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Diabetic Medicine : a Journal of the... Jun 2024AIMSWERNER SYNDROME IS A RARE PREMATURE AGEING AUTOSOMAL RECESSIVE DISORDER CAUSED BY PATHOGENIC VARIANTS IN THE WRN GENE. PEOPLE WITH WERNER SYNDROME MAY DEVELOP... (Review)
Review
UNLABELLED
AIMSWERNER SYNDROME IS A RARE PREMATURE AGEING AUTOSOMAL RECESSIVE DISORDER CAUSED BY PATHOGENIC VARIANTS IN THE WRN GENE. PEOPLE WITH WERNER SYNDROME MAY DEVELOP DIABETES MELLITUS. CHRONIC FOOT ULCERATION IS SEEN, WITH SOME CHARACTERISTICS OVERLAPPING WITH DIABETIC FOOT DISEASE. HOWEVER, THE CLINICAL COURSE OF THE ULCERATION IS ATYPICAL OF DIABETIC FOOT DISEASE. WE PRESENT FOUR SIBLINGS FROM AN IRISH TRAVELLER FAMILY WITH WERNER SYNDROME TO HIGHLIGHT THE COMPLEXITY OF THIS CONDITION. THE IRISH TRAVELLER POPULATION ARE AN INDIGENOUS, ENDOGAMOUS POPULATION IN WHICH CONSANGUINITY IS COMMON. AS A RESULT, RARE AUTOSOMAL RECESSIVE DISORDERS ARE PREVALENT AMONG THIS POPULATION: .
METHODS
We describe our experience managing the complex foot disease seen in all four siblings. Foot complications present in the siblings include painful peripheral neuropathy, chronic foor ulceration, underlying osteomyelitis and acral melanoma.
RESULTS
The cases are described individually, with a particular focus on the complex foot disease associated with the condition.
CONCLUSIONS
Although the siblings attend a diabetic foot clinic, we suggest that the combination of clinical features seen in these cases is unique to Werner syndrome and warrants the title 'Werner Syndrome' (rather than 'Diabetic') foot.
PubMed: 38924167
DOI: 10.1111/dme.15390 -
IEEE Transactions on Neural Systems and... Jun 2024The early diagnosis of diabetic neuropathy (DN) is fundamental in order to enact timely therapeutic strategies for limiting disease progression. In this work, we...
The early diagnosis of diabetic neuropathy (DN) is fundamental in order to enact timely therapeutic strategies for limiting disease progression. In this work, we explored the suitability of standing balance task for identifying the presence of DN. Further, we proposed two diagnosis pathways in order to succeed in distinguishing between different stages of the disease. We considered a cohort of non-neuropathic (NN), asymptomatic neuropathic (AN), and symptomatic neuropathic (SN) diabetic patients. From the center of pressure (COP), a series of features belonging to different description domains were extracted. In order to exploit the whole information retrievable from COP, a majority voting ensemble was applied to the output of classifiers trained separately on different COP components. The ensemble of kNN classifiers provided over 86% accuracy for the first diagnosis pathway, made by a 3-class classification task for distinguishing between NN, AN, and SN patients. The second pathway offered higher performances, with over 97% accuracy in identifying patients with symptomatic and asymptomatic neuropathy. Notably, in the last case, no asymptomatic patient went undetected. This work showed that properly leveraging all the information that can be mined from COP trajectory recorded during standing balance is effective for achieving reliable DN identification. This work is a step toward a clinical tool for neuropathy diagnosis, also in the early stages of the disease.
PubMed: 38923488
DOI: 10.1109/TNSRE.2024.3419235 -
Journal of Diabetes Investigation Jun 2024To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin-like growth factor-1 (IGF-1) and DPN in individuals...
AIMS/INTRODUCTION
To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin-like growth factor-1 (IGF-1) and DPN in individuals with type 2 diabetes.
MATERIALS AND METHODS
A total of 790 patients with type 2 diabetes participated in a cross-sectional study, divided into two groups: those with DPN (DPN) and those without DPN (non-DPN). Blood samples were taken to measure IGF-1 levels and other biochemical markers. Participants underwent nerve conduction studies and quantitative sensory testing.
RESULTS
Patients with DPN exhibited significantly lower levels of IGF-1 compared with non-DPN patients (P < 0.001). IGF-1 was positively correlated with the average amplitude of both motor (P < 0.05) and sensory nerves (P < 0.05), but negatively correlated with the vibration perception threshold (P < 0.05). No significant difference was observed between IGF-1 and nerve conduction velocity (P > 0.05), or the temperature detection threshold (P > 0.05). Multivariate regression analysis identified diabetes duration, HbA, and the low levels of IGF-1 as independent risk factors (P < 0.001). Receiver operating characteristic analysis determined that at 8 years duration of diabetes, 8.5% (69.4 mmol/mol) HbA and 120 ng/mL IGF-1, the optimal cut-off points, indicated DPN (P < 0.001).
CONCLUSIONS
A reduction of IGF-1 in patients with DPN suggests a potential protective role against axon injury in large fiber nerves of type 2 diabetes patients.
PubMed: 38923403
DOI: 10.1111/jdi.14260 -
Healthcare (Basel, Switzerland) Jun 2024Diabetic autonomic neuropathy is a common complication of type 2 diabetes mellitus (T2DM), especially in patients with long-term, poorly controlled diabetes. This study... (Review)
Review
BACKGROUND
Diabetic autonomic neuropathy is a common complication of type 2 diabetes mellitus (T2DM), especially in patients with long-term, poorly controlled diabetes. This study investigates the effects of exercise on autonomic nervous system activity in T2DM patients over time.
METHODS
A literature review using MEDLINE, Embase, Cochrane Library, Scopus, and PubMed identified studies assessed via heart rate variability. Papers were categorized into three groups: immediate effects (within 60 min), short-term effects (2-3 months), and long-term effects (over 4 months).
RESULTS
Nine articles with 161 T2DM patients were included in the meta-analysis. RMSSD changes after exercise were -4.3 ( = 0.227), 8.14 ( < 0.001), and 4.17 ( = 0.002) for the immediate, short-term, and long-term groups, respectively. LF/HF ratio changes were 0.21 ( = 0.264), -3.04 ( = 0.102), and -0.05 ( = 0.006) for the respective groups. Meta-regression indicated age, male gender, and exercise duration were associated with increased RMSSD, with coefficients of 2.36 ( = 0.001), 13.76 ( = 0.008), and 1.50 ( = 0.007), respectively. Age positively correlated with the LF/HF ratio, with a coefficient of 0.049 ( = 0.048).
CONCLUSIONS
Regular exercise (≥3 times per week) for over 2 months increases parasympathetic activity in T2DM patients, while sympathetic activity decreases significantly after 4 months. Further study is needed to validate these findings.
PubMed: 38921350
DOI: 10.3390/healthcare12121236 -
Journal of Diabetes Research 2024Spexin 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...
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. 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. 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-, IL-6, and MCP-1 in human PBMCs, while spexin treatment prevented this increase. These results suggested that spexin might serve as a protective factor for diabetes against neuropathology and pain-related pathogenesis.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Animals; Male; Middle Aged; Female; Diabetes Mellitus, Experimental; Mice; Aged; Peptide Hormones; Leukocytes, Mononuclear; Pain Threshold; China; Mice, Inbred C57BL
PubMed: 38919263
DOI: 10.1155/2024/4538199 -
Current Diabetes Reviews Jun 2024The term "Diabetic neuropathy" refers to a collection of clinical and subclinical symptoms caused by problems with the peripheral nervous system. Diabetes, which affects...
The term "Diabetic neuropathy" refers to a collection of clinical and subclinical symptoms caused by problems with the peripheral nervous system. Diabetes, which affects approximately 381 million people worldwide, is the source of dysfunction due to the emergence of microvascular complications. It is anticipated that in the next ten years, Diabetic neuropathy will manifest in about 50% of patients who are currently diagnosed with diabetes. Clinical diagnosis can be established by getting a thorough patient history and exploring the symptoms to rule out alternative causes. Although distal symmetrical polyneuropathy, or just, is the most common and well-researched variant of the disorder, this review will concentrate on it. The multifactorial pathogenesis is linked to various inflammatory, vascular, metabolic, and neurodegenerative illnesses. The three fundamental molecular alterations that lead to the development of diabetic neuropathic pain are oxidative stress, endothelial dysfunction, and chronic inflammation. These three elements are crucial in the development of polyneuropathy because their combination might result in direct axonal damage and nerve ischemia. The purpose of this article was to provide a narrative review of diabetic neuropathy. We provide an overview of the most recent data on biomarkers, the pathogenesis of the illness, the most recent epidemiology of diabetic neuropathy, and the existing screening and diagnosis outcome measures used in both clinical and research contexts.
PubMed: 38919000
DOI: 10.2174/0115733998295741240606104106 -
Current Molecular Medicine Jun 2024Targeting genes using siRNA shows promise as an approach to alleviate symptoms of diabetic neuropathy. It focuses on neuropathies and distal symmetric polyneuropathy...
Targeting genes using siRNA shows promise as an approach to alleviate symptoms of diabetic neuropathy. It focuses on neuropathies and distal symmetric polyneuropathy (DSPN) to explore the potential use of small interfering RNA (siRNA) as a treatment for diabetic neuropathy. Timely identification and management of neuropathy play a critical role in mitigating potential complications. RNAi success depends on understanding factors affecting small interfering RNA (siRNA) functionality and specificity. These include sequence space restrictions, structural and sequence features, mechanisms for nonspecific gene modulation, and chemical modifications. Addressing these factors enhances siRNA performance for efficient gene silencing and confidence in RNAi-mediated genomic studies. Diabetic retinopathy, particularly in South Asian, African, Latin American, and indigenous populations, is a significant concern due to its association with diabetes. Ethnicity plays a crucial role in its development and progression. Despite declining rates in the US, global trends remain concerning, and further research is needed to understand regional differences and reinforce ethnicity-based screening and treatment protocols. In this regard, siRNA emerges as a valuable instrument for early intervention strategies. While presenting promising therapeutic applications, siRNA utilization encounters challenges within insect pest control contexts, thereby providing insights into enhancing its delivery mechanisms for neuropathy treatment purposes. Recent advancements in delivery modalities, such as nanoparticles, allow for the controlled release of siRNA. More investigation is necessary to grasp the safety and efficacy of siRNA technology fully. It holds promise in transforming the treatment of diabetic neuropathy by honing in on particular genes and tackling issues such as inflammation and oxidative stress. Continuous advancements in delivery techniques have the potential to enhance patient results significantly. SiRNA targets genes in diabetic neuropathy, curbing nerve damage and pain and potentially preventing or delaying the condition. Customized treatments based on genetic variations hold promise for symptom management and enhancing quality of life.
PubMed: 38918983
DOI: 10.2174/0115665240307413240531111140 -
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