BACKGROUND: Nearly half of patients with diabetes experience diabetic peripheral neuropathy (DPN), resulting in a mere 53% survival rate within 3 years. Aberrations in coagulation function have been implicated in the pathogenesis of microvascular complications, prompting the need for a thorough investigation into its role as a contributing factor in the development and progression of DPN.
METHODS: Data were gathered from 1211 type 2 diabetes patients admitted to five centers from September 2018 to October 2022 in China. DPN was evaluated by symptoms and electromyography. Motor and sensory nerve conduction velocity (NCV) was appraised and the NCV sum score was calculated for the median, ulnar, and peroneal motor or sensory nerves.
RESULTS: Patients with DPN exhibited alterations in coagulation function. (i) Specifically, they exhibited prolonged thrombin time (p = 0.012), elevated fibrinogen (p < 0.001), and shortened activated partial thromboplastin time (APTT; p = 0.026) when compared to the control group. (ii) After accounting for potential confounders in linear regression, fibrinogen, and D-dimer were negatively related to the motor NCV, motor amplitude values, and mean velocity and amplitude. Also, fibrinogen was associated with higher Michigan neuropathy screening instrument (MNSI) scores (β 0.140; p = 0.001). This result of fibrinogen can be validated in the validation cohort with 317 diabetic patients. (iii) Fibrinogen was independently associated with the risk of DPN (OR 1.172; p = 0.035). In the total age group, DPN occurred at a slower rate until the predicted fibrinogen level reached around 3.75 g/L, after which the risk sharply escalated.
CONCLUSIONS: Coagulation function is warranted to be concerned in patients with type 2 diabetes to predict and prevent the occurrence of DPN in clinical practice.

OBJECTIVE: Diabetic polyneuropathy is a long-standing microvascular complication of diabetes that affects the postural control and functional mobility of patients. There are other microvascular complications, including pulmonary complications that reduce lung function. Multifactorial Inspiratory Muscle Training (IMT) can act as a home-based technique targeted to affect both these complications. This study aims to determine the effects of IMT on respiratory and functional parameters in diabetic polyneuropathy patients.
METHODS: This is a Pre-Test Post-Test Randomized Controlled Trial (NCT#04947163) with 62 diabetic polyneuropathy patients. Each was randomly assigned to the IMT or sham-IMT group. Both the groups performed OTAGO exercises , with the sham-IMT group performing IMT at 15% of baseline maximal inspiratory pressure (MIP), whereas IMT were trained at 50% of baseline MIP as an initial intensity, which was increased as per the tolerance of patients. Both groups performed training for 12 weeks. The study investigated diaphragmatic strength, pulmonary function, functional capacity through 6MWT, 30s sit to stand test and anterior trunk muscle endurance tested through sit up test as outcome variables. Data was analysed on SPSS v26 at the significance level of 0.0.5.
RESULTS: The IMT group significantly improved diaphragmatic strength, pulmonary function, 6MWT and anterior trunk muscle endurance when compared to the sham-IMT group.
CONCLUSIONS: The study concluded that home-based IMT can improve pulmonary parameters including diaphragmatic strength and lung function as well as functional parameters including functional capacity in patients with diabetic polyneuropathy. The study was registered at ClinicalTrials.gov, NCT#04947163.

OBJECTIVE: To explore the lifestyle-related characteristics of people having type 2 diabetes mellitus with peripheral neuropathy.
METHODS: The phenomenological study was conducted from July 5 to September 18, 2021, at Sadabuan Health Centre, Batunadua Health Centre and Wek 3 Health Centre, Padangsidimpuan, Indonesia, and comprised diabetic neuropathy patients who had cognitive impairment, anxiety and depression. Data was collected using in-depth interviews. Data was analysed using Collaizi\'s method.
RESULTS: There were 8 subjects with mean age 48.38±13,606 years (range: 27-65 years), and mean duration of diabetes was 6±3.207 years. The majority of participants in this study were women 6 (75%). There were 7 themes that emerged from the collected data: level of physical activity, diet, sleep pattern, habit of consuming sweet drinks, smoking habit, social interaction, and self-care.
CONCLUSIONS: Diabetes mellitus patient with peripheral neuropathy had not been able to completely switch to a healthier lifestyle.

UNASSIGNED: Plai or Zingiber cassumunar Roxb. was registered into the Thai Traditional Medicine list since 2011. However, there is limited evidence regarding Plai as a treatment in painful diabetic neuropathy (PDN). Therefore, this study aimed to evaluate the efficacy of topical Zingiber cassumunar.
UNASSIGNED: A RCT was conducted in patients with PDN during February to March 2019. All participants received oral gabapentin 300 mg before bed as a standard regimen. The intervention group (n=16) received Plai balm 15%w/w 0.5 gram to apply on their feet three times a day and the control group (n=15) received placebo balm to similarly apply. Pain score at baseline, 2 nd and 4 th weeks were assessed and compared. Patients\' quality of life, and adverse events, were collected. Mean pain scores before and after treatment in each group and between groups were also analyzed.
UNASSIGNED: At the end of week two and week four, the Plai group showed statistically significant lesser mean pain scores than the placebo group by -1.47 (95%CI: -1.96 to -1.30, p-value < 0.001), and by -1.51 (95%CI: -1.92 to -0.13, p-value = 0.027), respectively. Moreover, the Plai group had more cases number/ percentages with at least 50% pain score reduction than the placebo group [12/16 (75%) vs 3/15 (20%), p-value = 0.004]. However, there was no statistically significant difference in quality of life between the two groups (overall p-value = 0.366). Adverse event was not found in any groups.
UNASSIGNED: Zingiber cassumunar balm (Plai) was efficacious for pain reduction in painful diabetic neuropathy.
UNASSIGNED: Registered with the Thai Clinical Trials Registry; TCTR20200221001.

Diabetic peripheral neuropathy is one of the diabetes most common microvascular complications. It is very prevalent in Sub-Saharan Africa due to a combination of causes, including rising diabetes prevalence, limited healthcare resources, and a lack of access to competent medical care. However, just a few studies have been undertaken in the study area. Institution-based cross-sectional study was conducted in the Amhara region referral hospitals, in 2022. By using a systematic random sampling technique, a total of 627 respondents were included. The data was entered into EPI Data version 4.6 and exported to SPSS version 25 for further analysis. A binary logistic regression was used to determine the relationship between the dependent and predictor variables. The association between predictor variables and the dependent variable was determined using multivariate logistic regression [p value < 0.05, 95% confidence interval]. The overall prevalence of diabetic peripheral neuropathy among the study participants was 48.2% (95% CI; 44.2, 52.1). Aged between 40 and 60 years (AOR = 4:27; 95% CI 2.62, 6.94), and 60 years and older (AOR = 4:47; 95% CI 2.40, 8.35), participants who have lived alone (AOR = 2:14; 95% CI 1.21, 3.79), patients with comorbidity (AOR = 1:83; 95% CI 1.22, 2.76), and being physically inactive (AOR = 1:69; 95% CI 1.14, 2.49) were significantly associated with Diabetic peripheral neuropathy. Diabetic peripheral neuropathy was high among diabetic patients. Healthcare providers should prioritize regular screening and early intervention for individuals at higher risk, particularly those aged 40 and above, those living alone, patients with comorbid conditions, and those who are physically inactive. Implementing community-based support programs, encouraging physical activity, and providing comprehensive management plans for diabetes and associated comorbidities can help mitigate the risk and improve the quality of life for these patients.

UNASSIGNED: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications.
UNASSIGNED: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications.
UNASSIGNED: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed.
UNASSIGNED: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.

UNASSIGNED: Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China.
UNASSIGNED: To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP.
UNASSIGNED: This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose.
UNASSIGNED: In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment.
UNASSIGNED: The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences.
UNASSIGNED: Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common.
UNASSIGNED: Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT04647773.

UNASSIGNED: Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications.
UNASSIGNED: A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP).
UNASSIGNED: First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation.
UNASSIGNED: A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates.
UNASSIGNED: The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

UNASSIGNED: Previous observational studies have suggested an association between gut microbiota and diabetic neuropathy (DN). However, confounding factors and reverse causality make the causal relationship between gut microbiota and DN uncertain. We aimed to investigate the interactive causal relationships between the abundance of gut microbiota and DN.
UNASSIGNED: We conducted a Mendelian randomization (MR) analysis to examine the causal relationship between gut microbiota and DN. Genomic data on gut microbiota at the genus level were obtained from the MiBioGen Consortium, including 18,340 individuals of European descent. Data on diabetic polyneuropathy (DPN) were obtained from the FinnGen Consortium, which included 1,048 cases and 374,434 controls, while data on diabetic autonomic neuropathy (DAN) were also obtained from the FinnGen Consortium, including 111 cases and 374,434 controls. Causal effects were primarily estimated using inverse variance weighted (IVW) analysis, supplemented with four validation methods, and additional sensitivity analyses to assess the pleiotropy, heterogeneity, and robustness of instrumental variables.
UNASSIGNED: The IVW analysis indicated that Prevotella 9 had a protective effect on DPN (OR = 0.715, 95% CI: 0.521-0.982, P = 0.038), and Bacteroides also showed a protective effect (OR = 0.602, 95% CI: 0.364-0.996, P = 0.048). On the other hand, Ruminococcus 2 had a promoting effect on DPN (OR = 1.449, 95% CI: 1.008-2.083, P = 0.045). Blautia (OR = 0.161, 95% CI: 0.035-0.733, P = 0.018), Clostridium innocuum group (OR = 3.033, 95% CI: 1.379-6.672, P = 0.006), and Howardella (OR = 2.595, 95% CI: 1.074-6.269, P = 0.034) were causally associated with DAN in the IVW analysis, with no evidence of heterogeneity or pleiotropy. Sensitivity analyses showed no significant pleiotropy or heterogeneity.
UNASSIGNED: Our study identified a causal relationship between gut microbiota and the increased or decreased risk of diabetic neuropathy. These findings underscore the importance of adopting a comprehensive approach that combines gut microbiota modulation with other therapeutic interventions in the management of diabetic neuropathy.

BACKGROUND: Cardiac autonomic neuropathy (CAN) in diabetes mellitus (DM) is independently associated with cardiovascular (CV) events and CV death. Diagnosis of this complication of DM is time-consuming and not routinely performed in the clinical practice, in contrast to fundus retinal imaging which is accessible and routinely performed. Whether artificial intelligence (AI) utilizing retinal images collected through diabetic eye screening can provide an efficient diagnostic method for CAN is unknown.
METHODS: This was a single center, observational study in a cohort of patients with DM as a part of the Cardiovascular Disease in Patients with Diabetes: The Silesia Diabetes-Heart Project (NCT05626413). To diagnose CAN, we used standard CV autonomic reflex tests. In this analysis we implemented AI-based deep learning techniques with non-mydriatic 5-field color fundus imaging to identify patients with CAN. Two experiments have been developed utilizing Multiple Instance Learning and primarily ResNet 18 as the backbone network. Models underwent training and validation prior to testing on an unseen image set.
RESULTS: In an analysis of 2275 retinal images from 229 patients, the ResNet 18 backbone model demonstrated robust diagnostic capabilities in the binary classification of CAN, correctly identifying 93% of CAN cases and 89% of non-CAN cases within the test set. The model achieved an area under the receiver operating characteristic curve (AUCROC) of 0.87 (95% CI 0.74-0.97). For distinguishing between definite or severe stages of CAN (dsCAN), the ResNet 18 model accurately classified 78% of dsCAN cases and 93% of cases without dsCAN, with an AUCROC of 0.94 (95% CI 0.86-1.00). An alternate backbone model, ResWide 50, showed enhanced sensitivity at 89% for dsCAN, but with a marginally lower AUCROC of 0.91 (95% CI 0.73-1.00).
CONCLUSIONS: AI-based algorithms utilising retinal images can differentiate with high accuracy patients with CAN. AI analysis of fundus images to detect CAN may be implemented in routine clinical practice to identify patients at the highest CV risk.
BACKGROUND: This is a part of the Silesia Diabetes-Heart Project (Clinical-Trials.gov Identifier: NCT05626413).