Resveratrol Modulates Diabetes-Induced Neuropathic Pain, Apoptosis, and Oxidative Neurotoxicity in Mice Through TRPV4 Channel Inhibition.

Diabetic peripheral neuropathy (DPN) is caused by several factors, including reactive free oxygen radicals (ROS)-induced excessive Ca2+ influx. Transient receptor potential (TRP) vanilloid 4 (TRPV4) is a member of the Ca2+-permeable TRP superfamily. Resveratrol (RESV) has been extensively utilized in TRP channel regulation due to its pharmacological properties, which include antioxidant and TRP inhibitory effects. The protective function of RESV and the contribution of TRPV4 to streptozotocin (STZ)-induced neuropathic pain in mice are still unclear. Here, we evaluated the effects of RESV through the modulation of TRPV4 on Ca2+ influx, ROS-mediated pain, apoptosis, and oxidative damage in the mouse dorsal root ganglion (DRGs). From the 32 mice, four groups were induced: control, RESV, STZ, and STZ + RESV. We found that the injection of RESV reduced the changes caused by the STZ-induced stimulation of TRPV4, which in turn increased mechanical/thermal neuropathic pain, cytosolic Ca2+ influx, TRPV4 current density, oxidants (lipid peroxidation, mitochondrial ROS, and cytosolic ROS), and apoptotic markers (caspase-3, -8, and -9). The RESV injection also increased the STZ-mediated reduction of viability of DRG and the amounts of glutathione, glutathione peroxidase, vitamin A, ß-carotene, and vitamin E in the brain, erythrocytes, plasma, liver, and kidney. All of these findings suggest that TRPV4 stimulation generates oxidative neurotoxicity, neuropathic pain, and apoptosis in the STZ-induced diabetic mice. On the other hand, neurotoxicity and apoptosis were reduced due to the downregulation of TRPV4 carried out through the RESV injection.

Acupuncture for the treatment of diabetic peripheral neuropathy in the elderly: a systematic review and meta-analysis.

Background: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus, often causing pain or numbness in the patient's limbs and even leading to amputation and death. Elderly patients with DPN usually have higher morbidity and more severe results. Acupuncture has been widely used as an effective treatment for DPN in China. However, the efficacy of acupuncture in the treatment of DPN remains unclear. In this review, we aimed to explore the impact of acupuncture in alleviating symptoms of DPN. Method and analysis: Six databases were searched from inception to October 2023. We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases, namely China National Knowledge Infrastructure (CNKI), SinoMed, and Wanfang. All randomized controlled trials related to the effect of acupuncture on DPN will be included. There was no restriction in language or publication year. The primary outcome is the response rate. The secondary outcomes are the Toronto clinical scoring system (TCSS), nerve conduction velocities (NCVs), and blood glucose before and after the treatment. Two researchers will be responsible for the selection of study, data extraction, and assessment of study quality independently. RevMan V5.1.0 software will be used to assess the risk of bias and generate data. Results: We searched 4518 studies, among which 9 RCTs were considered eligible. Overall, acupuncture treatment had a higher response rate than controls (relative risk (RR), -2.87 [95% confidence interval (CI), -5.27 to -0.48], p = 0.02) and significantly alleviated the symptoms of DPN patients, reduced their blood glucose levels, and improved their NCVs compared to the control group. This study will provide a high-quality synthesis of current available evidence for the clinical treatment of DPN with this therapy. Conclusion: The results suggested that acupuncture might be effective in improving symptoms of DPN in elderly patients. Owing to the overall low quality of the literature included, we need more large-sample, high-quality, and low-bias studies to prove it.

Neutrophil-to-Lymphocyte Ratio as a Marker for Cardiac Autonomic Neuropathy in Egyptian Patients With Type 2 Diabetes: A Cross-Sectional Study.

OBJECTIVE: Cardiac autonomic neuropathy (CAN) is one of the most serious complications of diabetes. This study aimed to analyze the correlation between neutrophil-to-lymphocyte ratio (NLR) and CAN in patients with type 2 diabetes (T2D) using 24-hour Holter ECG and to assess the relationship between NLR and severity of diabetic peripheral neuropathy (DPN). SUBJECTS & METHODS:  This cross-sectional study included 90 T2D patients with DPN confirmed by nerve conduction study (NCS). A 24-hour Holter ECG was done to detect the decrease in heart rate variability (HRV). Laboratory parameters, including fasting blood glucose, creatinine, cholesterol, triglyceride, and glycosylated hemoglobin (HbA1c) levels, as well as CBC, neutrophils, lymphocytes, NLR, and platelet-to-lymphocyte ratio (PLR), were calculated accordingly. An albumin-to-creatinine ratio (ACR) test was done and the estimated glomerular filtration rate (eGFR) was calculated. Chronic kidney disease was diagnosed by the presence of albuminuria (≥30 mg/g creatinine) and/or eGFR less than 60. RESULTS: Based on the 24-hour Holter ECG, 25 patients out of 90 (27.7%) had CAN. On comparing both the CAN and non-CAN groups, the CAN group had higher HbA1C (p = 0.005), higher NLR (p = 0.014), and higher neutrophils (p = 0.10). Also, PLR was higher in the CAN group than in the non-CAN group, but this was not statistically significant (p = 0.180). Receiver operator characteristic curve analysis revealed that NLR with a cutoff of 1.7 succeeded in detecting patients with CAN. CONCLUSION: NLR can be used as an inexpensive and accessible marker to detect patients with diabetes at risk for developing CAN.

The association of diabetic peripheral neuropathy with cardiac autonomic neuropathy in individuals with diabetes mellitus: A systematic review.

This systematic review aimed to explore the relationship between diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN) in individuals with type 1 and 2 diabetes mellitus (DM). METHODS: The systematic review follow the protocol registered in Prospero (CRD42020182899). Two authors independently searched the PubMed, Scopus, Embase, Cochrane, and Web of Science databases. Discrepancies were resolved by a third author. The review included observational studies investigating the relationship between CAN and DPN in individuals with DM. RESULTS: Initially, out of 1165 studies, only 16 were selected, with 42.8 % involving volunteers with one type of diabetes, 14.3 % with both types of diabetes and 14.3 % not specify the type. The total number of volunteers was 2582, mostly with type 2 DM. It was analyzed that there is a relationship between CAN and DPN. It was observed that more severe levels of DPN are associated with worse outcomes in autonomic tests. Some studies suggested that the techniques for evaluating DPN might serve as risk factors for CAN. CONCLUSION: The review presents a possible relationship between DPN and CAN, such as in their severity.

Expert opinion on screening, diagnosis and management of diabetic peripheral neuropathy: a multidisciplinary approach.

The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to provide a guidance document to assist clinicians for the best practice in DPN care. The participating experts consider the suspicion of the disease by clinicians as a key factor in early recognition and diagnosis, emphasizing an improved awareness of the disease by the first-admission or referring physicians. The proposed "screening and diagnostic" algorithm involves the consideration of DPN in a patient with prediabetes or diabetes who presents with neuropathic symptoms and/or signs of neuropathy in the presence of DPN risk factors, with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction in atypical cases. Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Alpha-lipoic acid (ALA) seems to be an important first-line pathogenesis-directed agent, given that it is a direct and indirect antioxidant that works with a strategy targeted directly against reactive oxygen species and indirectly in favor of endogenous antioxidant capacity for improving DPN conditions. There is still a gap in existing research in the field, necessitating well-designed, robust, multicenter clinical trials with sensitive endpoints and standardized protocols to facilitate the diagnosis of DPN via a simple and effective algorithm and to track progression of disease and treatment response. Identification of biomarkers/predictors that would allow an individualized approach from a potentially disease-modifying perspective may provide opportunities for novel treatments that would be efficacious in early stages of DPN, and may modify the natural course of the disease. This expert opinion document is expected to increase awareness among physicians about conceptual, clinical, and therapeutic aspects of DPN and to assist them in timely recognition of DPN and translating this information into their clinical practice for best practice in the management of patients with DPN.

Serum Spexin Level Is Negatively Associated With Peripheral Neuropathy and Sensory Pain in Type 2 Diabetes.

Background: Spexin is a novel peptide hormone and has shown antinociceptive effects in experimental mice. This study is aimed at evaluating the association of serum spexin level with diabetic peripheral neuropathy (DPN) and related pain in a Chinese population. Methods: We enrolled 167 type 2 diabetes mellitus (T2DM) including 56 patients without DPN (non-DPN), 67 painless DPN, and 44 painful DPN. Serum spexin was measured using ELISA. Logistic regression models were performed to analyze the independent effects of spexin on prevalence of DPN and painful DPN. In streptozotocin (STZ)-induced diabetic mice, mechanical pain threshold was measured using electronic von Frey aesthesiometer. Human peripheral blood mononuclear cells (PBMCs) were isolated and further stimulated with lipopolysaccharide without or with spexin. The gene expression was assayed by qPCR. Results: Compared with non-DPN, serum spexin level decreased in painless DPN and further decreased in painful DPN. The odds of DPN was associated with low spexin level in T2DM, which was similar by age, sex, BMI, and diabetes duration, but attenuated in smokers. The odds of having pain was associated with decreased spexin level in DPN, which was similar by age, sex, smoking status, and diabetes duration, but attenuated in normal weight. Furthermore, we observed that mechanical pain threshold increased in spexin-treated diabetic mice. We also found that lipopolysaccharide treatment increased the mRNA level of TNF-α, IL-6, and MCP-1 in human PBMCs, while spexin treatment prevented this increase. Conclusions: These results suggested that spexin might serve as a protective factor for diabetes against neuropathology and pain-related pathogenesis.

Pyroptosis in Diabetic Peripheral Neuropathy and its Therapeutic Regulation.

Pyroptosis is a pro-inflammatory form of cell death resulting from the activation of gasdermins (GSDMs) pore-forming proteins and the release of several pro-inflammatory factors. However, inflammasomes are the intracellular protein complexes that cleave gasdermin D (GSDMD), leading to the formation of robust cell membrane pores and the initiation of pyroptosis. Inflammasome activation and gasdermin-mediated membrane pore formation are the important intrinsic processes in the classical pyroptotic signaling pathway. Overactivation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome triggers pyroptosis and amplifies inflammation. Current evidence suggests that the overactivation of inflammasomes and pyroptosis may further induce the progression of cancers, nerve injury, inflammatory disorders and metabolic dysfunctions. Current evidence also indicates that pyroptosis-dependent cell death accelerates the progression of diabetes and its frequent consequences including diabetic peripheral neuropathy (DPN). Pyroptosis-mediated inflammatory reaction further exacerbates DPN-mediated CNS injury. Accumulating evidence shows that several molecular signaling mechanisms trigger pyroptosis in insulin-producing cells, further leading to the development of DPN. Numerous studies have suggested that certain natural compounds or drugs may possess promising pharmacological properties by modulating inflammasomes and pyroptosis, thereby offering potential preventive and practical therapeutic approaches for the treatment and management of DPN. This review elaborates on the underlying molecular mechanisms of pyroptosis and explores possible therapeutic strategies for regulating pyroptosis-regulated cell death in the pharmacological treatment of DPN.

Triglyceride Glucose Index for the Detection of Diabetic Kidney Disease and Diabetic Peripheral Neuropathy in Hospitalized Patients with Type 2 Diabetes.

INTRODUCTION: The triglyceride-glucose index (TyG) has been identified as a dependable and simple indicator marker of insulin resistance (IR). Research has demonstrated a correlation between macrovascular complications and TyG. However, limited research exists regarding the relationship between TyG and diabetic microvascular complications. Consequently, the objective of this study is to investigate the association between TyG and diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN). METHODS: This is a cross-sectional, observational study. A total of 2048 patients from Tongren Hospital, Shanghai Jiao Tong University School of Medicine were enrolled. The primary outcomes are DKD and DPN. Quantile regression analysis was employed to investigate the implicit factors of TyG quartiles. Subsequently, based on implicit factors, logistic regression models were constructed to further examine the relationship between TyG and DKD and DPN. RESULTS: In the baseline, TyG exhibited higher values across patients with DKD, DPN, and co-existence of DKD and DPN (DKD + DPN) in type 2 diabetes (T2D). Univariate logistic regressions demonstrated a significant association between an elevated TyG and an increased risk of DKD (OR = 1.842, [95% CI] 1.317-2.578, P for trend < 0.01), DPN (OR = 1.516, [95% CI] 1.114-2.288, P for trend < 0.05), DKD + DPN (OR = 2.088, [95% CI] 1.429-3.052, P for trend < 0.05). Multivariable logistic regression models suggested a statistically significant increase in the risk of DKD (OR = 1.581, [95% CI] 1.031-2.424, p < 0.05), DKD + DPN (OR = 1.779, [95% CI] 1.091-2.903, p < 0.05) after adjusting the implicit factors of TyG quartiles. However, no significant relationship was observed between TyG and DPN in the multivariable regression analysis. CONCLUSIONS: Elevated TyG was significantly associated with an increased risk of DKD in T2D, but no significant relationship was shown with DPN. This finding provided further evidence for the clinical significance of integrating TyG into the initial assessment of diabetic microvascular complications.

Assessment of subclinical LV myocardial dysfunction in T2DM patients with diabetic peripheral neuropathy: a cardiovascular magnetic resonance study.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most prevalent complication of diabetes, and has been demonstrated to be independently associated with cardiovascular events and mortality. This aim of this study was to investigate the subclinical left ventricular (LV) myocardial dysfunction in type 2 diabetes mellitus (T2DM) patients with and without DPN. METHODS: One hundred and thirty T2DM patients without DPN, 61 patients with DPN and 65 age and sex-matched controls who underwent cardiovascular magnetic resonance (CMR) imaging were included, all subjects had no symptoms of heart failure and LV ejection fraction ≥ 50%. LV myocardial non-infarct late gadolinium enhancement (LGE) was determined. LV global strains, including radial, circumferential and longitudinal peak strain (PS) and peak systolic and diastolic strain rates (PSSR and PDSR, respectively), were evaluated using CMR feature tracking and compared among the three groups. Multivariable linear regression analyses were performed to determine the independent factors of reduced LV global myocardial strains in T2DM patients. RESULTS: The prevalence of non-infarct LGE was higher in patients with DPN than those without DPN (37.7% vs. 19.2%, p = 0.008). The LV radial and longitudinal PS (radial: 36.60 ± 7.24% vs. 33.57 ± 7.30% vs. 30.72 ± 8.68%; longitudinal: - 15.03 ± 2.52% vs. - 13.39 ± 2.48% vs. - 11.89 ± 3.02%), as well as longitudinal PDSR [0.89 (0.76, 1.05) 1/s vs. 0.80 (0.71, 0.93) 1/s vs. 0.77 (0.63, 0.87) 1/s] were decreased significantly from controls through T2DM patients without DPN to patients with DPN (all p < 0.001). LV radial and circumferential PDSR, as well as circumferential PS were reduced in both patient groups (all p < 0.05), but were not different between the two groups (all p > 0.05). Radial and longitudinal PSSR were decreased in patients with DPN (p = 0.006 and 0.003, respectively) but preserved in those without DPN (all p > 0.05). Multivariable linear regression analyses adjusting for confounders demonstrated that DPN was independently associated with LV radial and longitudinal PS (ß = - 3.025 and 1.187, p = 0.014 and 0.003, respectively) and PDSR (ß = 0.283 and - 0.086, p = 0.016 and 0.001, respectively), as well as radial PSSR (ß = - 0.266, p = 0.007). CONCLUSIONS: There was more severe subclinical LV dysfunction in T2DM patients complicated with DPN than those without DPN, suggesting further prospective study with more active intervention in this cohort of patients.

Diabetic peripheral neuropathy and glycemic variability assessed by continuous glucose monitoring: A systematic review and meta-analysis.

Continuous glucose monitoring (CGM)-derived metrics have been used to accurately assess glycemic variability (GV) to facilitate management of diabetes mellitus, yet their relationship with diabetic peripheral neuropathy (DPN) is not fully understood. We performed a systematic review and meta-analysis to evaluate the association between GV metrics and the risk of developing DPN. Nine studies totaling 3,649 patients with type 1 and type 2 diabetes mellitus were included. A significant association was found between increased GV, as indicated by metrics including standard deviation (SD) with OR and 95% CI of 2.58 (1.45-4.57), mean amplitude of glycemic excursions (MAGE) with OR and 95% CI of 1.90 (1.01-3.58), mean of daily difference (MODD) with OR and 95% CI of 2.88 (2.17-3.81) and the incidence of DPN. Our findings support a link between higher GV and an increased risk of DPN in patients with diabetes. These findings highlight the potential of GV metrics as indicators for the development of DPN, advocating for their inclusion in diabetes management strategies to potentially mitigate neuropathy risk. Longitudinal studies with longer observation periods and larger sample sizes are necessary to validate these associations across diverse populations.

Correlation of serum Meteorin-like (Metrnl) level with type 2 diabetic peripheral neuropathy.

OBJECTIVE: Meteorin-like (Metrnl), a secreted myokine, is a newly discovered neurotrophic factor. The aim of this study was to determine if there is a correlation between the Metrnl level and diabetic peripheral neuropathy (DPN). METHODS: The investigation was conducted on a sample of 80 patients with type 2 diabetes mellitus (T2DM) and 60 healthy controls. The T2DM patients were categorized into two subgroups based on skin biopsy: the DPN subgroup (n = 20) and the diabetes without neuropathy subgroup (n = 60). RESULTS: The T2DM groups had higher serum Metrnl concentrations compared with the controls. The serum Metrnl concentration was significantly lower in the DPN group than in T2DM patients without neuropathy. Logistic regression analysis demonstrated a notable correlation between serum Metrnl and DPN (OR: 0.997, 95% CI: 0.995-1.000, P < 0.05). Serum Metrnl level was negatively correlated with age and SBP after a simple logistic regression analysis. CONCLUSION: Serum Metrnl concentration is independently correlated with DPN.

Relationship of lncRNA FTX and miR-186-5p levels with diabetic peripheral neuropathy in type 2 diabetes and its bioinformatics analysis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) frequently occurs as a secondary condition in individuals with type 2 diabetes mellitus (T2DM). OBJECTIVE: To explore the relationship of lncRNA FTX and miR-186-5p levels with DPN in T2DM. METHODS: The study enrolled 50 patients with T2DM and 45 patients with DPN. Expression levels of FTX and miR-186-5p were measured by RT-qPCR. The levels of MDA, GSH, and SOD in the serum were measured to assess the patients' oxidative stress levels. In addition, the target genes of miR-186-5p were analyzed by bioinformatics. RESULTS: Serum FTX levels were increased and miR-186-5p levels were decreased in patients with T2DM and DPN. Both of them had high diagnostic value for T2DM and DPN. In addition, FTX and miR-186-5p were risk factors for the onset of DPN in people with T2DM and were significantly correlated with oxidative stress indicators in patients. CONCLUSION: FTX and miR-186-5p are closely related to the disease progression of DPN in people with T2DM and may become therapeutic targets for DPN in people with T2DM.

MiR-503-5p alleviates peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 to inhibit astrocyte activation.

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.

HDAC1 Promotes Mitochondrial Pathway Apoptosis and Inhibits the Endoplasmic Reticulum Stress Response in High Glucose-Treated Schwann Cells via Decreased U4 Spliceosomal RNA.

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.

Pathological evaluation of the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy.

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.

Diabetic peripheral neuropathy: age-stratified glycemic control.

Background: We explore the effect of suboptimal glycemic control on the incidence of diabetic peripheral neuropathy (DPN) in both non-elderly and elderly patients with type 2 diabetes mellitus (T2DM). Methods: A 6-year follow-up study (2013-2019) enrolled T2DM patients aged >20 without DPN. Participants were classified into two groups: those below 65 years (non-elderly) and those 65 years or older (elderly). Biochemical measurements, including glycated hemoglobin (HbA1C), were recorded regularly. DPN was diagnosed using the Michigan Neuropathy Screening Instrument examination. The outcome was DPN occurrence in 2019. Results: In 552 enrollments (69% non-elderly), DPN occurred in 8.4% non-elderly and 24.0% elderly patients. A higher initial HbA1C level was significantly linked with a higher risk of future DPN in the non-elderly group (adjusted odds ratio [AOR] 1.46, 95% CI 1.13-1.89, p=0.004). In comparison, HbA1c at the end of the study period was not associated with DPN in the non-elderly group (AOR 1.17, 95% CI 0.72-1.90, p=0.526). In the elderly group, no statistical relationship was found between HbA1C levels and DPN, either in 2013 or in 2019. Conclusion: Suboptimal glycemic control at baseline, rather than at the end of the study period, predicts an increased risk of future DPN in individuals with T2DM under age 65. This correlation is not seen in elderly patients. Therefore, we recommend implementing enhanced glycemic control early in middle-aged T2DM patients and propose individualized therapeutic strategies for diabetes in different age groups.

Comprehensive assessment of ocular parameters for identifying diagnostic indicators of diabetic peripheral neuropathy.

PURPOSE: To explore variations in systemic and ocular parameters among patients with diabetes, both with and without diabetic peripheral neuropathy (DPN) and to identify sensitive indicators for DPN diagnosis. METHODS: Ninty-five patients with type 2 diabetes mellitus (T2DM) were involved in this cross-sectional study, including 49 without DPN and 46 with DPN. Ocular parameters were obtained using optical coherence tomography angiography (OCTA) and corneal confocal microscopy (CCM). RESULT: Patients with DPN presented with significantly higher HbA1c (p < 0.05) and glycated albumin (GA, p < 0.01) levels, increased prevalence of diabetic retinopathy (DR, p < 0.05), and lower serum albumin (ALB, p < 0.01) and red blood cell (RBC, p < 0.05) levels. Ocular assessments revealed reduced corneal nerve fiber length (CNFL, p < 0.001) and enlarged foveal avascular zone (FAZ) area (p < 0.05) in DPN group. Logistic regression analysis indicated a significant association of presence of DR, RBC, GA, ALB, CNFL and DPN (p < 0.05, respectively). In the binary logistic regression for DPN risk, all three models including the presence of DR and CNFL exhibited the area under the curve (AUC) exceeding 0.8. CONCLUSION: The study establishes a strong correlation between ocular parameters and DPN, highlighting CCM's role in early diagnosis. Combining systemic and ocular indicators improves DPN risk assessment and early management.

Development and validation of a risk nomogram model for predicting peripheral neuropathy in patients with type 2 diabetes mellitus.

Objective: Diabetic peripheral neuropathy frequently occurs and presents severely in individuals suffering from type 2 diabetes mellitus, representing a significant complication. The objective of this research was to develop a risk nomogram for DPN, ensuring its internal validity and evaluating its capacity to predict the condition. Methods: In this retrospective analysis, Suqian First Hospital's cohort from January 2021 to June 2022 encompassed 397 individuals diagnosed with T2DM. A random number table method was utilized to allocate these patients into two groups for training and validation, following a 7:3 ratio. By applying univariate and multivariable logistic regression, predictive factors were refined to construct the nomogram. The model's prediction accuracy was assessed through metrics like the ROC area, HL test, and an analysis of the calibration curve. DCA further appraised the clinical applicability of the model. Emphasis was also placed on internal validation to confirm the model's dependability and consistency. Results: Out of 36 evaluated clinicopathological characteristics, a set of four, duration, TBIL, TG, and DPVD, were identified as key variables for constructing the predictive nomogram. The model exhibited robust discriminatory power, evidenced by an AUC of 0.771 (95% CI: 0.714-0.828) in the training cohort and an AUC of 0.754 (95% CI: 0.663-0.845) in the validation group. The congruence of the model's predictions with actual findings was corroborated by the calibration curve. Furthermore, DCA affirmed the clinical value of the model in predicting DPN. Conclusion: This research introduces an innovative risk nomogram designed for the prediction of diabetic peripheral neuropathy in individuals suffering from type 2 diabetes mellitus. It offers a valuable resource for healthcare professionals to pinpoint those at elevated risk of developing this complication. As a functional instrument, it stands as a viable option for the prognostication of DPN in clinical settings.

Systematic investigation of Radix Salviae for treating diabetic peripheral neuropathy disease based on network Pharmacology.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus with limited available treatment options. Radix Salviae, a traditional Chinese herb, has shown promise in treating DPN, but its therapeutic mech-anisms have not been systematically investigated. AIM: Radix Salviae (Danshen in pinin), a traditional Chinese medicine (TCM), is widely used to treat DPN in China. However, the mechanism through which Radix Salviae treats DPN remains unclear. Therefore, we aimed to explore the mechanism of action of Radix Salviae against DPN using network pharmacology. METHODS: The active ingredients and target genes of Radix Salviae were screened using the TCM pharmacology database and analysis platform. The genes associated with DPN were obtained from the Gene Cards and OMIM databases, a drug-com-position-target-disease network was constructed, and a protein-protein inter-action network was subsequently constructed to screen the main targets. Gene Ontology (GO) functional annotation and pathway enrichment analysis were performed via the Kyoto Encyclopedia of Genes and Genomes (KEGG) using Bioconductor. RESULTS: A total of 56 effective components, 108 targets and 4581 DPN-related target genes of Radix Salviae were screened. Intervention with Radix Salviae for DPN mainly involved 81 target genes. The top 30 major targets were selected for enrichment analysis of GO and KEGG pathways. CONCLUSION: These results suggested that Radix Salviae could treat DPN by regulating the AGE-RAGE signaling pathway and the PI3K-Akt signaling pathway. Therefore, Danshen may affect DPN by regulating inflammation and apoptosis.