the only significant risk factor for DPAD, DPN, and DFU, independent of type 2 diabetes, fasting glucose, fasting insulin, and HbA1c. Educational attainment stood out as the sole significant protective factor against DPAD, DPN, and DFU. Glycemic traits below the type 2 diabetes diagnosis threshold showed associations with DPAD and DPN. While smoking history exhibited suggestive associations with DFU, indicators of poor nutrition, particularly total protein, mean corpuscular hemoglobin, and mean corpuscular volume, may also signal potential DFU occurrence.
CONCLUSIONS
Enhanced glycemic control and foot care are essential for the diabetic population with high BMI, limited education, smoking history, and indicators of poor nutrition. By focusing on these specific risk factors, healthcare interventions can be better tailored to prevent and manage DFU effectively.
Topics: Humans; Diabetic Foot; Diabetes Mellitus, Type 2; Mendelian Randomization Analysis; Risk Factors
PubMed: 37989345
DOI: 10.1136/bmjdrc-2023-003523 -
Cytokine May 2024Emerging evidence suggests systemic inflammation as a critical mechanism underlying diabetic neuropathy. This study aimed to investigate the causal relationship between...
BACKGROUND
Emerging evidence suggests systemic inflammation as a critical mechanism underlying diabetic neuropathy. This study aimed to investigate the causal relationship between 41 circulating inflammatory cytokines and diabetic neuropathy.
METHODS
Summary statistics from previous Genome-Wide Association studies (GWAS) included pooled data on 41 inflammatory cytokines and diabetic neuropathy. A two-sample Mendelian Randomization (MR) design was employed, and the robustness of the results was confirmed through comprehensive sensitivity analyses.
RESULTS
Our study reveals that the linkage between increased levels of IFN_G (OR = 1.31, 95 %CI: 1.06-1.63; P = 0.014), IP_10 (OR = 1.18, 95 %CI: 1.01-1.36; P = 0.031) and an elevated risk of diabetic neuropathy. Conversely, higher levels of IL_9 (OR = 0.86, 95 %CI: 0.75-1.00; P = 0.048) and SCF (OR = 0.83, 95 %CI: 0.73-0.94; P = 0.003) are genetically determined to protect against diabetic neuropathy. Furthermore, the sensitivity analysis affirmed the results' dependability, revealing no heterogeneity or pleiotropy.
CONCLUSION
Our MR research identified four upstream inflammatory cytokines implicated in diabetic neuropathy. Overall, these findings suggest the potential for innovative therapeutic strategies. Further large-scale cohort studies are required for validation.
Topics: Humans; Cytokines; Diabetic Neuropathies; Genome-Wide Association Study; Mendelian Randomization Analysis; Interferon-gamma; Diabetes Mellitus
PubMed: 38395012
DOI: 10.1016/j.cyto.2024.156548 -
Disease Models & Mechanisms Oct 2023Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms...
Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background. Glomeruli and sciatic nerve transcriptomic data from T1D and T2D mice were analyzed by self-organizing map and differential gene expression analysis. Consistent with prior literature, pathways related to immune function and inflammation were dysregulated in both complications in T1D and T2D mice. Gene-level analysis identified a high degree of concordance in shared differentially expressed genes (DEGs) in both complications and across diabetes type when using mice from the same cohort and genetic background. As we have previously shown a low concordance of shared DEGs in DPN when using mice from different cohorts and genetic backgrounds, this suggests that genetic background may influence diabetic complications. Collectively, these findings support the role of inflammation and indicate that genetic background is important in complications of both T1D and T2D.
Topics: Humans; Mice; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Diabetes Mellitus, Type 1; Transcriptome; Diabetic Neuropathies; Gene Expression Profiling; Inflammation
PubMed: 37791586
DOI: 10.1242/dmm.050080 -
Irish Journal of Medical Science Aug 2023Diabetic gastroparesis carries a heavy burden on people with diabetes and the healthcare system. It remains underdiagnosed and represents challenges to treat. This... (Review)
Review
Diabetic gastroparesis carries a heavy burden on people with diabetes and the healthcare system. It remains underdiagnosed and represents challenges to treat. This article reviews the epidemiology, pathophysiology, clinical features, diagnosis and treatment of diabetic gastroparesis. The disorder is characterized by delayed gastric emptying without evidence of mechanical gastric outflow obstruction. It presents with upper gastrointestinal (GI) symptoms such as nausea, vomiting, early satiety, postprandial fullness, upper abdominal discomfort and or bloating. As the prevalence of diabetes has been growing over the last few decades, we would expect an increased incidence of delayed gastric emptying in poorly controlled diabetes and perhaps in line with the increasing use of medications that act on the GI tract such as incretin-based therapy. The disease results from multiple reversible and irreversible mechanisms. Diagnosing diabetic gastroparesis requires careful history, examination and investigations to exclude other disorders that could mimic its clinical presentation. Treatment involves a wide variety of options starting with optimization of glycaemic control, stopping any offending medications and lifestyle modifications followed by the introduction of medical therapeutics such as prokinetics. Then, surgical interventions are considered in refractory cases.
Topics: Humans; Diabetic Neuropathies; Gastroparesis; Gastric Emptying; Prognosis
PubMed: 36266392
DOI: 10.1007/s11845-022-03191-8 -
Journal of Advanced Research Dec 2023Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial... (Review)
Review
BACKGROUND
Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial disease. Diabetic foot ulcers (DFU) are difficult to heal, which makes patients susceptible to infections and can ultimately conduce to limb amputation or even death in severe cases. An increasing number of studies have found that epigenetic alterations are strongly associated with poor wound healing in diabetes.
AIM OF REVIEW
This work provides significant insights into the development of therapeutics for improving chronic diabetic wound healing, particularly by targeting and regulating DNA methylation and demethylation in DFU. Key scientific concepts of review: DNA methylation and demethylation play an important part in diabetic wound healing, via regulating corresponding signaling pathways in different breeds of cells, including macrophages, vascular endothelial cells and keratinocytes. In this review, we describe the four main phases of wound healing and their abnormality in diabetic patients. Furthermore, we provided an in-depth summary and discussion on how DNA methylation and demethylation regulate diabetic wound healing in different types of cells; and gave a brief summary on recent advances in applying cellular reprogramming techniques for improving diabetic wound healing.
Topics: Humans; Diabetic Foot; DNA Methylation; Endothelial Cells; Wound Healing; Demethylation; Diabetes Mellitus
PubMed: 36706989
DOI: 10.1016/j.jare.2023.01.009 -
Molecular Medicine (Cambridge, Mass.) Jul 2023Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound...
BACKGROUND
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN.
METHODS
Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected.
RESULTS
CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs.
CONCLUSIONS
CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.
Topics: Rats; Animals; Diabetic Neuropathies; Rats, Sprague-Dawley; Endoplasmic Reticulum Stress; Myelin Sheath; Signal Transduction; Sciatic Nerve; Diabetes Mellitus
PubMed: 37464341
DOI: 10.1186/s10020-023-00698-3 -
The Cochrane Database of Systematic... Jan 2024Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN.... (Review)
Review
BACKGROUND
Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN. Although alpha-lipoic acid (ALA, also known as thioctic acid) is widely used, there is no consensus about its benefits and harms.
OBJECTIVES
To assess the effects of alpha-lipoic acid as a disease-modifying agent in people with diabetic peripheral neuropathy.
SEARCH METHODS
On 11 September 2022, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two clinical trials registers. We also searched the reference lists of the included studies and relevant review articles for additional references not identified by the electronic searches.
SELECTION CRITERIA
We included randomised clinical trials (RCTs) that compared ALA with placebo in adults (aged 18 years or older) and that applied the study interventions for at least six months. There were no language restrictions.
DATA COLLECTION AND ANALYSIS
We used standard methods expected by Cochrane. The primary outcome was change in neuropathy symptoms expressed as changes in the Total Symptom Score (TSS) at six months after randomisation. Secondary outcomes were change in neuropathy symptoms at six to 12 months and at 12 to 24 months, change in impairment, change in any validated quality of life total score, complications of DPN, and adverse events. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
Our analysis incorporated three trials involving 816 participants. Two studies included people with type 1 or type 2 diabetes, while one study included only people with type 2 diabetes. The duration of treatment was between six months and 48 months. We judged all studies at high risk of overall bias due to attrition. ALA compared with placebo probably has little or no effect on neuropathy symptoms measured by TSS (lower score is better) after six months (mean difference (MD) -0.16 points, 95% confidence interval (CI) -0.83 to 0.51; 1 study, 330 participants; moderate-certainty evidence). The CI of this effect estimate did not contain the minimal clinically important difference (MCID) of 0.97 points. ALA compared with placebo may have little or no effect on impairment measured by the Neuropathy Impairment Score-Lower Limbs (NIS-LL; lower score is better) after six months (MD -1.02 points, 95% CI -2.93 to 0.89; 1 study, 245 participants; low-certainty evidence). However, we cannot rule out a significant benefit, because the lower limit of the CI surpassed the MCID of 2 points. There is probably little or no difference between ALA and placebo in terms of adverse events leading to cessation of treatment within six months (risk ratio (RR) 1.48, 95% CI 0.50 to 4.35; 3 studies, 1090 participants; moderate-certainty evidence). No studies reported quality of life or complications associated with DPN.
AUTHORS' CONCLUSIONS
Our analysis suggests that ALA probably has little or no effect on neuropathy symptoms or adverse events at six months, and may have little or no effect on impairment at six months. All the studies were at high risk of attrition bias. Therefore, future RCTs should ensure complete follow-up and transparent reporting of any participants missing from the analyses.
Topics: Adult; Humans; Thioctic Acid; Diabetic Neuropathies; Diabetes Mellitus, Type 2; Lower Extremity; MEDLINE
PubMed: 38205823
DOI: 10.1002/14651858.CD012967.pub2 -
Acta Cirurgica Brasileira 2023To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ).
PURPOSE
To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ).
METHODS
STZ (60 mg/kg) was administered to adult Sprague-Dawley rats to induce diabetes. On the 30th day after STZ administration, electromyography (EMG) and motor function tests confirmed the presence of DPN. Group 1: Control (n = 10), Group 2: DM + 0.1 mg/kg Rilmenidine (n = 10), and Group 3: DM + 0.2 mg/kg Rilmenidine (n = 10) were administered via oral lavage for four weeks. EMG, motor function test, biochemical analysis, and histological and immunohistochemical analysis of sciatic nerves were then performed.
RESULTS
The administration of Rilmenidine to diabetic rats substantially reduced sciatic nerve inflammation and fibrosis and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves from saline-treated rats revealed increased perineural thickness, HMGB-1, tumor necrosis factor-α, and a decrease in nerve growth factor (NGF), LC-3. In contrast, Rilmendine significantly inhibited inflammation markers and prevented the reduction in NGF expression. In addition, Rilmenidine significantly decreased malondialdehyde and increased diabetic rats' total antioxidative capacity.
CONCLUSIONS
The findings of this study suggest that Rilmenidine may have therapeutic effects on DNP by modulating antioxidant and autophagic pathways.
Topics: Rats; Animals; Diabetic Neuropathies; Rats, Sprague-Dawley; Diabetes Mellitus, Experimental; Rilmenidine; Nerve Growth Factor; Sciatic Nerve; Antioxidants; Inflammation
PubMed: 38055406
DOI: 10.1590/acb387823 -
Biochemical Pharmacology Sep 2023Diabetic neuropathy is a neuro-degenerative disorder that encompasses numerous factors that impact peripheral nerves in the context of diabetes mellitus (DM). Diabetic... (Review)
Review
Diabetic neuropathy is a neuro-degenerative disorder that encompasses numerous factors that impact peripheral nerves in the context of diabetes mellitus (DM). Diabetic peripheral neuropathy (DPN) is very prevalent and impacts 50% of diabetic patients. DPN is a length-dependent peripheral nerve lesion that primarily causes distal sensory loss, discomfort, and foot ulceration that may lead to amputation. The pathophysiology is yet to be fully understood, but current literature on the pathophysiology of DPN revolves around understanding various signaling cascades involving the polyol, hexosamine, protein-kinase C, AGE, oxidative stress, and poly (ADP ribose) polymerase pathways. The results of research have suggested that hyperglycemia target Schwann cells and in severe cases, demyelination resulting in central and peripheral sensitization is evident in diabetic patients. Various diagnostic approaches are available, but detection at an early stage remains a challenge. Traditional analgesics and opioids that can be used "as required" have not been the mainstay of treatment thus far. Instead, anticonvulsants and antidepressants that must be taken routinely over time have been the most common treatments. For now, prolonging life and preserving the quality of life are the ultimate goals of diabetes treatment. Furthermore, the rising prevalence of DPN has substantial consequences for occupational therapy because such therapy is necessary for supporting wellness, warding off other chronic-diseases, and avoiding the development of a disability; this is accomplished by engaging in fulfilling activities like yoga, meditation, and physical exercise. Therefore, occupational therapy, along with palliative therapy, may prove to be crucial in halting the onset of neuropathic-symptoms and in lessening those symptoms once they have occurred.
Topics: Humans; Diabetic Neuropathies; Quality of Life; Hyperglycemia; Signal Transduction; Protein Kinase C; Diabetes Mellitus
PubMed: 37536473
DOI: 10.1016/j.bcp.2023.115723 -
MMW Fortschritte Der Medizin Apr 2024
Review
Topics: Humans; Diabetic Neuropathies; Diabetes Mellitus
PubMed: 38637392
DOI: 10.1007/s15006-024-3735-4