-
Nature Medicine Jun 2024Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African...
Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.
PubMed: 38918629
DOI: 10.1038/s41591-024-03089-1 -
Neurochemical Research Jun 2024Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic...
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.
PubMed: 38916813
DOI: 10.1007/s11064-024-04200-1 -
Neurological Research Jun 2024Diabetic Peripheral Neuropathy (DPN) disrupts body and movement biomechanics, increases mechanical stress during walking, and predisposes individuals to injuries owing...
BACKGROUND
Diabetic Peripheral Neuropathy (DPN) disrupts body and movement biomechanics, increases mechanical stress during walking, and predisposes individuals to injuries owing to the repetitive effects of these stresses.
AIMS
This study aimed to assess and compare the impact of neuropathy on gait and pelvic kinematics in individuals with DPN.
METHODS
This case-control study included two groups: 23 individuals diagnosed with DPN aged between 35-70 and 23 healthy individuals aged-35-70. The BTS-G, a wireless motion sensor, was used to assess the time-distance characteristics of walking in all participants. The system analyzed data pertaining to walking speed, cadence, percentages of stance and swing phases, durations of walking cycles, double-step lengths, pelvic tilt, obliquity, and rotation symmetries.
RESULTS
There were no statistically significant differences between the groups in cadence, left and right stance phase percentages, or left and right swing phase percentages ( > 0.05). However, significant differences were observed between the groups in terms of speed, left and right walking cycle durations, and left and right double-step lengths ( < 0.05). Additionally, no statistically significant difference was found between the groups in pelvic tilt symmetry and left and right pelvic tilt range of motion values ( > 0.05). Nevertheless, significant differences were identified between the groups in pelvic obliquity symmetry, pelvic rotation symmetry, left and right pelvic obliquity range of motion, and left and right pelvic rotation range of motion values ( < 0.05).
CONCLUSIONS
The findings of this study suggest that individuals with DPN exhibit decreased walking speed, prolonged gait cycle duration, increased double step length, and reduced pelvic obliquity and rotation range of motion.
PubMed: 38916096
DOI: 10.1080/01616412.2024.2367938 -
BioRxiv : the Preprint Server For... Jun 2024Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus that is caused by metabolic toxicity to peripheral axons. We aimed to gain deep...
Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus that is caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease process using bulk and spatial RNA sequencing on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population. First, our approach comparing mixed sensory and motor tibial and purely sensory sural nerves shows key pathway differences in affected nerves, with distinct immunological features observed in sural nerves. Second, spatial transcriptomics analysis of sural nerves reveals substantial shifts in endothelial and immune cell types associated with severe axonal loss. We also find clear evidence of neuronal gene transcript changes, like in nerves with axonal loss suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons generating clear evidence of robust localization of mRNAs such as and in human sensory axons. Our work gives new insight into the altered cellular and transcriptomic profiles in human nerves in DPN and highlights the importance of sensory axon mRNA transport as an unappreciated potential contributor to peripheral nerve degeneration.
PubMed: 38915676
DOI: 10.1101/2024.06.15.599167 -
Cardiovascular Diabetology Jun 2024Diabetic peripheral neuropathy (DPN) is the most prevalent complication of diabetes, and has been demonstrated to be independently associated with cardiovascular events...
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 (β = - 3.025 and 1.187, p = 0.014 and 0.003, respectively) and PDSR (β = 0.283 and - 0.086, p = 0.016 and 0.001, respectively), as well as radial PSSR (β = - 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.
Topics: Humans; Male; Female; Middle Aged; Ventricular Dysfunction, Left; Ventricular Function, Left; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Aged; Predictive Value of Tests; Asymptomatic Diseases; Magnetic Resonance Imaging, Cine; Case-Control Studies; Diabetic Cardiomyopathies; Risk Factors; Prevalence; Cross-Sectional Studies; Stroke Volume; Myocardial Contraction
PubMed: 38915040
DOI: 10.1186/s12933-024-02307-x -
Pain and Therapy Jun 2024Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on...
INTRODUCTION
Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain.
METHODS
This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified.
RESULTS
A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations.
CONCLUSIONS
The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition.
CLINICAL TRIAL REGISTRATION
NCT03749642.
PubMed: 38914876
DOI: 10.1007/s40122-024-00624-3 -
Computers, Informatics, Nursing : CIN Jun 2024Diabetic peripheral neuropathy is a major cause of disability and death in the later stages of diabetes. A retrospective chart review was performed using a...
Diabetic peripheral neuropathy is a major cause of disability and death in the later stages of diabetes. A retrospective chart review was performed using a hospital-based electronic medical record database to identify 1020 patients who met the criteria. The objective of this study was to explore and analyze the early risk factors for peripheral neuropathy in patients with type 2 diabetes, even in the absence of specific clinical symptoms or signs. Finally, the random forest algorithm was used to rank the influencing factors and construct a predictive model, and then the model performance was evaluated. Logistic regression analysis revealed that vitamin D plays a crucial protective role in preventing diabetic peripheral neuropathy. The top three risk factors with significant contributions to the model in the random forest algorithm eigenvalue ranking were glycosylated hemoglobin, disease duration, and vitamin D. The areas under the receiver operating characteristic curve of the model ware 0.90. The accuracy, precision, specificity, and sensitivity were 0.85, 0.83, 0.92, and 0.71, respectively. The predictive model, which is based on the random forest algorithm, is intended to support clinical decision-making by healthcare professionals and help them target timely interventions to key factors in early diabetic peripheral neuropathy.
PubMed: 38913980
DOI: 10.1097/CIN.0000000000001157 -
Journal of Orthopaedic Case Reports Jun 2024Charcot arthropathy consists of a rapid and destructive complication of the joints following the loss of innervation caused by many complicated etiologies. Diabetic...
INTRODUCTION
Charcot arthropathy consists of a rapid and destructive complication of the joints following the loss of innervation caused by many complicated etiologies. Diabetic neuropathy has become the most common etiological factor.
CASE REPORT
We present a case of a 64-year-old female patient with a history of chronic renal failure on hemodialysis, hypertension, hypothyroidism, and Type 2 diabetes, complicated with neuropathy and Charcot disease, who referred to our department. Initially, the patient was managed with a restraint orthotic device due to a bimalleolar ankle fracture. An unsuccessful treatment and the presence of a pressure ulcer with pus-like drainage on the lateral malleolus 2 months later led to the decision for a below-knee amputation.
CONCLUSION
High clinical suspicion by the attending physician may reduce the risk of complications and lead to proper treatment with better outcomes.
PubMed: 38910990
DOI: 10.13107/jocr.2024.v14.i06.4498 -
Zhongguo Gu Shang = China Journal of... Jun 2024To explore clinical effect of vancomycin calcium sulfate combined with internal fixation on calcaneal beak-like fracture secondary to calcaneal osteomyelitis caused by...
OBJECTIVE
To explore clinical effect of vancomycin calcium sulfate combined with internal fixation on calcaneal beak-like fracture secondary to calcaneal osteomyelitis caused by diabetic foot.
METHODS
From April 2018 to October 2021, a retrospective analysis was performed on 5 patients with calcaneal bone osteomyelitis secondary to diabetic foot, including 2 males and 3 females, aged from 48 to 60 years old;diabetes course ranged from 5 to 13 years;the courses of diabetic foot disease ranged from 18 to 52 days;5 patients were grade Ⅲ according to Wagner classification. All patients were treated with debridement, vancomycin bone cement implantation, negative pressure aspiration at stageⅠ, vancomycin calcium sulfate and internal fixation at stageⅡfor calcaneal beak-like fracture. Surgical incision and fracture healing time were recorded, and the recurrence of osteomyelitis was observed. American Orthopedic Foot Andankle Society (AOFAS) score and exudation at 12 months after operation were evaluated.
RESULTS
Five patients were successfully completed operation without lower extremity vascular occlusion, and were followed up for 16 to 36 months. The wound healing time after internal fixation ranged from 16 to 26 days, and healing time of fractures ranged from 16 to 27 weeks. AOFAS score ranged from 65 to 91 at 12 months after operation, and 2 patients got excellent result, 2 good and 1 fair. Among them, 1 patient with skin ulcer on the back of foot caused by scalding at 5 months after operation (non-complication), was recovered after treatment;the wound leakage complication occurred in 2 patients, and were recovered after dressing change. No osteomyelitis or fracture occurred in all patients.
CONCLUSION
Vancomycin calcium sulfate with internal fixation in treating calcaneal osteomyelitis secondary to calcaneal osteomyelitis caused by diabetic foot could not only control infection, but also promote fracture healing, and obtain good clinical results.
Topics: Humans; Male; Middle Aged; Female; Osteomyelitis; Diabetic Foot; Calcaneus; Retrospective Studies; Fracture Fixation, Internal; Fractures, Bone
PubMed: 38910385
DOI: 10.12200/j.issn.1003-0034.20230327 -
Scientific Reports Jun 2024Peripheral neuropathy and amputation are common complications of diabetes mellitus (DM) that significantly impact the quality of life of the affected individuals. This...
Peripheral neuropathy and amputation are common complications of diabetes mellitus (DM) that significantly impact the quality of life of the affected individuals. This study aims to investigate the prevalence of peripheral neuropathy, the level of amputation, and the quality of life in patients with DM. This cross-sectional study was conducted after approval of the synopsis involving 225 diagnosed patients with DM on pre-defined eligibility criteria, selected from public sector OPDs, specialized diabetes centres, and centres manufacturing orthotics and prosthetics. Data were collected through interviews, observations, and the administration of the Michigan Neuropathy Screening Instrument and the Asian Diabetes Quality of Life Questionnaire. The level of amputation was recorded for each participant. Data was entered into SPSS, and results were synthesized. Pearson correlation is applied to find an association between gender and the quality of life of the participants, while P ≤ 0.05 will be considered significant. The prevalence of peripheral neuropathy in a sample of 225, based on a self-administered questionnaire, was (44.4%), and in terms of foot examination was (51.1%). As people progressed in age, the prevalence increased to 20.0% in patients above 60 years and 8.9% in ≤ 35 years of age. The majority of participants (56.0%) have had DM for less than five years. Females were 57.8% of the study population, while 97.8% of participants had type II DM. Below-knee amputation of the right limb was observed in 22(9.8%) of the participants. The QoL was poor in the majority of the participants (96.9%) patients with DM (P = 0.638 and T = -0.471). This cross-sectional study highlights a high prevalence of peripheral neuropathy and amputation and poor QoL in patients with diabetic mellitus.
Topics: Humans; Quality of Life; Male; Female; Middle Aged; Amputation, Surgical; Prevalence; Cross-Sectional Studies; Adult; Aged; Diabetic Neuropathies; Surveys and Questionnaires; Peripheral Nervous System Diseases; Diabetes Mellitus
PubMed: 38910161
DOI: 10.1038/s41598-024-65495-2