Genetic Variants Influence the Development of Diabetic Neuropathy.

The exact mechanism by which diabetic neuropathy develops is still not fully known, despite our advances in medical knowledge. Progressing neuropathy may occur with a persistently favorable metabolic status in some patients with diabetes mellitus, while, in others, though seldom, a persistently unfavorable metabolic status is not associated with significant neuropathy. This might be significantly due to genetic differences. While recent years have brought compelling progress in the understanding of the pathogenetic background-in particular, accelerated progress is being made in understanding molecular biological mechanisms-some aspects are still not fully understood. A comparatively small amount of information is accessible on this matter; therefore, by summarizing the available data, in this review, we aim to provide a clearer picture of the current state of knowledge, identify gaps in the previous studies, and possibly suggest directions for future studies. This could help in developing more personalized approaches to the prevention and treatment of diabetic neuropathy, while also taking into account individual genetic profiles.

Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes.

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 recQ-mediated genome instability protein 2 (RMI2) gene), rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07-0.08-fold) risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p = 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus (p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant relationship between rs91778 and cold perception threshold (p = 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.

The handgrip test - A historical test for diabetic autonomic neuropathy or a marker of something else?

Cardiovascular autonomic neuropathy (CAN) is a frequent complication of diabetes mellitus and is associated with increased morbidity and mortality in patients with diabetes. Hence, early and correct diagnosis of CAN is crucial. Standard cardiovascular reflex rests (CARTs) have been the gold standard of CAN assessment. Originally, CARTs consisted of five reflex tests, but measuring diastolic blood pressure response to sustained handgrip exercise has no longer been suggested as an established clinical test. Increasing body of evidence suggests that isometric handgrip test should no longer be used for the evaluation of sympathetic dysfunction during cardiovascular autonomic neuropathy assessment in diabetic patients. The associations of isometric handgrip test results with parameters of hypertension and markers of hypertension-related target-organ damage in diabetic and non-diabetic individuals point toward its potential role as a screening tool to identify patients with high cardiovascular risk. The current review summarizes historical view of standard cardiovascular reflex tests and latest data on isometric handgrip test.

The association between distal symmetric polyneuropathy in diabetes with all-cause mortality - a meta-analysis.

Background: Distal symmetric polyneuropathy (DSPN) is a common microvascular complication of both type 1 and 2 diabetes with substantial morbidity burden and reduced quality of life. Its association with mortality is equivocal. Purpose: To describe the association between DSPN and all-cause mortality in people with diabetes and further stratify by the type of diabetes based on a meta-analysis of published observational studies. Data Sources: We searched Medline from inception to May 2021. Study Selection: Original data were collected from case-control and cohort studies that reported on diabetes and DSPN status at baseline and all-cause mortality during follow-up. Data Extraction: was completed by diabetes specialists with clinical experience in neuropathy assessment. Data Synthesis: Data was synthesized using random-effects meta-analysis. The difference between type 1 and 2 diabetes was investigated using meta-regression. Results: A total of 31 cohorts (n=155,934 participants, median 27.4% with DSPN at baseline, all-cause mortality 12.3%) were included. Diabetes patients with DSPN had an almost twofold mortality (HR: 1.96, 95%CI: 1.68-2.27, I2 = 91.7%), I2 = 91.7%) compared to those without DSPN that was partly explained by baseline risk factors (adjusted HR: 1.60, 95%CI: 1.37-1.87, I2 = 78.86%). The association was stronger in type 1 compared to type 2 diabetes (HR: 2.22, 95%CI: 1.43-3.45). Findings were robust in sensitivity analyses without significant publication bias. Limitations: Not all papers reported multiple adjusted estimates. The definition of DSPN was heterogeneous. Conclusions: DSPN is associated with an almost twofold risk of death. If this association is causal, targeted therapy for DSPN could improve life expectancy of diabetic patients.

Vitamin D in the Prevention and Treatment of Diabetic Neuropathy.

PURPOSE: Neuropathy is one of the most important complications of diabetes. According to recent advances, vitamin D deficiency might play a role in the development and progression of diabetic neuropathy. Moreover, therapeutic vitamin D supplementation has the potential to improve this condition. The aim of the present review was to summarize new data available in this area. METHODS: The PubMed database was searched for articles written in English and published through September 2021, using combinations of the following key words: vitamin D, diabetes, diabetes mellitus, diabetic neuropathy, polyneuropathy, peripheral neuropathy, cardiac autonomic neuropathy, supplementation, and therapy. FINDINGS: A number of studies have suggested that vitamin D deficiency can play a significant role in the development of peripheral neuropathy, diabetic foot ulcers, as well as cardiovascular autonomic neuropathy in patients with type 2 diabetes. Vitamin D supplementation might serve as an effective adjuvant therapy for neuropathic pain and may slow or stop the progression of neural damage. IMPLICATIONS: Vitamin D therapy for diabetic complications could be a reliable option; however, further studies are needed to confirm this notion.

Association of Cardiovascular Autonomic Neuropathy and Distal Symmetric Polyneuropathy with All-Cause Mortality: A Retrospective Cohort Study.

BACKGROUND: People with diabetic cardiovascular autonomic neuropathy (CAN) have increased cardiovascular mortality. However, the association between distal symmetric polyneuropathy (DSPN) or CAN with all-cause mortality is much less investigated. Thus, we set out to examine the effect of CAN and DSPN on all-cause mortality in a well-phenotyped cohort. METHODS: All diabetes cases (n = 1,347) from the catchment area of a secondary diabetes care centre who had medical examination including neuropathy assessment between 1997 and 2016 were followed up for all-cause mortality in the NHS Hungary reimbursement database until 2018. We investigated the association of CAN (Ewing tests) and DSPN (Neurometer) with all-cause mortality using Cox models stratified by diabetes type. RESULTS: Altogether, n = 131/1,011 persons with type 1/type 2 diabetes were included. Of the participants, 53%/43% were male, mean age was 46 ± 12/64 ± 10 years, diabetes duration was 13 ± 10/7 ± 8 years, 42%/29% had CAN, and 39%/37% had DSPN. During the 9 ± 5/8 ± 5-year follow-up, n = 28/494 participants died. In fully adjusted models, participants with type 1 diabetes patients with versus without DSPN had an increased mortality (HR 2.99, 95% CI 1.4-8.63), while no association with CAN was observed. In type 2 diabetes, both DSPN and CAN independently increased mortality (HR 1.32, 95% CI: 1.07-1.64, and HR 1.44, 95% CI: 1.17-1.76). CONCLUSIONS: Our results are compatible with an increased risk of mortality in people with type 1 diabetes and DSPN. Furthermore, we report a similarly strong association between DSPN and CAN and all-cause mortality in type 2 diabetes mellitus.

Comparison of clinical characteristics of patients with pandemic SARS-CoV-2-related and community-acquired pneumonias in Hungary - a pilot historical case-control study.

The distinction between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related and community-acquired pneumonias poses significant difficulties, as both frequently involve the elderly. This study aimed to predict the risk of SARS-CoV-2-related pneumonia based on clinical characteristics at hospital presentation. Case-control study of all patients admitted for pneumonia at Semmelweis University Emergency Department. Cases (n = 30) were patients diagnosed with SARS-CoV-2-related pneumonia (based on polymerase chain reaction test) between 26 March 2020 and 30 April 2020; controls (n = 82) were historical pneumonia cases between 1 January 2019 and 30 April 2019. Logistic models were built with SARS-CoV-2 infection as outcome using clinical characteristics at presentation. Patients with SARS-CoV-2-related pneumonia were younger (mean difference, 95% CI: 9.3, 3.2-15.5 years) and had a higher lymphocyte count, lower C-reactive protein, presented more frequently with bilateral infiltrate, less frequently with abdominal pain, diarrhoea, and nausea in age- and sex-adjusted models. A logistic model using age, sex, abdominal pain, C-reactive protein, and the presence of bilateral infiltrate as predictors had an excellent discrimination (AUC 0.88, 95% CI: 0.81-0.96) and calibration (p = 0.27-Hosmer-Lemeshow test). The clinical use of our screening prediction model could improve the discrimination of SARS-CoV-2 related from other community-acquired pneumonias and thus help patient triage based on commonly used diagnostic approaches. However, external validation in independent datasets is required before its clinical use.

Diabetic Cardiovascular Autonomic Neuropathy, the Handgrip Test and Ambulatory Blood Pressure Monitoring Parameters: Are There Any Diagnostic Implications?

Cardiovascular autonomic neuropathy (CAN) is a common complication of diabetes mellitus. Cardiovascular reflex tests (CARTs) are the gold standard in the diagnosis of CAN, but the handgrip test is no longer recommended to be performed. Previously, the inverse association between the presence of hypertension and handgrip test abnormality was demonstrated and hypertension as major cause for excessive diastolic blood pressure rise during handgrip testing in diabetic individuals proposed. The aim of the present study is to describe more precisely the association between handgrip test and hypertension by performing ambulatory blood pressure monitoring (ABPM) among diabetic patients. A more comprehensive evaluation of the relationship between cardiovascular autonomic function, hypertension and the handgrip test was targeted using heart rate variability (HRV) analysis. Our study involved 163 patients with diabetes. Cardiovascular autonomic neuropathy was assessed by the CARTs and sustained handgrip test was performed. All patients underwent ABPM and HRV analysis well. CAN was diagnosed in 69 patients. Significant associations were found between the diastolic blood pressure increase in response to handgrip exercise and the 24-h (rho = 0.245, p = 0.003), daytime (rho = 0.230, p = 0.005) and night-time (rho = 0.230, p = 0.006) mean systolic and 24-h diastolic (rho = 0.176, p = 0.034) blood pressure values, systolic blood pressure load (rho = 0.252, p = 0.003) and systolic (rho = 0.236, p = 0.005) and diastolic (rho = 0.165, p = 0.047) hyperbaric impacts. Higher values of ambulatory blood pressure monitoring parameters are associated with greater increases in diastolic blood pressure during isometric handgrip exercise. Diastolic blood pressure elevations during the handgrip test are also correlated, in order to diminished heart rate variability parameters attributable to parasympathetic dysfunction highlighting the pivotal role of sympathetic overactivity in evolving handgrip test results. Our study provides further evidence on the inverse association between handgrip test abnormality and hypertension in diabetic patients.

Cardiovascular Autonomic Neuropathy and Glucose Variability in Patients With Type 1 Diabetes: Is There an Association?

INTRODUCTION: The oxidative stress associated with glucose variability might be responsible for neuronal damage while autonomic neuropathy (AN) has a detrimental effect on metabolism. The aim of the study was to find relationship between AN and GV in type 1 diabetic patients and to identify further factors that affect GV. PATIENTS AND METHODS: Twenty type 1 diabetic patients were involved (age: 39.5 ± 3.4 years, duration of diabetes: 17.5 ± 2.5 years; HbA1c: 8.1 ± 0.2%, mean ± SE). AN was assessed by the cardiovascular reflex tests. The interstitial glucose levels were determined following insertion of a subcutaneous electrode during the continuous glucose monitoring (CGM) method on six consecutive days. GV was characterized by calculation of four parameters. RESULTS: SD of interstitial glucose values correlated positively with the overall AN score and the degree of the orthostatic reduction of systolic blood pressure (AN-score-SD ρ = 0.47, p < 0.05; orthostasis-SD: ρ = 0.51, p < 0.05). Mean absolute glucose (MAG) correlated with three parameters of AN (AN-score-MAG: ρ = 0.62, p < 0.01; 30/15 ratio-MAG: ρ = -0.50, p < 0.05; orthostasis-MAG: ρ = 0.59, p < 0.01). The HbA1c also correlated with two parameters of GV (HbA1c-continuous overlapping net glycemic action: ρ = 0.56, p < 0.05; HbA1c-MAG: ρ = 0.45, p < 0.05). The frequency of hypoglycemia did not exhibit any correlation with measures of GV. CONCLUSION: Severity of glucose variability but not overall glucose load correlates with both parasympathetic and sympathetic dysfunctions in type 1 diabetes. Higher HbA1c is associated with more severe glucose variability. The observed correlation between increased glucose variability and the severity of AN necessitates the further exploration of this relationship.

Why Not to Use the Handgrip Test in the Assessment of Cardiovascular Autonomic Neuropathy Among Patients with Diabetes Mellitus?

OBJECTIVE: Historically, a set of 5 Cardiovascular Autonomic Reflex Tests (CARTs) were considered to be the gold standard in the assessment of Cardiovascular Autonomic Neuropathy (CAN). However, measuring diastolic Blood Pressure (BP) response to sustained handgrip is omitted in recent guidelines. We aimed to assess the association between the handgrip and the other 4 tests as well as to identify determinants of the handgrip test results in diabetic patients. PATIENTS AND METHODS: 353 patients with diabetes (DM) were recruited (age: 60.2±7.4 years; female: 57.2%; BMI: 29.3±2.1 kg/m2; DM duration: 15.6±9.9 years; HbA1c: 7.8±1.4% (66 mmol/mol); with type 1 DM: 18.1%). CAN was assessed by 5 CARTs: the deep breathing test, Valsalva ratio, 30/15 ratio, handgrip and orthostatic hypotension test. RESULTS: Sensitivity and specificity of the handgrip test in the diagnosis of definite CAN were 24.6% (95%CI 17.7-33.1%) and 79.4% (95%CI 73.3-84.4%), respectively. Results of the handgrip test did not show any association with those of the deep-breathing test (y=0.004, p=0.563), 30/15 ratio (y=0.282, p=0.357), Valsalva ratio (y=-0.058, p=0.436) and orthostatic hypotension (y=-0.026, p=0.833). Handgrip test abnormality showed an independent association with higher initial diastolic BP (OR 1.05, p=0.0009) and an independent inverse association with the presence of hypertension (OR=0.42, p=0.006). CONCLUSION: Our data confirm that the handgrip test should no longer be part of the cardiovascular autonomic testing being highly dependent on hypertensive status and baseline diastolic BP. Exaggerated exercise pressor response is proposed as putative mechanism for the inverse association between abnormal results of the handgrip test and hypertension. Adequate CARTs are important to allow their use in clinical trials and for the prevention of DM-associated complications by initiating early treatment.

Is there an association between diabetic neuropathy and low vitamin D levels?

In the past few years, the effects of vitamin D that go beyond its relationship with bone metabolism have come into the focus of scientific attention. Research concerning diabetes and its complications has become a public health priority. An increasing number of reports link vitamin D deficiency to diabetes; however, so far, there has only been limited and contradictory data available on the correlation between diabetic peripheral neuropathy and vitamin D. Studies of people with type 2 diabetes confirmed the relationship between vitamin D deficiency and neuropathy incidence as well as the severity of the symptoms caused by neuropathy. The latest studies are also suggesting a relationship between the incidence of plantar ulcers and vitamin D deficiency.

Heart rate variability is severely impaired among type 2 diabetic patients with hypertension.

INTRODUCTION: The aim of our study was to evaluate the relative effect of diabetes and hypertension on heart rate variability. RESEARCH DESIGN AND METHODS: Four age-matched groups including type 2 diabetic patients with and without hypertension, non-diabetic patients with essential hypertension and healthy control subjects were studied. Autonomic function was evaluated by the standard cardiovascular reflex tests and 24-hour heart rate variability measurement. Heart rate variability was characterized by the triangular index value and by the spectral components of the frequency domain analysis. RESULTS: According to the two-way analysis of variance on ranks, all parameters were influenced negatively by diabetes (heart rate variability triangular index: p < 0.001; low-frequency component: p < 0.0001; high-frequency component: p < 0.001; and total power: p < 0.0001), whereas hypertension had a negative effect only on the low-frequency component (p < 0.05). The interaction between hypertension and diabetes was not significant, indicating that their effects on the heart rate variability parameters are additive. Beat-to-beat variation upon deep breathing, the most sensitive cardiovascular reflex test was also negatively influenced by both diabetes (p < 0.001) and hypertension, (p < 0.05), and their effects were additive. CONCLUSIONS: Diabetes appears to have a greater effect on autonomic dysfunction compared with hypertension. Patients suffering from both diabetes and hypertension are at the highest risk of reduced heart rate variability. Early assessment of the autonomic nerve function is suggested in diabetic patients with hypertension.

[Vitamin D and neuropathy]. / D-vitamin és neuropathia.

Diabetes is a widespread disease and, therefore, studies dealing with diabetes and its complications are very important for public health. Numerous reports link vitamin D deficiency to the increased risk of diabetes mellitus and complications such as neuropathy. However, there are limited and conflicting data available on vitamin D deficiency in patients with diabetic peripheral neuropathy. Studies in type 2 diabetics confirmed the relationship between vitamin D deficiency and incidence of neuropathy. Recent reports suggest a relationship between the incidence of plantar ulcers and vitamin D deficiency.