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International Journal of Molecular... Feb 2024Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of...
Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22-49-fold) risk of neuropathy (rs2032930 and rs2032931 of (, rs604349 of ( and with reduced (0.07-0.08-fold) risk (rs917778 of and rs2234753 of (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus ( = 0.042 and = 0.003, respectively) and at 5 Hz for n. peroneus ( = 0.037), as well as the deep breath test ( = 0.022) and the NTSS ( = 0.023). The rs2032931 was associated with current perception thresholds ( = 0.003 and = 0.037, respectively), deep breath test ( = 0.022), and NTSS ( = 0.023). The rs604349 correlated with values measured at 2000 ( = 0.049), 250 ( = 0.018), and 5 Hz ( = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device ( = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus ( = 0.020), deep breath test ( = 0.040), and NTSS ( = 0.003). There was a significant relationship between rs91778 and cold perception threshold ( = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.
Topics: Humans; Diabetes Mellitus, Type 2; Sensory Thresholds; Diabetic Neuropathies; Autonomic Nervous System; Sensation
PubMed: 38339094
DOI: 10.3390/ijms25031815 -
Scientific Reports Jan 2024Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires...
Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.
Topics: Humans; Female; Retrospective Studies; Cross-Sectional Studies; Surveys and Questionnaires; Postural Orthostatic Tachycardia Syndrome; Penicillanic Acid
PubMed: 38291116
DOI: 10.1038/s41598-024-52368-x -
Annual Review of Medicine Jan 2024Diabetic neuropathy is a highly prevalent complication of diabetes. It consists of a broad range of neuropathic conditions, such as distal symmetric polyneuropathy and... (Review)
Review
Diabetic neuropathy is a highly prevalent complication of diabetes. It consists of a broad range of neuropathic conditions, such as distal symmetric polyneuropathy and various forms of autonomic neuropathies involving the cardiovascular, gastrointestinal, and urogenital systems. Prevention or diagnosis in early stages of disease is crucial to prevent symptomatic onset and progression, particularly in the absence of current disease-modifying therapies. In this review, we describe the four main types of diabetic neuropathy. We review current understanding with respect to diagnosis and treatment while highlighting knowledge gaps and future directions.
Topics: Humans; Diabetic Neuropathies; Diabetes Mellitus
PubMed: 38285516
DOI: 10.1146/annurev-med-043021-033114 -
Cureus Dec 2023Charcot Neuroarthropathy (CN) is a complex and incapacitating disorder characterized by neuropathy, progressive deformity, and joint destruction. It is of substantial... (Review)
Review
Charcot Neuroarthropathy (CN) is a complex and incapacitating disorder characterized by neuropathy, progressive deformity, and joint destruction. It is of substantial interest within the diabetic population as this ailment chiefly affects individuals with diabetes. The pathophysiology of CN is multidimensional, connecting peripheral neuropathy, repetitive trauma, and autonomic dysfunction. The review analyses the mechanisms directing the development of CN, emphasizing the influence of diabetes in individuals who lean toward this condition. Clinical presentation and diagnosis of CN in diabetic patients present unique challenges. Complex clinical features have also been discussed, including joint deformities, insidious onset, and painless swelling, which mimic other musculoskeletal conditions. The diagnostic approaches, involving clinical examination and radiological imaging, are analyzed for early and accurate diagnosis. Risk factors and epidemiology emphasize the prevalence of CN within the diabetic population and draw attention to common risk factors contributing to its development. Significant factors such as glycemic control, duration of the disease, and type of diabetes are important in estimating an individual's risk for CN. Complications, such as foot ulcers and amputations, provide an understanding of the severe outcome of this condition on patients' quality of life. Management approaches and treatment involving conservative and surgical approaches are reviewed in depth. A multidisciplinary approach to patient care is emphasized, given the complex nature of CN and the comorbidities existing in diabetic individuals. Prognosis and prevention comprise approaches for mitigating the risk of CN in diabetic patients, such as glycemic control, regular foot examinations, and patient education. This thorough review aims to outline the intricate relationship between CN and diabetes, offering an understanding of pathophysiology, clinical complexities, diagnostic nuances, treatment modalities, and prevention strategies.
PubMed: 38259415
DOI: 10.7759/cureus.50988 -
International Journal of Molecular... Jan 2024Major depressive disorder (MDD) is a common complication of diabetes and is often observed alongside diabetic neuropathic pain (DNP) as a comorbidity in diabetic...
Major depressive disorder (MDD) is a common complication of diabetes and is often observed alongside diabetic neuropathic pain (DNP) as a comorbidity in diabetic patients. Long non-coding RNA (lncRNA) plays an important role in various pathophysiological processes. The P2X7 receptor is responsible for triggering inflammatory responses, such as pyroptosis, linked to pain and depression. The aim of this study was to investigate the effect of lncRNA MSTRG.81401 on hippocampal pyroptosis induced by the P2X7 receptor in diabetic rats with DNP combined with MDD (DNP + MDD). Our results showed that the expression of lncRNA MSTRG.81401 was significantly elevated in the hippocampus of DNP + MDD rats compared with the control group. Following the administration of shRNA targeting lncRNA MSTRG.81401, a notable elevation in mechanical and thermal pain thresholds was observed in rats with comorbid DNP and MDD. Additionally, significant improvements in depression-like behaviors were evident in the open-field test (OFT), sucrose preference test (SPT), and forced swim test (FST). In the DNP + MDD rats, elevated levels in hippocampal P2X7 receptor mRNA and protein were observed, along with increased co-expression of P2X7 and the astrocytic marker glial fibrillary acidic protein (GFAP). Meanwhile, in DNP + MDD rats, the heightened mRNA expression of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), pyroptosis-related protein Gasdermin D (GSDMD), caspase-1, IL-1β, IL-18, and TNF-α was detected, in addition to increased serum levels of IL-1β, IL-18 and TNF-α. After shRNA treatment with lncRNA MSTRG.81401, the above abnormal changes in indicators for pyroptosis and inflammation were improved. Therefore, our study demonstrates that shRNA of lncRNA MSTRG.81401 can alleviate the pain and depression-like behaviors in diabetic rats associated with the comorbidity of DNP and MDD by inhibiting the hippocampal P2X7 receptor-mediated pyroptosis pathway and pro-inflammatory responses. This suggests that the P2X7R/NLRP3/caspase-1 implicated pyroptosis and inflammatory scenario may serve as a potential target for the management of comorbid DNP and MDD in diabetes.
Topics: Humans; Animals; Rats; RNA, Long Noncoding; Interleukin-18; Receptors, Purinergic P2X7; Depressive Disorder, Major; Pyroptosis; Depression; Diabetes Mellitus, Experimental; NLR Family, Pyrin Domain-Containing 3 Protein; Tumor Necrosis Factor-alpha; Neuralgia; Diabetic Neuropathies; Caspases; Hippocampus; RNA, Messenger; RNA, Small Interfering; Diabetes Mellitus, Type 2
PubMed: 38256257
DOI: 10.3390/ijms25021186 -
Healthcare (Basel, Switzerland) Jan 2024Type 2 diabetes mellitus (T2DM) is characterized by several complications, such as retinopathy, renal failure, cardiovascular disease, and diabetic neuropathy. Among...
Type 2 diabetes mellitus (T2DM) is characterized by several complications, such as retinopathy, renal failure, cardiovascular disease, and diabetic neuropathy. Among these, neuropathy is the most severe complication, due to the challenging nature of its early detection. The linear Hearth Rate Variability (HRV) analysis is the most common diagnosis technique for diabetic neuropathy, and it is characterized by the determination of the sympathetic-parasympathetic balance on the peripheral nerves through a linear analysis of the tachogram obtained using photoplethysmography. We aimed to perform a multifractal analysis to identify autonomic neuropathy, which was not yet manifest and not detectable with the linear HRV analysis. We enrolled 10 healthy controls, 10 T2DM-diagnosed patients with not-full-blown neuropathy, and 10 T2DM diagnosed patients with full-blown neuropathy. The tachograms for the HRV analysis were obtained using finger photoplethysmography and a linear and/or multifractal analysis was performed. Our preliminary results showed that the linear analysis could effectively differentiate between healthy patients and T2DM patients with full-blown neuropathy; nevertheless, no differences were revealed comparing the full-blown to not-full-blown neuropathic diabetic patients. Conversely, the multifractal HRV analysis was effective for discriminating between full-blown and not-full-blown neuropathic T2DM patients. The multifractal analysis can represent a powerful strategy to determine neuropathic onset, even without clinical diagnostic evidence.
PubMed: 38255121
DOI: 10.3390/healthcare12020234 -
Diabetes Research and Clinical Practice Dec 2023The diabetic neuropathies represent the commonest long-term complications of diabetes, and may be the presenting feature of Type 2 diabetes. In clinical practice, distal... (Review)
Review
The diabetic neuropathies represent the commonest long-term complications of diabetes, and may be the presenting feature of Type 2 diabetes. In clinical practice, distal symmetrical polyneuropathy (DSPN) and the autonomic neuropathies are the most frequently seen forms of diabetic neuropathy. The 2017 American Diabetes Association classification system for the neuropathies of diabetes are in general use. Treatment challenges remain and the need for revised recommendations and further discussion of management of severely painful DSPN that does not fully respond to conventional medical management is clear, especially in light of the recent opioid crisis in the USA.
Topics: Humans; Autonomic Nervous System; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Pain; Polyneuropathies
PubMed: 38245328
DOI: 10.1016/j.diabres.2023.110758 -
Diabetes Research and Clinical Practice Dec 2023This article summarizes the latest epidemiology of diabetic autonomic neuropathy (DAN), and provides a brief overview on epidemiology, current outcomes measures for... (Review)
Review
This article summarizes the latest epidemiology of diabetic autonomic neuropathy (DAN), and provides a brief overview on epidemiology, current outcomes measures for screening and diagnosis in research and clinical settings, the latest evidence on effective management, and novel perspectives on the impacts of social determinants of health in development and management of DAN. Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy, are by far the most studied. However, emerging data highlight the impact of other forms of autonomic neuropathies such as gastrointestinal and urogenital autonomic neuropathies, on healthcare and patients' reported outcomes [1].
Topics: Humans; Diabetic Neuropathies
PubMed: 38245325
DOI: 10.1016/j.diabres.2023.110762 -
Medicine Jan 2024Hereditary sensory and autonomic neuropathy type IV (HSAN IV) may be misdiagnosed because of low awareness among clinical professionals and overlap with other subtypes...
RATIONALE
Hereditary sensory and autonomic neuropathy type IV (HSAN IV) may be misdiagnosed because of low awareness among clinical professionals and overlap with other subtypes of congenital insensitivity to pain (CIP).
PATIENT
The patient was a 1-year-and-5-months-old boy whose main symptoms were delayed psychomotor development and recurrent fever. Whole-exome sequencing (WES) revealed a compound heterozygous mutation (c. 1927C > T, c. 851-33T > A) in the NTRK1 gene of the child. Pathological analysis showed decreased autonomic small nerve fibers, sparse hair follicles, and atrophy of the sweat glands. Sweat glands lack innervating nerve fibers. Brain magnetic resonance imaging (MRI) of the patient showed delayed myelination in the brain, slightly enlarged bilateral lateral ventricles, and patchy abnormal signals in the brain.
DIAGNOSIS
hereditary sensory and autonomic neuropathy type IV (HSAN IV).
INTERVENTION
Inform parents about the illness and take good care of the child.
OUTCOMES
The children had less self-harming behavior and no painless fractures during follow-up at 2 years.
LESSONS
This report describes the pathological and imaging features and clinical manifestations of a child with HSAN IV in early life to provide a reference for the early diagnosis of the disease. Early diagnosis can help avoid self-mutilation and painless injury and reduce wound infection.
Topics: Male; Humans; Child, Preschool; Infant; Hereditary Sensory and Autonomic Neuropathies; Pain Insensitivity, Congenital; Phenotype; Self-Injurious Behavior; Mutation
PubMed: 38241559
DOI: 10.1097/MD.0000000000036955