Treatment-induced neuropathy of diabetes complicated by orthostatic hypotension

Background: The incidence of peripheral neuropathy among chronic diabetic patients is escalating, with a notable rise observed in Pakistan. This trend has been partly attributed to the predominant reliance on pharmacotherapy, while the role of physical exercise in management remains underutilized. Aerobic exercise is widely recommended in clinical guidelines for the treatment and prevention of diabetic complications, and it is hypothesized that the addition of strength training could yield even more benefits. Objective: This study aimed to evaluate the effects of combined aerobic and strength training exercises on neuropathic symptoms in patients with diabetic peripheral neuropathy. Methods: In this randomized clinical trial, 40 patients with diabetic peripheral neuropathy were equally divided into two groups: Group A underwent a combined regimen of aerobic and strength training exercises, whereas Group B engaged in aerobic exercises alone. The effectiveness of these interventions was assessed using the Michigan Neuropathy Screening Instrument (MNSI), Numeric Pain Rating Scale (NPRS), and Clinical Global Impression of Change (CGIC). Data were analyzed using SPSS version 20.0, employing independent t-tests, repeated measures ANOVA, and descriptive statistics for in-depth analysis. Results: Group A demonstrated a significant reduction in MNSI scores with a mean difference of 1.700 and a p-value < 0.001, indicating a substantial improvement in neuropathic symptoms compared to Group B. While both groups showed significant improvements in NPRS and CGIC scores, the differences were not statistically significant, with p-values of 0.599 and 0.330, respectively, and mean differences of 0.1500 and 0.2500 for NPRS and CGIC. The overall statistical analysis revealed a high significance level (p < 0.001) within both groups in all measured outcomes, suggesting considerable improvements post-intervention. Conclusion: The addition of strength training to aerobic exercises significantly enhances the reduction of neuropathic symptoms in diabetic patients. However, for pain relief and overall clinical improvement, both treatment approaches—combined aerobic and strength training or aerobic exercise alone—were equally effective.

Current trends in evaluating and diagnosing syncope due to orthostatic hypotension: A case report

The World Health Organisation estimated that in the year 2000, 150 million people had diabetes mellitus, and it is predicted that this number will rise to 366 million by the year 2030.[1][1] Neuropathy is a common complication of diabetes and is characterised by a progressive loss of peripheral

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM), significantly affecting patients' quality of life and imposing a substantial economic burden. Recent studies have highlighted the role of thyroid hormones in diabetes complications, particularly in elderly patients with T2DM. However, the relationship between thyroid hormone sensitivity and DPN remains unclear. To investigate the correlation between thyroid hormone sensitivity and DPN in elderly patients with T2DM. In a cohort of 256 elderly patients with T2DM, propensity score matching was used to balance age, sex, and diabetes duration. Clinical data were collected to calculate thyroid hormone sensitivity and analyze its correlation with DPN. A random forest model was used to evaluate the diagnostic value of free triiodothyronine/free thyroxine (FT3/FT4) for DPN. Patients with DPN had a lower FT3/FT4 ratio [ (0.302 ± 0.053) vs (0.316 ± 0.049), P = 0.040]. Quartile stratification showed decreasing DPN prevalence with higher FT3/FT4 ratios. Spearman's correlation analysis showed that a lower FT3/FT4 ratio was associated with higher glycated hemoglobin, fasting blood glucose, reduced nerve conduction velocity, and electrical skin conductance. Logistic regression indicated a positive relationship between the median FT3/FT4 ratio and bilateral foot electrochemical skin conductance [odds ratio (OR): 1.019; 95%CI: 1.005-1.034; P = 0.007] and sural nerve sensory amplitude (OR: 1.310; 95%CI: 1.008-1.703; P = 0.043). Receiver operating characteristic analysis using a random forest model showed that incorporating FT3/FT4 improved predictive performance for DPN, with an area under the curve of 0.74, sensitivity of 0.79, specificity of 0.64, and accuracy of 0.77. In elderly patients with T2DM with euthyroidism, a lower FT3/FT4 ratio is correlated with increased DPN incidence, affecting both large and small nerve fibers. FT3/FT4 is an effective predictor of DPN.

Background & objective: Diabetes mellitus is quite common and globally prevalent condition affecting patients’ quality of life. Patients who have type 2 diabetes mellitus (T2DM), are more likely to get diabetic peripheral neuropathy (DPN), which may affect feet, legs, hand, and arm. A BDNF gene rs6265 polymorphism in humans results in the substitution of valine with methionine at codon 66 (Val66Met). We aimed to find the possible link between human BDNF rs6265 gene polymorphism and T2DM with and without peripheral neuropathy and compare it with healthy subjects in Kirkuk City, Iraq. Methodology: One hundred subjects were chosen to participate in this research, aged from 35 to 75 y and divided into three groups: 35 DPN, 35 T2DM patients, and 30 healthy controls were selected randomly for BDNF gene rs6265 SNP screening by using conventional PCR with specific sets of primers. Products of PCR for patients and control groups were run on the gel electrophoresis to detect the SNP rs6265 fragment. A nerve-conducting study was used to examine DPN. Results: The observed results demonstrated the presence of two types of alleles identified as genotypic variants (GG and GA) among all participants in this investigation. By applying the Hardy-Weinberg Equilibrium principle (HWE) for both patient and control groups, the results proved that there was a statistically significant variance (P < 0.05) in the genotypic frequencies between each of the groups that had been studied. The wild homozygous GG genotype in type 2 diabetic without neuropathy, with DPN, and healthy control group were 51.4%, 40% and 80% respectively. The heterozygous GA genotype were 48.6%, 60% and 20%, respectively in the three groups. Conclusion: The present study showed that the BDNF (Val66Met) rs6265 polymorphism is associated with type 2 diabetes mellitus and diabetic peripheral neuropathy in heterozygous allele G/A (Met/Met) and homozygous allele GG (Val/Val) genotype. Also, the current study found the absence of the mutant genotype AA, possibly due to the evidence that the distribution of the BDNF polymorphisms varies widely among different ethnic groups. Abbreviations: BDNF - Brain-derived neurotrophic factor; DPN - Diabetic peripheral neuropathy Keywords: Type2 diabetes mellitus; Diabetic peripheral neuropathy; Brain-Derived Neurotrophic Factor; BDNF rs6265 SNP; BDNF Val66Met polymorphism. Citation: Hamid R, Al-Wasiti E, Jabbar AM. Correlation between human BDNF rs6265 gene polymorphism and type-2 diabetes and diabetic peripheral neuropathy. Anaesth. pain intensive care 2024;28(4):752−756. DOI: 10.35975/apic.v28i4.2517 Received: March 08, 2024; Reviewed: April 20, 2024; Accepted: April 28, 2024

Diabetic Microvascular Complications: Novel Risk Factors, Biomarkers, and Risk Prediction Models.

Background and Aims. Diabetic neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). Genetic susceptibility and oxidative stress may play a role in the appearance of T2DM and diabetic neuropathy. We investigated the relation between polymorphism in genes related to oxidative stress such as GSTM1, GSTT1, and GSTP1 and the presence of T2DM and diabetic neuropathy (DN). Methods. Samples were collected from 84 patients with T2DM (42 patients with DN and 42 patients without DN) and 98 healthy controls and genotyped by using polymerase chain reaction and restriction fragment length polymorphism method. Results. GSTP1 Ile105Val polymorphism was associated with the risk of developing T2DM (p = 0.05) but not with the risk of developing DN in diabetic cases. GSTM1 and GSTT1 gene polymorphisms were associated with neither the risk of developing T2DM nor the risk of DN occurrence in diabetic patients. No association was observed between the patients with T2DM and DSPN (diabetic sensorimotor peripheral neuropathy) and T2DM without DSPN regarding investigated polymorphism. Conclusion. Our data suggest that GSTP1 gene polymorphisms may contribute to the development of T2DM in Romanian population. GSTM1, GSTT1, and GSTP1 gene polymorphisms are not associated with susceptibility of developing diabetic neuropathy in T2DM patients.

Background: We aimed to investigate whether there was a relationship between diabetic peripheral distal neuropathy (DPDN), one of the most common chronic complications in patients with type 2 diabetes mellitus (T2DM), and the uric acid/HDL ratio, which can be used as an indicator of poor metabolic status.Methodology: The study consisted of a total of 150 subjects, including 50 patients with T2DM (group 1) who were determined to have diabetic peripheral distal neuropathy with electroneuromyography (ENMG), 50 patients with T2DM who were determined to not have DPDN in their ENMG (group 2), and 50 healthy individuals (group 3). Participants’ serum fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), uric acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were analyzed. The uric acid/HDL-C ratio (UHR) was calculated. The relationship between UHR and other parameters was evaluated in all three groups.Results: Patients with T2DM who had diabetic neuropathy (group 1), did not have diabetic neuropathy (group 2), and healthy subjects (group 3) were similar in terms of age and gender (p=0.066, p=0.185). Groups 1 and 2 were similar in terms of the duration of diabetes and FBG values (p=0.825, p=0.572), but these values were lower in group 3 than in groups 1 and 2 (p<0.05). HbA1c did not differ significantly between groups 1 and 2 (p=0.607). Creatinine levels were similar in the three groups. Uric acid levels were significantly higher in group 1 than in group 2 (p=0.040), but there was no significant difference between groups 1 and 3 or between groups 2 and 3 (p>0.05). UHR was significantly lower in group 1 than in groups 2 and 3 (p<0.001), but no significant difference was found between groups 2 and 3.Conclusion: In our study, we found that the UHR level of the group with diabetic neuropathy was statistically significant compared to the levels of the other two groups. However, no significant difference was found between the patients with diabetes who did not have neuropathy and the healthy group. Based on the findings of our study, we can say that the UHR level is a predictor of the microvascular complications of diabetes.

Background:Vitamin D deficiency has been reported to be associated with diabetic microvascular complications, but previous studies have only focused on the relationship between vitamin D and specific complications. Therefore, we aimed to explore the relationship between vitamin D level and diabetic microvascular complications in general, including diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN).Methods:This was a cross-sectional study of 815 patients with type 2 diabetes mellitus (T2DM). Clinical information and laboratory results were collected from the medical records. The relationship between vitamin D and the three diabetic microvascular complications was investigated.Results:The serum 25-hydroxyvitamin D (25 [OH] D) level of patients with DPN and/or DN was significantly lower than that of T2DM patients without any microvascular complications (P < 0.01). Univariate analysis showed that the 25 (OH) D level was related to DPN and DN, but not DR. After adjustment, the 25 (OH) D level was confirmed to be an independent protective factor for DPN (odds ratio [OR]: 0.968, P = 0.004]) and DN (OR: 0.962, P = 0.006). The prevalence of DPN and DN increased significantly as the serum 25 (OH) D levels decreased. Furthermore, patients with both DPN and DN had the lowest concentration of serum 25 (OH) D (P < 0.001), and the prevalence of macroalbuminuria increased more abruptly than that of microalbuminuria across the 25 (OH) D tertiles. Among the patients with vitamin D insufficiency, those with DPN presented more comorbid macroalbuminuria than those without DPN (15.32% vs. 4.91%; P = 0.001).Conclusions:Vitamin D deficiency is independently associated with higher risk of DPN and DN, but not DR, in T2DM patients. Further, it may be a potential predictor for both the occurrence and severity of DPN and DN.

Background: Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of type 2 diabetes mellitus (T2DM) with a prevalence ranging from 18.8% to 61.9% in India. For patients with T2DM, identifying those who are at risk of developing DPN is crucial for planning and implementing secondary preventive interventions, as well as for stepping up efforts to address risk factors. Very few studies have discovered a connection between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and the onset and progression of DPN in T2DM. Objectives: The current study intends to investigate the relationship between ACE gene I/D polymorphism with T2DM and DPN subjects among the South Tamil Nadu regional population. Materials and Methods: Thirty T2DM patients with DPN, 30 T2DM patients without DPN, and 30 control (nondiabetic) subjects were enrolled in this study. DPN was diagnosed using clinical and neurophysiological evaluation. Blood samples were collected and subjected to relevant investigations including blood glucose, glycated hemoglobin, serum creatinine, and serum lipids. Polymerase chain reaction amplification was performed to genotype the DNA for ACE I/D polymorphism using specific primers. Results: The ACE genotypes were distributed as II, 17 (57%); DD, 3 (10%); and ID, 10 (33%) in control group; II, 7 (23%); DD, 11 (37%); and ID, 12 (40%) in T2DM without DPN group, II, 3 (10%); DD, 16 (53%); and ID, 11 (37%) in T2DM with DPN group. The frequency of DD genotype was significantly higher in T2DM (P = 0.03) and T2DM patients with DPN (P = 0.001) compared to controls. The DD genotype versus II genotype was found to be associated with an increased risk of DPN (odds ratio [OR] = 10.28; 95% confidence interval [CI] =2.55–41.37). The D allele was more frequent among T2DM patients with DPN (71.6%) followed by T2DM patients (56.6%) compared to controls (26.6%). The D allele (vs. the I allele) is associated with an increased risk of T2DM (OR = 3.59, 95% CI = 1.670–7.742) and DPN (OR = 6.95, 95% CI = 3.120–15.507). Conclusion: The D allele and DD genotype of the ACE gene may both be risk factors for T2DM; in fact, the D allele of this polymorphism may potentially be linked to the development of DPN in T2DM patients. This finding implies that it may be possible to prevent DPN by early detection by identifying defects in ACE I/D polymorphisms in the south Indian regional population.

Objective To evaluate the clinical significance of quantitative sensory testing (QST) in screening diabetic peripheral neuropathy of the early stage. Methods One hundred patients with type 2 diabetes mellitus were examined by nerve conduction velocity (NCV) and QST examination. With the NCV positive as the gold criterion for screening diabetic peripheral neuropathy of the early stage, the sensitivity and specificity of QST was further analyzed for diagnosis of the early stage diabetic peripheral neuropathy. Results Among the 100 patients with type 2 diabetes mellitus,there were 41 cases positive and 59 cases negative in NCV examination. On the other hand,there were 74 cases positive,and 26 cases negative in QST. The sensitivity and specificity of QST for the diagnosis of early stage diabetic peripheral neuropathy was 97.56% (40/41) and 42.37% (25/59). Conclusions In the screening of early stage diabetic peripheral neuropathy,QST shows higher detection sensitivity,but lower specificity than NCV examination. Therefore, QST may be an examination for the supplement of the routine electromyography. Key words: Diabetic neuropathies; Sensitivity and specificity; Electromyography; Quantitative sensory testing

ObjectivesWe aimed to explore the shared and specific signalling pathways involved in diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN).MethodsDifferentially expressed mRNAs and lncRNAs were identified by high-throughput sequencing. Subsequently, functional enrichment analysis, protein-protein interaction (PPI) analysis and lncRNAs-mRNAs networks were conducted to determine the pathogenic mechanisms underlying DR, DPN and DN.ResultsTwenty-six biological pathways were shared among DR, DPN and DN groups compared to the type 2 diabetes mellitus (T2DM) group without complications, and most of the shared pathways and core proteins were involved in immune and inflammatory responses of microvascular damage. Cytokine‒cytokine receptor interactions and chemokine signalling pathway were the most significant and specific pathways for DR, and the lncRNA‒mRNA regulatory networks affected DR by targeting these pathways. Sphingolipid metabolism and neuroactive ligand-receptor pathways were found to be specific for the pathogenesis of DPN. Moreover, multiple amino acid metabolic pathways were involved in the occurrence and progression of DN.ConclusionsDiabetic retinopathy, DPN and DN exhibited commonality and heterogeneity simultaneously. The shared pathologic mechanisms underlying these diabetic complications are involved in diabetic microvascular damage via immune and inflammatory pathways. Our findings predict several biomarkers and therapeutic targets for these diabetic complications.

Objective To explore the association of nocturnal serum cortisol levels with diabetic microvascular complications in overweight or obese patients with type 2 diabetes mellitus. Methods Serum cortisol levels of 316 overweight or obese type 2 diabetic patients were tested at midnight by the method of chemiluminescence. Diabetic microvascular complications were compared among various groups according to nocturnal serum cortisol levels. All the patients with nocturnal serum cortisol level >50 nmol/L were asked to undergo overnight low-dose dexamethasone suppression test to rule out the possibility of subclincal Cushing′s syndrome. The incidences of diabetic nephropathy (DN), diabetic retinopathy (DR), and diabetic peripheral neuropathy (DPN) were examined in all the patients. Results (1)The incidence of DN was gradually increased from 13.3% to 27.7% and 44.2% in patients with low, medium, and high cortisol level groups, showing a statistical difference among 3 groups(P<0.05). The incidences of DR in medium and high cortisol level groups were higher than that in low cortisol level group (40.6% and 47.7% vs 22.7%, both P<0.01). The incidence of DPN in high cortisol level group was higher as compared with low cortisol level group (60.5% vs 38.7%, P<0.01). (2)Nocturnal serum cortisol level in patients with diabetic microvascular complications was higher than that in patients without complications [ (136.87±105.78 vs 97.55±93.48) nmol/L, P<0.01]. Nocturnal serum cortisol level in patients with multiple diabetic microvascular complications was higher than that in patients with single diabetic microvascular complication [ (151.66±114.54 vs 117.69±90.26) nmol/L, P<0.05]. (3)Single factor logistic regression analysis showed that higher nocturnal serum cortisol level was a risk factor for diabetic microvascular complications in addition to female, age, longer diabetic duration, higher fasting plasma glucose (FPG). Multivariate logistic regression analysis showed that higher nocturnal serum cortisol level was still a risk factor for diabetic microvascular complications after adjusted by diabetic duration, FPG, HbA1C, and the use of insulin (P=0.013). Conclusion Nocturnal serum cortisol level seems to be a risk factor for diabetic microvascular complications in overweight or obese patients with type 2 diabetes mellitus. (Chin J Endocrinol Metab, 2018, 34: 834-838) Key words: Overweight; Obese; Diabetes mellitus, type 2; Cortisol; Diabetic microvascular complications

Osteoprotegerin (OPG) has been linked to different diabetes complications, including cardiovascular disease, and new findings have indicated a specific role in diabetic peripheral neuropathy, but the exact mechanism is unknown. To investigate a possible association between OPG and diabetic peripheral sensory neuropathy, we therefore analysed plasma OPG in Type 1 and Type 2 diabetic patients with and without peripheral neuropathy. Two hundred Type 1 diabetes mellitus (T1DM) patients and 305 Type 2 diabetes mellitus (T2DM) patients participated in the study. Plasma OPG was measured with a sandwich immunoassay. Peripheral neuropathy was assessed by the Semmes-Weinstein monofilament test. In T2DM, plasma OPG concentrations were significantly higher in the peripheral neuropathy group (P < 0.001). Furthermore, there was a significant relationship between the presence of neuropathy in T2DM and plasma OPG levels on logistic regression (P = 0.006). However, when investigated in a full multiple regression model including other long-term diabetes complications, the association became insignificant (P = 0.092). In T1DM, the difference in plasma OPG between groups did not reach significance (P = 0.066). However, plasma OPG significantly correlated to peripheral neuropathy in this group also (P = 0.022), although this correlation was not significant in a multiple linear regression model (P = 0.051). Plasma OPG levels are related to peripheral neuropathy in both Type 1 and Type 2 diabetes, although with the strongest relationship in T2DM. Before understanding the significance of this, the pathological mechanism involved and, speculatively, a possible use of plasma OPG as a peripheral sensory neuropathy marker, a larger prospective study is needed.

Background &amp; objective: Persistent hyperglycemia is the driving force for the progression of diabetic vascular complications and inflammatory response. S100A8 and S100A9 are small calcium-binding proteins involved in various cellular processes, including inflammation and immune responses. Tristetraprolin (TTP), alternatively known as zinc finger protein 36, acts as an RNA-binding molecule that has an important role in regulating the expression of messenger RNAs containing AU-rich elements. We aimed to address the involvement of inflammatory mediators like S100A8/A9 proteins and, RNA-binding proteins, in microvascular complications of type 2 diabetes mellitus (T2DM). Methodology: The study was conducted from October 2022 to April 2023. We enrolled 200 subjects in this study involved in five equal groups: T2DM, diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy (DNR) and 40 normal healthy subjects as control group. CBC analysis was performed directly using the hematology analyzer CBC (Sysmex, Japan) technique. Serum S100 A8/A9 were measured by ELISA, and TTP gene expression was measured by RT-qPCR. Results: The study's findings revealed a notable increase in neutrophil/lymphocytes ratio (NLR) and S100A8/A9 levels in patients groups compared to the healthy group (P &lt; 0.05), while decreased TTP mRNA expression was observed in all patient groups compared to control (P &lt; 0.05) Conclusion: An increase in S1008A/9A levels with down regulation of anti-inflammatory binding protein (TTP) in patients suffering from type 2 diabetes mellitus with diabetic nephropathy, diabetic retinopathy, or diabetic neuropathy, suggests to be the therapeutic targets to regulate inflammatory response in type 2 diabetes mellitus and its complications. Abbreviations: T2DM - Type 2 Diabetes Mellitus; DN - Diabetic Nephropathy; DR - Diabetic Retinopathy; DNR - Diabetic Neuropathy; NLR- Neutrophil/Lymphocyte Ratio; TTP - Tristetraprolin Key words: Diabetes Mellitus; Inflammation; S100A8/A9; Inflammation; RNA-binding protein; T2DM; Neutrophil/Lymphocyte Ratio Citation: Sarhan A, Almzaiel AJ, Majeed Alrufaie MM. Potential role of S100A8/A9 and RNA-binding protein in microvascular complications of type2 diabetes mellitus. Anaesth. pain intensive care 2023;27(6):673−680. DOI: 10.35975/apic.v27i6.2338 Received: August 15, 2023; Reviewed: September 03, 2023; Accepted: September 15, 2023