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Objective: The primary objective of this study was to investigate the risk factors for diabetic peripheral neuropathy (DPN) and to establish an early diagnostic prediction model for its onset, based on clinical data and biochemical indices., Methods: Retrospective data were collected from 1,446 diabetic patients at the First Affiliated Hospital of Anhui University of Chinese Medicine and were split into training and internal validation sets in a 7:3 ratio. Additionally, 360 diabetic patients from the Second Affiliated Hospital were used as an external validation cohort. Feature selection was conducted within the training set, where univariate logistic regression identified variables with a p-value < 0.05, followed by backward elimination to construct the logistic regression model. Concurrently, the random forest algorithm was applied to the training set to identify the top 10 most important features, with hyperparameter optimization performed via grid search combined with cross-validation. Model performance was evaluated using ROC curves, decision curve analysis, and calibration curves. Model fit was assessed using the Hosmer-Lemeshow test, followed by Brier Score evaluation for the random forest model. Ten-fold cross-validation was employed for further validation, and SHAP analysis was conducted to enhance model interpretability., Results: A nomogram model was developed using logistic regression with key features: limb numbness, limb pain, diabetic retinopathy, diabetic kidney disease, urinary protein, diastolic blood pressure, white blood cell count, HbA1c, and high-density lipoprotein cholesterol. The model achieved AUCs of 0.91, 0.88, and 0.88 for the training, validation, and test sets, respectively, with a mean AUC of 0.902 across 10-fold cross-validation. Hosmer-Lemeshow test results showed p-values of 0.595, 0.418, and 0.126 for the training, validation, and test sets, respectively. The random forest model demonstrated AUCs of 0.95, 0.88, and 0.88 for the training, validation, and test sets, respectively, with a mean AUC of 0.886 across 10-fold cross-validation. The Brier score indicates a good calibration level, with values of 0.104, 0.143, and 0.142 for the training, validation, and test sets, respectively., Conclusion: The developed nomogram exhibits promise as an effective tool for the diagnosis of diabetic peripheral neuropathy in clinical settings., (© 2024. The Author(s).)

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., Trial Registration: This is a part of the Silesia Diabetes-Heart Project (Clinical-Trials.gov Identifier: NCT05626413)., (© 2024. The Author(s).)

Background: Symptoms of autonomic neuropathy (AN) are common in patients with diabetes and advanced renal disease. As yet different domains of autonomic neuropathy cannot be detected by a singular laboratory or invasive test. COMPASS 31, a new self-assessment test, has shown reliable results not only in cardiac autonomic neuropathy but also in different sub-domains when judging manifestation of AN by scores., Methods: One hundred eighty-three patients with or without diabetes were enrolled, one hundred nineteen of them were treated with permanent dialysis therapy (HD), sixty-four patients served as controls (eGFR > 60 ml/min.) Using COMPASS 31 different symptoms of AN were assessed (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor changes) and transferred into AN-scores., Results: AN was more pronounced in dialysis patients compared with controls (AN-score 27,5 vs. 10,0; p < 0,01). These differences were present also in every sub-domain of AN (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, pupillomotor changes; p < 0,05 for all sub-domains). In diabetic patients there was a strong correlation between symptoms of AN and diabetes duration (correlation coefficient r = 0,45, p < 0,001). Current glycemic control (HbA1c), body mass index (BMI), sex, and height had no influence on AN when comparing dialysis patients and controls. C-reactive protein (CRP) showed a positive linear correlation with AN-scores (correlation coefficient r = 0,21; p < 0,05)., Conclusion: Symptoms of AN are more pronounced in dialysis patients not only in total but also in all different domains of neuropathic changes. Longlasting diabetic disease promotes development of AN, as duration of diabetes was positively correlated with AN. Future longitudinal studies might help to identify the high cardiovascular and mortality risk in dialysis patients by the easy-to-use COMPASS 31 without need of invasive and time-spending methods for diagnosing AN., (© 2024. The Author(s).)

Background: The white blood cell count to mean platelet volume ratio (WMR) is considered a promising inflammatory marker, and its recognition is increasing. Inflammation is closely related to metabolic diseases such as diabetes and its complications. However, there are currently no reports on the correlation between WMR and type 2 diabetic peripheral neuropathy (DPN). This study aims to explore the correlation between WMR and DPN in type 2 diabetes patients. By understanding this association, we hope to provide a theoretical basis for preventing DPN through the improvement of inflammatory responses., Methods: This was a cross-sectional study involving 2515 patients with T2DM. Logistic regression analysis was conducted to assess the associations between WMR and DPN. Finally, the receiver operating characteristic curve (ROC curve) was employed to evaluate the predictive efficacy of WMR for DPN., Results: Patients in higher WMR quartiles exhibited increased presence of DPN. Additionally, WMR remained significantly associated with a higher odds ratio (OR) of DPN (OR 4.777, 95% confidence interval [CI] 1.296-17.610, P < 0.05) after multivariate adjustment. Moreover, receiver operating characteristic curve analysis indicated that the optimal cutoff value for WMR in predicting DPN presence was 0.5395 (sensitivity: 65.40%; specificity: 41.80%; and area under the curve [AUC]: 0.540)., Conclusions: In patients with T2DM, WMR was significantly increased in DPN and independently associated with an increased risk of DPN presence in Chinese patients. This suggests that WMR may serve as a useful and reliable biomarker of DPN, highlighting the importance of paying more attention to T2DM patients with high WMR to further prevent and reduce the development of DPN and related unfavorable health outcomes., (© 2024. The Author(s).)

Background: Diabetic peripheral neuropathy (DPN) is the most prevalent complication of diabetes, and has been demonstrated to be independently associated with cardiovascular events and mortality. This aim of this study was to investigate the subclinical left ventricular (LV) myocardial dysfunction in type 2 diabetes mellitus (T2DM) patients with and without DPN., Methods: One hundred and thirty T2DM patients without DPN, 61 patients with DPN and 65 age and sex-matched controls who underwent cardiovascular magnetic resonance (CMR) imaging were included, all subjects had no symptoms of heart failure and LV ejection fraction ≥ 50%. LV myocardial non-infarct late gadolinium enhancement (LGE) was determined. LV global strains, including radial, circumferential and longitudinal peak strain (PS) and peak systolic and diastolic strain rates (PSSR and PDSR, respectively), were evaluated using CMR feature tracking and compared among the three groups. Multivariable linear regression analyses were performed to determine the independent factors of reduced LV global myocardial strains in T2DM patients., Results: The prevalence of non-infarct LGE was higher in patients with DPN than those without DPN (37.7% vs. 19.2%, p = 0.008). The LV radial and longitudinal PS (radial: 36.60 ± 7.24% vs. 33.57 ± 7.30% vs. 30.72 ± 8.68%; longitudinal: - 15.03 ± 2.52% vs. - 13.39 ± 2.48% vs. - 11.89 ± 3.02%), as well as longitudinal PDSR [0.89 (0.76, 1.05) 1/s vs. 0.80 (0.71, 0.93) 1/s vs. 0.77 (0.63, 0.87) 1/s] were decreased significantly from controls through T2DM patients without DPN to patients with DPN (all p < 0.001). LV radial and circumferential PDSR, as well as circumferential PS were reduced in both patient groups (all p < 0.05), but were not different between the two groups (all p > 0.05). Radial and longitudinal PSSR were decreased in patients with DPN (p = 0.006 and 0.003, respectively) but preserved in those without DPN (all p > 0.05). Multivariable linear regression analyses adjusting for confounders demonstrated that DPN was independently associated with LV radial and longitudinal PS (β = - 3.025 and 1.187, p = 0.014 and 0.003, respectively) and PDSR (β = 0.283 and - 0.086, p = 0.016 and 0.001, respectively), as well as radial PSSR (β = - 0.266, p = 0.007)., Conclusions: There was more severe subclinical LV dysfunction in T2DM patients complicated with DPN than those without DPN, suggesting further prospective study with more active intervention in this cohort of patients., (© 2024. The Author(s).)

Objective: Meteorin-like (Metrnl), a secreted myokine, is a newly discovered neurotrophic factor. The aim of this study was to determine if there is a correlation between the Metrnl level and diabetic peripheral neuropathy (DPN)., Methods: The investigation was conducted on a sample of 80 patients with type 2 diabetes mellitus (T2DM) and 60 healthy controls. The T2DM patients were categorized into two subgroups based on skin biopsy: the DPN subgroup (n = 20) and the diabetes without neuropathy subgroup (n = 60)., Results: The T2DM groups had higher serum Metrnl concentrations compared with the controls. The serum Metrnl concentration was significantly lower in the DPN group than in T2DM patients without neuropathy. Logistic regression analysis demonstrated a notable correlation between serum Metrnl and DPN (OR: 0.997, 95% CI: 0.995-1.000, P < 0.05). Serum Metrnl level was negatively correlated with age and SBP after a simple logistic regression analysis., Conclusion: Serum Metrnl concentration is independently correlated with DPN., (© 2024. The Author(s).)

Background: Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, impacting the autonomic nerves that regulate the heart and blood vessels. Timely recognition and treatment of CAN are crucial in averting the onset of cardiovascular complications. Both clinically apparent autonomic neuropathy and subclinical autonomic neuropathy, particularly CAN pose a significant risk of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Notably, CAN can progress silently before manifesting clinically. In our study, we assessed patients with poor metabolic control, without symptoms, following the ISPAD 2022 guideline. The objective is is to determine which parameters we can use to diagnose CAN in the subclinical period., Methods: Our study is a cross-sectional case-control study that includes 30 children diagnosed with T1DM exhibiting poor metabolic control (average HbA1c > 8.5% for at least 1 year) according to the ISPAD 2022 Consensus Guide. These patients, who are under the care of the pediatric diabetes clinic, underwent evaluation through four noninvasive autonomic tests: echocardiography, 24-h Holter ECG for heart rate variability (HRV), cardiopulmonary exercise test, and tilt table test., Results: The average age of the patients was 13.73 ± 1.96 years, the average diabetes duration was 8 ± 3.66 years, and the 1-year average HbA1c value was 11.34 ± 21%. In our asymptomatic and poorly metabolically controlled patient group, we found a decrease in HRV values, the presence of postural hypotension with the tilt table test, and a decrease in ventricular diastolic functions that are consistent with the presence of CAN. Despite CAN, the systolic functions of the ventricles were preserved, and the dimensions of the cardiac chambers and cardiopulmonary exercise test were normal., Conclusions: CAN is a common complication of T1DM, often associated with the patient's age and poor glycemic control. HRV, active orthostatic tests, and the evaluation of diastolic dysfunctions play significant roles in the comprehensive assessment of CAN. These diagnostic measures are valuable tools in identifying autonomic dysfunction at an early stage, allowing for timely intervention and management to mitigate the impact of cardiovascular complications associated with T1DM., (© 2024. The Author(s).)

Background: The morbidity of type 1 diabetes mellitus (T1DM) in children is increasing and diabetic peripheral neuropathy (DPN) is one of the main microvascular complications of T1DM. The aim of this study was to explore sympathetic skin response (SSR) characteristics in children with T1DM and analyze the value of early diagnosis and follow-up in T1DM complicated with DPN., Methods: Our prospective study enrolling 85 participants diagnosed with T1DM and 30 healthy controls (HCs) in the Children's Hospital of Hebei Province from 2017 to 2020. Compared the outcomes of SSR and nerve conduction study (NCS) in T1DM, and evaluated the variations in SSR and NCS of different durations, as well as changes after six months of therapy., Results: SSR latency of T1DM group showed statistical difference as compared to HCs (p < 0.05). The SSR test was more sensitive than the NCS test in the early diagnosis of T1DM with DPN (p < 0.05). The abnormal rates of SSR and NCS in long duration of disease were higher than those in short duration of disease (p < 0.05). Among 65 participants with diabetic neuropathy, the onset latencies of SSR were shortened and the NCS were improved after treatment (p < 0.05)., Conclusions: SSR could provide the accurate early diagnosis and follow-up of pediatric diabetic peripheral neuropathy., (© 2023. The Author(s).)

Background: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. Predicting the risk of developing DPN is important for clinical decision-making and designing clinical trials., Methods: We retrospectively reviewed the data of 1278 patients with diabetes treated in two central hospitals from 2020 to 2022. The data included medical history, physical examination, and biochemical index test results. After feature selection and data balancing, the cohort was divided into training and internal validation datasets at a 7:3 ratio. Training was made in logistic regression, k-nearest neighbor, decision tree, naive bayes, random forest, and extreme gradient boosting (XGBoost) based on machine learning. The k-fold cross-validation was used for model assessment, and the accuracy, precision, recall, F1-score, and the area under the receiver operating characteristic curve (AUC) were adopted to validate the models' discrimination and clinical practicality. The SHapley Additive exPlanation (SHAP) was used to interpret the best-performing model., Results: The XGBoost model outperformed other models, which had an accuracy of 0·746, precision of 0·765, recall of 0·711, F1-score of 0·736, and AUC of 0·813. The SHAP results indicated that age, disease duration, glycated hemoglobin, insulin resistance index, 24-h urine protein quantification, and urine protein concentration were risk factors for DPN, while the ratio between 2-h postprandial C-peptide and fasting C-peptide(C2/C0), total cholesterol, activated partial thromboplastin time, and creatinine were protective factors., Conclusions: The machine learning approach helped established a DPN risk prediction model with good performance. The model identified the factors most closely related to DPN., (© 2023. The Author(s).)

Background: The prevalence of microvascular complications in type 2 diabetes mellitus (T2DM) is increasing. The effect of lipid profiles on diabetic microvascular complications remains debated. This research aimed to study the correlation between lipid profiles and microvascular complications., Methods: This retrospective cross-sectional study included 1096 T2DM patients. The patients were divided into the control, diabetic retinopathy (DR), nephropathy (DKD), and peripheral neuropathy (DPN) groups based on the existence of corresponding complications. The lipid profiles were analyzed, and the effect on complications was assessed by logistic regression., Results: Compared with the control group, the diabetic microvascular complications group had a higher dyslipidemia rate. The rate of high TGs increased significantly with an increasing number of complications. High TG levels contributed to the risk of DKD, DR, and DPN [odds ratios (ORs): 2.447, 2.267, 2.252; 95% confidence interval: 1.648-3.633, 1.406-3.655, 1.472-3.445]. In the age (years) > 55, T2DM duration (years) > 10, and HbA1c (%) ≥ 7 groups, the risk of high TGs was higher for DKD (ORs: 2.193, 2.419, 2.082), DR (ORs: 2.069, 2.317, 1.993), and DPN (ORs: 1.811, 1.405, 1.427)., Conclusion: High TG levels increase the risk of diabetic microvascular complications, and patients with older age, longer T2DM duration, and higher HbA1c levels are recommended to keep lipid levels more strictly., (© 2023. The Author(s).)

Background: Increased levels of low-density lipoprotein cholesterol (LDL-C) have been identified as one potential risk factor for diabetic peripheral neuropathy (DPN) in patients. The current study seeks to clarify the link between LDL-C, hyperglycemia, and DPN in patients with type 2 diabetes mellitus (T2DM)., Methods: Here, a total of 120 T2DM individuals were recruited. These volunteers with T2DM were divided into 2 groups, based on the presence or absence of peripheral neuropathy. Additionally, their baseline characteristics were compared. Association among LDL-C and glycosylated hemoglobin (HbA1c) levels and DPN, particularly with respect to specific nerve conduction velocity were analyzed. To identify factors influencing DPN, regression was performed. Furthermore, mediation analysis was employed to evaluate the indirect, direct and total effects of LDL-C on specific nerve conduction velocity, with HbA1c serving as a mediator., Results: Compared to 55 patients without DPN, 65 patients with DPN demonstrated elevated levels of LDL-C and HbA1c. Both LDL-C and HbA1c have been found to be associated with reduced the motor fiber conduction velocities of Ulnar (or the Common peroneal) nerve in diabetic patients. HbA1c is one of the known risk factors for DPN in individuals with T2DM. Further mediation analysis revealed that the effect of LDL-C on the Ulnar (or the Common peroneal) nerve motor fiber conduction velocities are fully mediated by HbA1c in patients with T2DM., Conclusions: The impact of elevated LDL-C levels upon the Ulnar (or the Common peroneal) nerve motor fiber conduction velocities in patients with T2DM was found to be entirely mediated by increased HbA1c levels., (© 2023. The Author(s).)

Background: Diabetic cardiovascular autonomic neuropathy (CAN) and distal symmetrical polyneuropathy (DSPN) are severe diabetic complications. Collagen type VI (COL6) and III (COL3) have been associated with nerve function. We investigated if markers of COL6 formation (PRO-C6) and COL3 degradation (C3M) were associated with neuropathy in people with type 1 diabetes (T1D)., Methods: In a cross-sectional study including 300 people with T1D, serum and urine PRO-C6 and C3M were obtained. CAN was assessed by cardiovascular reflex tests: heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva maneuver (VM). Two or three pathological CARTs constituted CAN. DSPN was assessed by biothesiometry. Symmetrical vibration sensation threshold above 25 V constituted DSPN., Results: Participants were (mean (SD)) 55.7 (9.3) years, 51% were males, diabetes duration was 40.0 (8.9) years, HbA 1c was 63 (11 mmol/mol, (median (IQR)) serum PRO-C6 was 7.8 (6.2;11.0) ng/ml and C3M 8.3 (7.1;10.0) ng/ml. CAN and DSPN were diagnosed in 34% and 43% of participants, respectively. In models adjusted for relevant confounders a doubling of serum PRO-C6, was significantly associated with odds ratio > 2 for CAN and > 1 for DSPN, respectively. Significance was retained after additional adjustments for eGFR only for CAN. Higher serum C3M was associated with presence of CAN, but not after adjustment for eGFR. C3M was not associated with DSPN. Urine PRO-C6 analyses indicated similar associations., Conclusions: Results show previously undescribed associations between markers of collagen turnover and risk of CAN and to a lesser degree DSPN in T1D., (© 2023. The Author(s).)

Pain, although unpleasant, is an essential warning mechanism against injury and damage of the organism. An intricate network of specialised sensors and transmission systems contributes to reception, transmission and central sensitization of pain. Here, we briefly introduce some of the main aspects of pain signal transmission, including nociceptors and nociceptive signals, mechanisms of inflammatory and neuropathic pain, and the situation of diabetes-associated neuropathic pain. The role of glia-astrocytes, microglia, satellite glia cells-and their specific channels, transporters and signaling pathways is described. A focus is on the contribution of inhibitory synaptic signaling to nociception and a possible role of glycine receptors in glucose-mediated analgesia and treatment-induced diabetic neuropathy. Inhibitory receptors such as GABA A - and glycine receptors are important contributors to nociceptive signaling; their contribution to altered pain sensation in diabetes may be of clinical relevance, and they could be promising therapeutic targets towards the development of novel analgesics., (© 2023. The Author(s).)

Background: The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed., Methods: We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using 99m Tc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination., Results: After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45-3.26]) and 54% (HR 1.54 [1.01-2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52-10.26]), followed by CKD&DR (HR 2.95 [1.63-5.32]), and CAN&DR (HR 2.07 [1.11-3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87-2.67]), while increased by 203% (HR 3.03 [1.62-5.68]) and 692% (HR 7.92 [2.93-21.37]) in patients with two and three concomitant MVC, respectively., Conclusions: Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment., (© 2022. The Author(s).)

Background: Research suggests that fibrinogen (Fib) is related to mild cognitive impairment (MCI) and diabetic peripheral neuropathy (DPN) and the risk of MCI in patients with DPN is greatly increased, although no studies have evaluated the predictive value of Fib for the risk of MCI in patients with DPN., Methods: This prospective observational clinical study enrolled 207 type 2 diabetes mellitus (T2DM) patients, who were divided into diabetes with no neuropathy (102 cases) and diabetes with neuropathy (105 cases) groups. Meanwhile, 90 healthy unrelated subjects were recruited as controls. The incidence of MCI in the DPN patients was followed up for 2 years. Divide patients in the DPN group into subgroups according to whether MCI occur, use multivariate logistic regression to analyze independent factors of MCIs in DPN patients within 2 years, and use ROC curve to analyze the predictive value of Fib for MCI in DPN patients., Results: Fib levels were significantly higher in diabetic subjects with neuropathy compared with those without (P < 0.001). In further subgroup analysis of DPN patients who were divided according to the occurrence of MCI, baseline data of the MCI subgroup showed Fib levels were higher than that in the non-MCI group while education levels declined (P < 0.001). The education level and increased Fib levels were independent factors for the occurrence of MCI within 2 years after the onset of DPN (OR = 0.769, 95% CI: 0.605 ~ 0.968, P = 0.037; OR = 2.674, 95% CI: 1.094 ~ 3.168, P = 0.002). The ROC curve indicated that the predictive value of Fib was (AUC = 0.764, 95% CI: 0.671 ~ 0.842, P < 0.001)., Conclusions: Fib may function as a predictor for assessing the risk of MCI in DPN patients., (© 2022. The Author(s).)

Background: The accumulation of advanced glycation end products (AGEs) occurring in skin tissues can be measured by AGE Reader. Here, we assessed the correlation between AGEs values and the development of type 2 diabetic peripheral neuropathy (DPN)., Methods: The basic clinical information of 560 patients with T2DM was collected through an electronic system. AGEs and diabetic complication risk score was measured by AGE Reader, a non-invasive optical signal detector. All of the participants were classified into 4 groups based on Dyck criteria: grade 0 (non-DPN group), grade 1 (early stage group), grade 2 (middle stage group) and grade 3 (advanced group). Pearson correlation analysis and Spearman correlation analysis were used to evaluate the correlation between AGEs and other indexes. The sensitivity and specificity of glycosylated products were evaluated by ROC curve., Results: With the increase of DPN severity, the accumulative AGEs showed an increasing trend. Significant differences (P = 0.000) of AGEs were found among grades 0, 1, 2, and 3 of DPN, and significant differences (P = 0.000) of AGEs were found between grades 1 and 3. There were significant differences in DPN risk score between grades 0, 1, 2, and 3, between grades 1, 2, and 3, and between grades 2 and 3 (P < 0.01 or P < 0.05). AGEs were positively correlated with age, blood uric acid, disease course, systolic blood pressure, the risk scores of the four major complications of diabetes, renal function indicators (serum creatinine, Cystatin C, homocysteine, the ratio of urinary albumin and creatinine, urinary microalbumin, α-microglobulin, urinary transferrin, urinary immunoglobulin), inflammatory indicators (white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, C-reactive protein), and TCSS score. However, it was negatively correlated with BMI,fasting insulin, insulin 1-3 h postprandial, lymphocyte count, HOMA insulin resistance index and estimated glomerular filtration rate. The area under the AGEs cumulant and neuropathy risk score curve was 0.769 and 0.743, respectively. The confidence intervals were (71.2-82.6%) and (68.8-79.9%), respectively. The maximum Youden's index of AGEs cumulant was 0.440, and the corresponding AGEs cumulant value was 77.65. The corresponding sensitivity and specificity were 0.731 and 0.709, respectively. Furthermore, the maximum Youden's index of neuropathy risk score was 0.385, and the corresponding neuropathy risk score was 66.25. The corresponding sensitivity and the specificity were 0.676 and 0.709, respectively., Conclusion: The cumulative amount of skin AGEs can be used as the diagnostic index and the prediction and evaluation index of DPN severity. Moreover, the diabetic peripheral neuropathy risk score can predict the risk of DPN in patients with T2DM., (© 2022. The Author(s).)

Advanced glycation end-products (AGEs) are heterogeneous molecules produced by the non-enzymatic glycation of proteins, lipids, or nucleic acids during hyperglycaemia. Accumulation of AGEs in the peripheral nerves has recently been proposed as an additional risk factor for the development of diabetic neuropathy (DN). The gold standard for measurement of tissue-bound AGEs is tissue biopsy. However, their assessment with the newer, fast and simple method of skin autofluorescence (sAF) has recently gained special interest by virtue of its non-invasive, highly reproducible nature and its acceptable correlation with the reference method of skin biopsy. Accumulation of tissue AGEs evaluated by sAF has been shown to independently correlate with DN. Importantly, increasing evidence underscores their potential value as early biomarkers of the latter. Further important associations include diabetic nephropathy, diabetic retinopathy and cardiovascular autonomic neuropathy. However, the value of the implementation of screening with skin AGEs for DN remains unclear. The aim of the present review is to critically summarise current evidence on the association between skin AGEs and diabetic microvascular complications, with a particular emphasis on diabetic neuropathy, and to note the most important limitations of existing knowledge. Longer follow-up studies are also highly anticipated to clarify its role and provide data on patient selection and cost-effectiveness.

Background: Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM)., Methods: The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed., Results: After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI - 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference - 0.33 V (95% CI - 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA 1c did not confound the associations., Conclusions: Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA 1c . Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Background: We aimed to investigate the correlation of factors involved in the change of Mini-Mental State Examination (MMSE) and type 2 diabetes in the elderly., Methods: This study was a secondary analysis of a prospective cohort study. Type 2 diabetes patients aged > 55 years were recruited and assigned into three groups based on their glycated hemoglobin (HbA1c) levels: HbA1c < 7, 7% ≤ HbA1c < 8% and HbA1c ≥8%. MMSE decline was considered the endpoint. Factors related to MMSE decline were identified by univariate and multivariate regression analyses., Results: Altogether, 1519 subjects were included, 883 in the Low group, 333 in the Median group, and 303 in the High group. Age ≥ 75 years, education below elementary school level, not participating in seminars or consultation on healthcare, physical activity less than 30 min/day, cerebrovascular disease history, MMSE score at baseline, and HBA1c ≥8% were associated with cognitive decline by univariate and multivariate analysis. When the other factors were adjusted for, HBA1c ≥8% was independently associated with the severity of cognitive decline (β = 0.58, 95%CI:0.06-1.11, P = 0.029) and the occurrence of cognitive decline (odds ratio (OR) = 1.55, 95%CI:1.13-2.12, P = 0.007)., Conclusions: In elderly patients with type 2 diabetes, HbA1c ≥8% is an independent factor for cognitive decline and is also associated with the severity of the cognitive decline.

Background: Diabetic foot is an underestimated and redoubtable diabetes complication. The aims of our study were to assess diabetic foot ulcer risk factors according to International Working Group on the Diabetic Foot (IWGDF) classification, stratify patients into risk categories and identify factors associated with higher-risk grade., Methods: Cross-sectional setting over a period of 07 months, patients were randomly selected from the diabetic outpatients attending our unit of diabetology. Questionnaire and clinical examination were made by the same physician. Patients free of active foot ulcer were included., Results: Among 230 patients evaluated, 10 had an active foot ulcer and were excluded. Five patients (2.27%) had a history of foot ulcer and 3(1.36%) had a lower-limb amputation. Sensory neuropathy, as measured by the 5.07(10 g) Semmes-Weinstein monofilament testing, was present in 23.63% of patients, whereas 36.82% had a peripheral arterial disease based on clinical findings, and 43.63% had foot deformities. According to the IWGDF classification, Group 0: 72.72%, Group 1: 5.9%, Group 2: 17.73% and Group 3: 3.63%. After univariate analysis, patients in higher-risk groups were significantly more often female, had higher age and BMI, longer diabetes duration, elevated waist circumference, low school level, retinopathy and hyperkeratosis. Multivariate logistic regression analysis identified 3 significant independent factors associated with high-risk groups: retinopathy (OR = 2.529, CI95 [1.131-5.655], p = 0.024), hyperkeratosis (OR = 2.658, CI95 [1.222-5.783], p = 0.014) and school level (OR = 0.489, CI95 [0.253-9.44], p = 0.033)., Conclusions: Risk factors for foot ulceration were rather common in outpatients with diabetes. The screening of patients at risk for foot ulceration should start early, integrated with sustainable patient education.

Background: This study is a part of a series of two clinical trials. We consider diabetic polyneuropathy (DPN), a common chronic and progressive complication of diabetes mellitus that has several impacts on individuals' foot health and quality of life. Based on the current trends of self-monitoring and self-care, providing a tool with foot-related exercises and educational care may help patients to avoid or reduce the musculoskeletal complications resulting from DPN, improving autonomous performance in daily living tasks. The aim of this trial is to evaluate the effects of an educational booklet for foot care and foot muscle strengthening on DPN symptoms and severity, clinical outcomes, and gait biomechanics in patients with DPN., Methods/design: The FOotCAre (FOCA) trial II study has been designed as a single-blind, two-parallel-arm randomized controlled trial. It will include 48 patients with DPN who will be randomly allocated to a control (recommended foot care by international consensus with no foot exercises) group or an intervention (foot-related exercises using an educational booklet three times/week at home for 8 weeks) group. Participants from both groups will be assessed at baseline, after 8 weeks, and at 16 weeks for follow-up. The primary outcomes are the DPN symptoms and severity, and the secondary outcomes are foot-ankle kinematics, gait kinetics, plantar pressure distribution during gait, tactile and vibratory sensitivities, foot strength, functional balance, and foot health and functionality., Discussion: The booklet is a management tool that allows users to be autonomous in their treatment by choosing how and where to perform the exercises. This allows the patients to perform the exercises regularly as a continuous habit for foot care and health, which is an important element in the management of the diabetic foot. As the booklet focuses on specific foot-ankle exercises, we expect that it will improve the clinical aspects of DPN and produce beneficial biomechanical changes during gait, becoming a powerful self-management tool that can be easily implemented to improve the performance of daily living tasks., Trial Registration: ClinicalTrials.gov, NCT04008745. Registered on 2 July 2019.

Background: Compositional abnormalities in lipoproteins and cardiovascular risk factors play an important role in the progression of diabetic peripheral neuropathy (DPN). This systematic review aimed to estimate the predicting value of low-density lipoprotein (LDL) and systolic blood pressure (SBP) level in type-2 diabetes mellitus (T2DM) patients with and without peripheral neuropathy. We also tried to determine whether LDL and SBP are associated with an increased collision risk of DPN., Methods: A systematic search was conducted for eligible publications which explored the LDL and SBP level in T2DM patients with and without peripheral neuropathy. The quality of the included studies was assessed by the QUADAS-2 tool. The standardized mean difference (SMD) with 95% CI of LDL and SBP level were pooled to assess the correlation between LDL and SBP level with DPN. We performed random effects meta-regression analyses to investigate factors associated with an increased collision risk of DPN., Results: There was a significant association between LDL and SBP with poor prognosis of DPN in those included studies (I 2  = 88.1% and I 2  = 84.9%, respectively, Both P < 0.001). European T2DM patients have higher serum level of LDL in compare with the European DPN patients (SMD = 0.16, 95% CI: - 0.06 - 0.38; P < 0.001). SBP level was associated with a 2.6-fold decrease in non-DPN patients of T2DM (SMD = - 2.63, 95% CI: - 4.00 - -1.27, P < 0.001). Old age European T2DM patients have significantly high risk for diabetes drivers. Furthermore, the results of the case-control study design model are more precise to show the accuracy of SBP in Asian T2DM patients., Conclusion: Our finding supports the LDL and SBP status could be associated with increased risk of peripheral neuropathy in T2DM patients.

Background: To compare neurocognitive functioning of Type 1 diabetic mellitus (T1DM) and healthy adults, and explore risk factors of cognitive dysfunction of T1DM patients, especially the association between cognitive impairment and diabetic peripheral neuropathy (DPN)., Methods: Seventy T1DM (age: 32.17 ± 9.57 yr., duration: 8.99 ± 7.02 yr) patients and 48 healthy volunteers were included. All subjects received evaluation of MMSE and MoCA scales. Cognitive function of T1DM patients was evaluated in different cognitive domains. Risk factors affecting cognitive function were further explored., Results: Three patients with educational level ≤ 6-year were excluded from final analysis. Scores of both MMSE (28.4 ± 1.7 vs. 29.1 ± 1.0, P = 0.005) and MoCA scales (25.9 ± 2.7 vs.27.1 ± 2.4, P = 0.017) in T1DM group were lower than that in control group. For MMSE scale, scores of orientation (9.60 ± 0.79 vs.9.87 ± 0.39, P < 0.001) and language function (8.56 ± 0.65 vs.8.83 ± 0.38, P < 0.001) in T1DM groups were lower than that in control group. For MoCA scale, scores of attention and concentration (2.30 ± 0.74 vs.2.57 ± 0.58, P < 0.001), visuospatial/executive function (4.32 ± 0.91 vs.4.64 ± 0.63, P < 0.001), memory (2.96 ± 1.50 vs.3.66 ± 1.28, P < 0.001), language function (5.71 ± 0.69 vs.5.87 ± 0.39, P = 0.007), and abstraction (1.55 ± 0.68 vs.1.82 ± 0.42, P < 0.001) were lower in T1DM group than that in control group. Logistic regression showed age, fasting C peptide, educational level and nerve conduction velocity (NCV) were associated with cognitive dysfunction diagnosed by MoCA scores for the patients with type 1 diabetes., Conclusions: T1DM adults had mild to moderate cognitive impairment, mainly presenting as dysfunctions of attention and concentration, visuospatial/executive, language, and abstraction. In addition to age, fasting C peptide level, and educational level, DPN, as a diabetic complication, was identified to be associated with cognitive impairments.

Background: Cardiovascular autonomic neuropathy (CAN) is a major cause of morbidity and mortality in diabetes patients. Although several risk factors for CAN progression have been established, whether CAN is reversible remains unclear and the clinical factors associated with CAN recovery have not been identified. This study aimed to determine clinical factors related to CAN recovery., Methods: Type 2 diabetes patients with CAN but free of cardiovascular disease at baseline were enrolled and followed for 2-3 years in this retrospective longitudinal study. CAN was classified as early (one abnormal parasympathetic test), definite (two or more abnormal parasympathetic tests), severe (definite plus orthostatic hypotension), or atypical (early plus orthostatic hypotension or orthostatic hypotension alone) based on Ewing's method. CAN recovery was classified as partial or complete: Partial recovery was defined as one-step improvement in CAN stage (early to normal, definite to early, or severe to definite), including the disappearance of only one abnormal result in any stage. Complete recovery was defined as normalization from definite or severe CAN., Results: Among 759 subjects with CAN, 29.9% (n = 227) experienced CAN recovery, and 1.2% (n = 9) recovered completely. In a multivariate model, younger age (odds ratio [OR] per 5-year decrease 1.49; 95% confidence interval [CI] 1.25-1.78, P < 0.001), shorter duration of diabetes (OR per 5-year decrease 1.33; 95% CI 1.05-1.67, P = 0.016), presence of micro/macroalbuminuria (OR 0.34; 95% CI 0.15-0.78, P = 0.011), body weight reduction (OR per 1-kg decrease 1.11; 95% CI 1.02-1.21, P = 0.016), and HbA1c reduction (OR per 1% decrease 1.32; 95% CI 1.05-1.67, P = 0.019) were significantly associated with composite events of partial and complete CAN recovery. Age had the highest relative significance among the associated clinical factors. In addition, younger age was the only significant factor in complete CAN recovery., Conclusions: Younger age was the most important factor in CAN recovery in subjects with type 2 diabetes, including recovery from the definite or severe stage. HbA1c reduction, body weight reduction, no concurrent micro/macroalbuminuria, and shorter duration of diabetes were also significantly associated with CAN recovery.

Background: To examine whether the progression rate of cardiovascular autonomic neuropathy (CAN) stage is an independent predictive factor for cardiovascular disease (CVD) in type 2 diabetes., Methods: Standardized cardiovascular autonomic reflex tests (CARTs) using traditional Ewing method were performed at baseline. The follow-up CARTs was recommended once every two years. We estimated the primary CVD endpoint, defined as coronary artery disease and ischemic stroke. The association between the progression rate of CAN stage and CVD was examined using time-dependent Cox proportional hazard models., Results: At baseline, 578 patients completed follow-up CARTs; the cohort comprised 329 women (56.9%) with a mean age of 58.3 ± 10.3 years and a mean diabetes duration of 10.1 ± 6.2 years. One hundred and seventy-six patients (30.4%) developed CAN progression between baseline and follow-up CARTs. In the multivariable Cox proportional hazards regression analysis, patients with CAN progression demonstrated a 3.32 times higher risk (95% confidence interval, CI 1.81-6.14, P < 0.001) of CVD than those without CAN progression. Patients who experienced CAN progression from the normal to definite stage had the greatest risk of CVD compared to other patients (hazard ratio 4.91, 95% CI 2.05-11.77, P for trend = 0.001)., Conclusions: CAN stage progression was associated with an increased risk of CVD in this type 2 diabetes cohort. Patients with rapid CAN progression had the greatest risk of CVD. Thus, regular screening and risk management of CAN progression is necessary to prevent CVD.

Background: The relationship between long-term glycemic variability (GV) represented by visit-to-visit HbA1c variability and baroreflex sensitivity (BRS) in type 2 diabetes mellitus (T2DM) has not been clarified by previous literature. The present study is the first to examine the relationships between visit-to-visit HbA1c variability and BRS., Methods: This retrospective study initially analyzed data on 94 patients with T2DM. Visit-to-visit HbA1c variability was evaluated using the intrapersonal coefficient of variation (CV), standard deviation (SD), and adjusted SD of 8 or more serial measurements of HbA1c during a 2-year period. The BRS was analyzed using the sequence method. Short-term GV was assessed by measuring the glucose CV during 24-h continuous glucose monitoring (CGM). The primary objective was to determine if there was a relationship between visit-to-visit HbA1c variability (HbA1c CV) and BRS. Secondary objectives were to examine the relationship between other variables and BRS and the respective and combined effects of long-term GV (HbA1c CV) and short-term GV (CGM CV) on BRS., Results: A total of 57 patients (mean age 67.2 ± 7.7 years, mean HbA1c 7.3 ± 1.0%) who met this study's inclusion criteria were finally analyzed. In the univariate analysis, HbA1c CV (r = - 0.354, p = 0.007), HbA1c SD (r = - 0.384, p = 0.003), and adjusted HbA1c SD (r = - 0.391, p = 0.003) were significantly related to low levels of BRS. Multiple regression analysis showed that HbA1c CV, HbA1c SD, and adjusted HbA1c SD were inversely related to BRS. Furthermore, although the increase in either long-term GV (HbA1c CV) or short-term GV (CGM CV) as determined by 24-h CGM was inversely correlated with BRS, additional reductions in BRS were not shown in participants with both HbA1c CV and CGM CV values above the median., Conclusions: Visit-to-visit HbA1c variability was inversely related to BRS independently of the mean HbA1c in patients with T2DM. Therefore, visit-to-visit HbA1c variability might be a marker of reduced BRS in T2DM.

Background: It is presently unclear whether glycemic variability (GV) is associated with baroreflex sensitivity (BRS), which is an early indicator of cardiovascular autonomic neuropathy. The present study is the first to examine the relationships between BRS and GV measured using continuous glucose monitoring (CGM)., Methods: This was a multicenter, prospective, open-label clinical trial. A total of 102 patients with type 2 diabetes were consecutively recruited for this study. GV was assessed by measuring the standard deviation (SD), glucose coefficient of variation (CV), and the mean amplitude of glycemic excursions (MAGE) during CGM. The BRS was analyzed from electrocardiogram and blood pressure recordings using the sequence method on the first day of hospitalization., Results: A total of 94 patients (mean diabetes duration 9.7 ± 9.6 years, mean HbA1c 61.0 ± 16.8 mmol/mol [7.7 ± 1.5%]) were analyzed. In the univariate analysis, CGM-SD (r = - 0.375, p = 0.000), CGM-CV (r = - 0.386, p = 0.000), and MAGE (r = - 0.395, p = 0.000) were inversely related to BRS. In addition to GV, the level of BRS correlated with the coefficient of variation in the R-R intervals (CVR-R) (r = 0.520, p = 0.000), heart rate (HR) (r = - 0.310, p = 0.002), cardio-ankle vascular index (CAVI) (r = - 0.326, p = 0.001), age (r = - 0.519, p = 0.000), and estimated glomerular filtration rate (eGFR) (r = 0.276, p = 0.007). Multiple regression analysis showed that CGM-CV and MAGE were significantly related to a decrease in BRS. These findings remained after adjusting the BRS for age, sex, hypertension, dyslipidemia, HR, eGFR, CAVI, and CGM-mean glucose. Additionally, BRS was divided according to quartiles of the duration of diabetes (Q1-4). BRS decreased after a 2-year duration of diabetes independently of age and sex., Conclusions: GV was inversely related to BRS independently of blood glucose levels in type 2 diabetic patients. Measurement of BRS may have the potential to predict CV events in consideration of GV. Trial registration UMIN Clinical Trials Registry UMIN000025964, 28/02/2017.

Background: We investigated whether glycated albumin (GA) and its variability are associated with cardiovascular autonomic neuropathy (CAN) and further compared their associations with glycated hemoglobin (HbA1c)., Methods: This retrospective longitudinal study included 498 type 2 diabetic patients without CAN. CAN was defined as at least two abnormal results in parasympathetic tests or presence of orthostatic hypotension. The mean, standard deviation (SD), and coefficient of variance (CV) were calculated from consecutively measured GA (median 7 times) and HbA1c levels (median 8 times) over 2 years. Logistic regression analysis was used to compare the associations between CAN and GA- or HbA1c-related parameters. Receiver operating characteristic (ROC) curve analysis was used to compare the predictive power for CAN between GA- and HbA1c-related parameters., Results: A total of 53 subjects (10.6%) developed CAN over 2 years. The mean, SD, and CV of GA or HbA1c were significantly higher in subjects with CAN. Higher mean GA and GA variability were associated with the risk of developing CAN, independent of conventional risk factors and HbA1c. In ROC curve analysis, the SD and CV of GA showed higher predictive value for CAN compared to the SD and CV of HbA1c, whereas the predictive value of mean GA did not differ from that of mean HbA1c. The mean, SD, and CV of GA showed additive predictive power to detect CAN development along with mean HbA1c., Conclusions: Higher serum GA and its variability are significantly associated with the risk of developing CAN. Serum GA might be a useful indicator for diabetic complications and can enhance HbA1c's modest clinical prediction for CAN.

Diabetic neuropathic osteoarthropathy (DNOAP) is an uncommon, but with considerable morbidity and mortality rates, complication of diabetes. The real pathogenesis is still unclear. The two popular theories are the neuro-vascular theory and neuro-traumatic theory. Most theories and pathways focused on the uncontrolled inflammations that resulted in the final common pathway, receptor activator of nuclear factor κβ ligand (RANKL)/osteoprotegerin (OPG) axis, for the decreased bone density in DNOAP with an osteoclast and osteoblast imbalance. However, the RANKL/OPG pathway does not explain all the changes, other pathways and factors also play roles. A lot of DNOAP potential relative risk factors were evaluated and reported in the literature, including age, gender, weight, duration and type of diabetes, bone mineral density, peripheral neuropathy and arterial disease, trauma history, and some others. However, most of them are still in debates. Future studies focus on the pathogenesis of DNOAP are still needed, especially for the genetic factors. And, the relationship between DNOAP and those potential relative risk factors are still need to further clarify.

Background: Extensively drug-resistant (XDR) tuberculosis (TB) and multidrug resistant (MDR)-TB with additional resistance to injectable agents or fluoroquinolones are challenging to treat due to lack of available, effective drugs. Linezolid is one of the few drugs that has shown promise in treating these conditions. Long-term linezolid use is associated with toxicities such as peripheral and optic neuropathies. Diabetes mellitus (DM), especially when uncontrolled, can also result in peripheral neuropathy. The global burden of DM is increasing, and DM has been associated with a three-fold increased risk of developing TB disease. TB and DM can be a challenging combination to treat. DM can inhibit the host immune response to tuberculosis infection; and TB and some anti-TB drugs can worsen glycaemic control. A child experiencing neuropathy that is a possible complication of both DM and linezolid used to treat TB has not been reported previously. We report peripheral neuropathy in a 15-year-old boy with type 1 DM, diagnosed with MDR-TB and additional resistance to injectable TB medications., Case Presentation: The boy was treated with a linezolid-based regimen, but after 8 months developed peripheral neuropathy. It was unclear whether the neuropathy was caused by the DM or the linezolid therapy. He had clinical improvement following cessation of linezolid and was declared cured following 21 months of treatment. Following completion of treatment, nerve conduction studies demonstrated significant improvement in neuropathy., Conclusions: To the best of our knowledge, this is the first case of peripheral neuropathy reported in a diabetic child on long-term linezolid therapy for tuberculosis. This case study underlines the importance of stringent follow-up for side effects of linezolid, especially when associated with co-morbidity such as DM that increases the chances of adverse effects. The presence of both DM and TB should alert a physician to strive for optimal glycaemic control to minimize the risk of complications as well as optimizing the chances of recovery from TB. Our case report shows the need for close and frequent monitoring for neuropathy to enable early intervention and thereby a favourable outcome in children who may otherwise suffer a long-lasting, debilitating, and painful neuropathy.

Background: Cardiovascular autonomic neuropathy (CAN) increases morbidity and mortality in diabetes through association with a high risk of cardiac arrhythmias and sudden death, possibly related to silent myocardial ischemia. During the sub-clinical stage, CAN can be detected through reduction in heart rate variability (HRV). The aim of our study was to estimate if the time and frequency-domain analysis can be valuable for detecting CAN in young patients with type 1 diabetes mellitus (T1DM)., Methods: For this case control study of evaluation of cardiovascular autonomic function the 15-25 years age group of patients with duration of T1DM more than 9 years (n = 208, 89 males and 119 females) were selected. 67 patients with confirmed CAN were assigned to the "case group" and 141 patients without CAN served as a control group, the duration of T1DM was similar (15.07 ± 4.89 years vs.13.66 ± 4.02 years; p = 0.06) in both groups. Cardiovascular autonomic reflex tests and time and frequency domains analysis of HRV were performed for all subjects., Results: Time domain measures were significantly lower in CAN group compared with control (p < 0.05). R-R max / R-R min ratio and coefficient of variation (CV) were the lowest during deep breathing among T1DM patients with CAN. Receivers operating characteristic (ROC) curves were constructed to compare the accuracies of the parameters of time-domain analysis for diagnosing CAN. We estimated a more reliable cut-off value of parameters of time-domain. The CV values in supine position <1.65, reflected sensitivity 94.3%, specificity 91.5%. The CV values during deep breathing <1.45 reflected sensitivity 97.3%, specificity 96.2%. The CV values in standing position <1.50 reflected sensitivity 96.2%, specificity 93.0%. The most valuable CV was during deep breathing (AUC 0.899). The results of frequency-domain (spectral analysis) analysis showed significant decrease in LF power and LFPA, HF Power and HFPA, total power among subjects with CAN than compared with subjects without CAN (p < 0.05)., Conclusions: Time and frequency domain analysis of HRV permits a more accurate evaluation of cardiovascular autonomic function, providing more information about sympathetic and parasympathetic activity. The coefficient of variation (time-domain analysis) especially during deep breathing could be valuable for detecting CAN.

An emerging treatment modality for reducing damage caused by ischaemia-reperfusion injury is ischaemic conditioning. This technique induces short periods of ischaemia that have been found to protect against a more significant ischaemic insult. Remote ischaemic conditioning (RIC) can be administered more conveniently and safely, by inflation of a pneumatic blood pressure cuff to a suprasystolic pressure on a limb. Protection is then transferred to a remote organ via humoral and neural pathways. The diabetic state is particularly vulnerable to ischaemia-reperfusion injury, and ischaemia is a significant cause of many diabetic complications, including the diabetic foot. Despite this, studies utilising ischaemic conditioning and RIC in type 2 diabetes have often been disappointing. A newer strategy, repeat RIC, involves the repeated application of short periods of limb ischaemia over days or weeks. It has been demonstrated that this improves endothelial function, skin microcirculation, and modulates the systemic inflammatory response. Repeat RIC was recently shown to be beneficial for healing in lower extremity diabetic ulcers. This article summarises the mechanisms of RIC, and the impact that type 2 diabetes may have upon these, with the role of neural mechanisms in the context of diabetic neuropathy a focus. Repeat RIC may show more promise than RIC in type 2 diabetes, and its potential mechanisms and applications will also be explored. Considering the high costs, rates of chronicity and serious complications resulting from diabetic lower extremity ulceration, repeat RIC has the potential to be an effective novel advanced therapy for this condition.

Background: Foot ulceration is the main precursor to lower limb amputation in patients with type 2 diabetes worldwide. Biomechanical factors have been implicated in the development of foot ulceration; however the association of these factors to ulcer healing remains less clear. It may be hypothesised that abnormalities in temporal spatial parameters (stride to stride measurements), kinematics (joint movements), kinetics (forces on the lower limb) and plantar pressures (pressure placed on the foot during walking) contribute to foot ulcer healing. The primary aim of this study is to establish the biomechanical characteristics (temporal spatial parameters, kinematics, kinetics and plantar pressures) of patients with plantar neuropathic foot ulcers compared to controls without a history of foot ulcers. The secondary aim is to assess the same biomechanical characteristics in patients with foot ulcers and controls over-time to assess whether these characteristics remain the same or change throughout ulcer healing., Methods/design: The design is a case-control study nested in a six-month longitudinal study. Cases will be participants with active plantar neuropathic foot ulcers (DFU group). Controls will consist of patients with type 2 diabetes (DMC group) and healthy participants (HC group) with no history of foot ulceration. Standardised gait and plantar pressure protocols will be used to collect biomechanical data at baseline, three and six months. Descriptive variables and primary and secondary outcome variables will be compared between the three groups at baseline and follow-up., Discussion: It is anticipated that the findings from this longitudinal study will provide important information regarding the biomechanical characteristic of type 2 diabetes patients with neuropathic foot ulcers. We hypothesise that people with foot ulcers will demonstrate a significantly compromised gait pattern (reduced temporal spatial parameters, kinematics and kinetics) at base line and then throughout the follow-up period compared to controls. The study may provide evidence for the design of gait-retraining, neuro-muscular conditioning and other approaches to off-load the limbs of those with foot ulcers in order to reduce the mechanical loading on the foot during gait and promote ulcer healing.

Background: Whereas a few studies have reported associations of serum omentin levels with subclinical atherosclerosis in patients with diabetes, little information is available with respect to the associations of serum omentin levels and diabetic microvascular complications. The aim of this study was to investigate the relationships of serum omentin levels and vascular complications including cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM)., Methods: We recruited 97 patients who evaluated complications of diabetes. CAN was assessed by five standard cardiovascular reflex tests according to Ewing's protocol. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) were evaluated. Serum omentin levels were assessed by ELISA. Atherosclerotic burden was evaluated by measuring the brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI)., Results: The prevalence of CAN increased borderline significantly across the omentin tertiles (p = 0.05) and CAN point increased significantly and progressively across the omentin tertiles (p = 0.013). The prevalence of other microvascular complications (DPN, DN, and DR) did not differ among omentin tertiles. The mean levels of baPWV also increased significantly and progressively across the omentin tertiles (p = 0.002). Serum omentin levels were significantly positively correlated with CAN point (p = 0.004) and borderline significantly correlated with baPWV (p = 0.05) after multivariate adjustment. Regarding linear regression analysis for CAN point, univariate regression analysis demonstrated that CAN point associated with omentin, diastolic blood pressure (DBP) and hsCRP. Multiple regression analysis revealed that omentin levels, together DBP and baPWV correlated with CAN point. This present study suggests that serum omentin levels may be independently associate with CAN in patients with T2DM.

Background: It is presently unclear whether glycemic variability is associated with diabetic cardiovascular autonomic neuropathy (CAN). The aim of this study was to examine whether short- and/or long-term glycemic variability (GV) contribute to CAN., Methods: A total of 110 patients with type 2 diabetes who underwent three-day continuous glucose monitoring (CGM) completed five standardized autonomic neuropathy tests. Short-term GV was measured by the standard deviation (SD), coefficient of variation (CV) of glucose, and the mean amplitude of glycemic excursions (MAGE) in CGM. HbA1c variability was calculated from the intrapersonal SD, adjusted SD, and CV of serial HbA1c over 2-year period. CAN was defined as the presence of at least two abnormal parasympathetic function tests. The severity of CAN was evaluated by total scores of five autonomic function tests., Results: In univariate analysis, not only SD and CV in CGM but also all parameters of HbA1c variability were significantly higher in the patients with CAN (n = 47, 42.7 %) than in those without CAN. In multivariate analysis, CV (Odds ratio [OR] 1.07, 95 % confidence interval [CI] 1.01-1.13; p = 0.033), but neither SD nor MAGE in CGM, independently correlated with the presence of CAN. All parameters of HbA1c variability, such as SD of HbA1c (OR 12.10 [95 % CI 2.29-63.94], p = 0.003), adjusted SD of HbA1c (OR 17.02 [95 % CI 2.66-108.86], p = 0.003), and log CV of HbA1c (OR 24.00 [95 % CI 3.09-186.48], p = 0.002), were significantly associated with the presence of CAN. The patients with higher HbA1c variability had an increased risk of advanced CAN., Conclusion: CV in CGM and all parameters of HbA1c variability were independently associated with the presence of CAN in patients with inadequately controlled type 2 diabetes requiring CGM.

Background: Painful neuropathy is the most common and debilitating complication of diabetes and results in hyperalgesia and allodynia. Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Current therapeutic approaches are only partially successful and they are only thought to reduce the pain associated with peripheral neuropathy. Some natural products offer combined antioxidant, anti-inflammatory and antinociceptive properties that may help to treat in a more integrative manner this condition. In this regard, the purpose of this study was to investigate the antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rats and mice without glucose control as well as the possible mechanism of action involved in this effect., Methods: Rats and mice were injected with 50 or 200 mg/kg streptozotocin, respectively, to produce hyperglycemia. The formalin test and von Frey filaments were used to assess the nociceptive activity. Rota-rod was utilized to measure motor activity and malondialdehyde assay to determine anti-oxidative properties., Results: After 3 weeks of diabetes induction, chemical hyperalgesia was observed in streptozotocin-injected rats. Oral acute administration of 7-hydroxy-3,4-dihydrocadalin (0.3-30 mg/kg) decreased in a dose-dependent manner formalin-evoked hyperalgesia in diabetic rats. In addition, methiothepin (non-selective 5-HT receptor antagonist, 1 mg/kg, i.p.) and ODQ (guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (opioid receptor antagonist, 1 mg/kg, s.c.), prevented 7-hydroxy-3,4-dihydrocadalin-induced antihyperalgesic effect. The anti-hyperalgesic effect of 7-hydroxy-3,4-dihydrocadalin was similar to that produced by pregabalin (10 mg/kg, p.o.). Furthermore, oral acute administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) reduced streptozotocin-induced changes in malondialdehyde concentration from plasma samples. Unlike pregabalin, 7-hydroxy-3,4-dihydrocadalin did not affect motor activity. Six weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. At this time, oral administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) or pregabalin (10 mg/kg) reduced in a similar way tactile allodynia in diabetic rats. Finally, chronic oral administration of 7-hydroxy-3,4-dihydrocadalin (30-300 mg/kg, 3 times/week, during 6 weeks), significantly prevented the development of mechanical hyperalgesia and allodynia in streptozotocin-induced diabetic mice., Conclusions: Data suggests that 7-hydroxy-3,4-dihydrocadalin has acute and chronic effects in painful diabetic neuropathy. This effect seems to involve antioxidant properties as well as activation of 5-HT receptors and inhibition of guanylyl cyclase enzyme.

Background: Accurate and precise estimates of glomerular filtration rate (GFR) are essential for clinical assessments, and many methods of estimation are available. We developed a radial basis function (RBF) network and assessed the performance of this method in the estimation of the GFRs of 207 patients with type-2 diabetes and CKD., Methods: Standard GFR (sGFR) was determined by (99m)Tc-DTPA renal dynamic imaging and GFR was also estimated by the 6-variable MDRD equation and the 4-variable MDRD equation., Results: Bland-Altman analysis indicated that estimates from the RBF network were more precise than those from the other two methods for some groups of patients. However, the median difference of RBF network estimates from sGFR was greater than those from the other two estimates, indicating greater bias. For patients with stage I/II CKD, the median absolute difference of the RBF network estimate from sGFR was significantly lower, and the P50 of the RBF network estimate (n = 56, 87.5%) was significantly higher than that of the MDRD-4 estimate (n = 49, 76.6%) (p < 0.0167), indicating that the RBF network estimate provided greater accuracy for these patients., Conclusions: In patients with type-2 diabetes mellitus, estimation of GFR by our RBF network provided better precision and accuracy for some groups of patients than the estimation by the traditional MDRD equations. However, the RBF network estimates of GFR tended to have greater bias and higher than those indicated by sGFR determined by (99m)Tc-DTPA renal dynamic imaging.

Background: Non-invasive measurements of 24 hour ambulatory central aortic systolic pressure (24 h-CASP) and central pulse pressure (24 h-CPP) are now feasible. We evaluate the relationship between 24 h central blood pressure and diabetes-related complications in patients with type 1 diabetes., Methods: The study was cross-sectional, including 715 subjects: 86 controls (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) without receiving antihypertensive treatment (SN), 211 with longstanding diabetes (≥ 10 years) and normoalbuminuria (LN), 163 with microalbuminuria (30-299 mg/24 h) (Mi) and 186 with macroalbuminuria (> 300 mg/24 h) (Ma).24 h-CASP and 24 h-CPP was measured using a tonometric wrist-watch-like device (BPro, HealthStats, Singapore) and derived using N-point moving average., Results: In C, SN, LN, Mi and Ma mean ± SD 24 h-CASP was: 114 ± 17, 115 ± 13, 121 ± 13, 119 ± 16 and 121 ± 13 mmHg (p < 0.001); and 24 h-CPP: 38 ± 8, 38 ± 7, 44 ± 10, 46 ± 11 and 46 ± 11 mmHg, (p < 0.001).Following rigorous adjustment (24 h mean arterial pressure and conventional risk factors), 24 h-CASP and 24 h-CPP increased with diabetes, albuminuria degree, previous cardiovascular disease (CVD), retinopathy and autonomic dysfunction (p ≤ 0.031).Odds ratios per 1 standard deviation increase in 24 h-CASP, 24 h-CPP and 24 h systolic blood pressure (24 h-SBP) were for CVD: 3.19 (1.68-6.05), 1.43 (1.01-2.02) and 2.39 (1.32-4.33), retinopathy: 4.41 (2.03-9.57), 1.77 (1.17-2.68) and 3.72 (1.85-7.47) and autonomic dysfunction: 3.25 (1.65-6.41), 1.64 (1.12-2.39) and 2.89 (1.54-5.42)., Conclusions: 24 h-CASP and 24 h-CPP was higher in patients vs. controls and increased with diabetic complications independently of covariates. Furthermore, 24 h-CASP was stronger associated to complications than 24 h-SBP.The prognostic significance of 24 h-CASP and 24 h-CPP needs to be determined in follow-up studies., Trial Registration: ClinicalTrials.gov ID NCT01171248.

Background: It's unknown whether the prognostic value of admission heart rate (HR) was different in patients with ST-segment elevation myocardial infarction (STEMI) with or without concomitant type 2 diabetes mellitus (T2DM)., Methods: Consecutive STEMI patients who presented within 12 hours of symptom onset were recruited from 274 hospitals in China. Participants were stratified into quartiles by admission HR. Baseline characteristics, current therapeutic recommenda- tions, laboratory biochemical tests, 30-day all-cause mortality and Cardiovascular Events (CVE, including all-cause death, reinfarction and stroke) were compared across admission HR quartiles., Results: We evaluated 7294 STEMI patients, of these 820 (11.2%) had known T2DM. The admission HR quartile stratification was significantly associated with all-cause mortality and CVE regardless of T2DM status (P < 0.001 both for survival and CVE). After adjusted other risk factors, in patients without T2DM, comparing with HR <66 b.p.m., the increase of HR level was associated with worse prognosis (P < 0.05). In patients with T2DM, the hazard ratios for 30-day CVE were 1.75 (95%CI), 1.92 (95%CI), 3.00 (95%CI) in the HR of 66-76 b.p.m., 77-88 b.p.m., and >88 b.p.m., respectively. Results were similar for 30-day all-cause mortality, but the hazard ratios in Q2 (P = 0.139 and P =0.086 for survival and CVE, respectively) and Q3 groups were non-significant (P = 0.072 and P =0.033 for survival and CVE, respectively). There was a significant interaction effect of HR and T2DM on 30-day CVE mortality (P = 0.035), which was not found on all-cause mortality (P = 0.126)., Conclusion: Admission heart rate was an important risk factor of 30-day all-cause mortality and CVE in patients with STEMI with or without T2DM. However, the predictive effect was modified by T2DM.

Background: Few large-scale, real-world studies have assessed the relative associations of lipid fractions with diabetic microvascular events. The main objective of this study was to evaluate the association of the lipid profile components, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high density lipoprotein cholesterol (non-HDL-C) with microvascular complications (MVCs) in type 2 diabetes mellitus (T2DM) patients., Methods: This observational cohort study queried the HealthCore Integrated Research Database (HIRDSM) for newly-diagnosed (Index Date) 18-64-year-old patients with diabetes mellitus between 01/01/2005-06/30/2010. Inclusion required ≥ 12 months pre-index continuous health plan eligibility and ≥ 1 pre-index lipid profile result. Patients with polycystic ovary syndrome and prior MVCs were excluded. Incident complications were defined as the earliest occurrence of diabetic retinopathy, peripheral neuropathy, and/or nephropathy post-index. Cox proportional models and Kaplan-Meier (KM) curves were used to evaluate associations among variables., Results: Of the patients (N=72,267), 50.05% achieved HDL-C, 64.28% LDL-C, 59.82% TG, and 56.79% non-HDL-C American Diabetes Association goals at baseline. During follow-up (mean, 21.74 months), there were 5.21 microvascular events per 1,000 patient-months. A 1-mg/dL increase in HDL-C was associated with 1% decrease in any MVC risk (P< .0001), but for LDL-C, TG, and non-HDL-C, 1-mg/dL increase resulted in increases of 0.2% (P< .0001), 0.1% (P<0.001) and 0.3% (P<0.001) in MVC risk. Patients achieving HDL-C goals had a 11% lower risk of MVC versus non-achievers (RR 0.895, [95% CI, 0.852-0.941], P< .0001). Similarly, TG goal attainment was associated with a lowered risk for any MVC (RR 0.849, [95% CI, 0.808-0.892], P< .0001). Evaluation of KM survival curves demonstrated no significant difference in the risk of MVCs between patients achieving vs. not achieving LDL-C goals, but did demonstrate a difference in MVC risk between patients achieving vs. not achieving non-HDL-C goals., Conclusion: This study demonstrates significant independent associations among lipid fractions and risk for microangiopathy. These findings suggest that attaining established ADA goals for HDL-C, TG, and non-HDL-C may reduce risk for microvascular events among patients with diabetes.

Background: Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. In addition, the autonomic imbalance is associated with cardiovascular disease (CVD) in diabetes. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, tumor necrosis factor-alpha (TNF-alpha), adiponectin in subjects with T2DM is limited.Therefore, in the present study, we examined the relationship between fasting serum leptin, TNF- alpha and adiponectin and CAN in Korean T2DM patients., Methods: A total of 142 T2DM patients (94 males, 48 females) were recruited. CAN was assessed by the five tests according to the Ewing's protocol and the time and frequency domain of the heart rate variability (HRV) was evaluated. Serum TNF-alpha and adiponectin levels were measured using enzyme-linked immunosorbent assay and serum leptin levels were measured using radioimmunoassay., Results: Although, the mean levels of leptin, TNF-alpha and adiponectin were not significantly different between the groups with and without CAN, the levels of leptin and adiponectin had a tendency to increase as the score of CAN increased (p = 0.05, p = 0.036). Serum leptin levels demonstrated a negative correlation with low frequency (LF) in the upright position (p = 0.037). Regarding TNF-alpha, a significant negative correlation was observed with SDNN and RMSSD in the upright position (p = 0.023, p = 0.019). Adiponectin levels were not related to any HRV parameters. Multivariate logistic regression analysis demonstrated that the odds of CAN increased with a longer duration of diabetes (1.25, [1.07-1.47]) and higher homeostatic model of assessment-insulin resistance (HOMA-IR) (5.47, [1.8-16.5]). The relative risks for the presence of CAN were 14.1 and 51.6 for the adiponectin 2nd, 3rd tertiles when compared with first tertile (p-value for trend = 0.022)., Conclusions: In the present study, the higher serum adiponectin levels and HOMA-IR were associated with an increased risk for the presence of CAN. Also, the CAN score correlated with the serum adiponectin. Serum adipocytokines such as leptin and TNF-alpha were significantly correlated with parameters of HRV, representative markers of CAN. Future prospective studies with larger number of patients are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of CAN.

Background: The various autonomic control systems lead to characteristic changes in heart rate (HR) and blood pressure (BP) during acute hemorrhage. However, cardiovascular autonomic neuropathy due to diabetes mellitus may interfere with the normal compensation for hemorrhage., Materials and Methods: A controlled graded bleeding (6 - 36% loss of estimated total blood volume: ETBV) was performed in streptozotocin-induced diabetic rats (STZ rats) under a conscious state. Hemodynamic and autonomic responses to acute hemorrhage were examined using analysis of BP-HR variability. The effects of dextran treatment after hemorrhage were also examined., Results: A significant reduction in mean arterial pressure began at 12% ETBV loss in STZ rats and 18% in the control rats, respectively. When blood loss reached 18% of TEBV, the decrease in HR was prominent in STD rats due to the activation of a parasympathetic drive, as indicated by the increase in high frequency (HF; 0.75~3.0 Hz) power in HR variability, while in the control rats this response was not observed. The administration of dextran prevented the activation of the parasympathetic drive in STZ rats during hemorrhaging. In the control rats, the dextran treatment sustained the initial increase in HR with reduced HF power in HR variability., Conclusion: STZ rats showed different hemodynamic and autonomic responses to acute hemorrhage from the control rats. STZ rats were prone to develop bradycardiac hypotension characterized by marked parasympathetic activation during hemorrhaging. This finding suggests enhancement of the Bezold-Jarisch reflex in STZ rats. Dextran treatment to maintain a normovolemic hemorrhage state inhibits this reflex.

Background: Type 2 Diabetes Mellitus (T2DM) and diabetic symmetrical polyneuropathy (DSP) impact multiple modalities of sensation including light touch, temperature, position sense and vibration perception. No study to date has examined the mechanosensitivity of peripheral nerves during limb movement in this population. The objective was to determine the unique effects T2DM and DSP have on nerve mechanosensitivity in the lower extremity., Methods: This cross-sectional study included 43 people with T2DM. Straight leg raise neurodynamic tests were performed with ankle plantar flexion (PF/SLR) and dorsiflexion (DF/SLR). Hip flexion range of motion (ROM), lower extremity muscle activity and symptom profile, intensity and location were measured at rest, first onset of symptoms (P1) and maximally tolerated symptoms (P2)., Results: The addition of ankle dorsiflexion during SLR testing reduced the hip flexion ROM by 4.3° ± 6.5° at P1 and by 5.4° ± 4.9° at P2. Individuals in the T2DM group with signs of severe DSP (n = 9) had no difference in hip flexion ROM between PF/SLR and DF/SLR at P1 (1.4° ± 4.2°; paired t-test p = 0.34) or P2 (0.9° ± 2.5°; paired t-test p = 0.31). Movement induced muscle activity was absent during SLR with the exception of the tibialis anterior during DF/SLR testing. Increases in symptom intensity during SLR testing were similar for both PF/SLR and DF/SLR. The addition of ankle dorsiflexion induced more frequent posterior leg symptoms when taken to P2., Conclusions: Consistent with previous recommendations in the literature, P1 is an appropriate test end point for SLR neurodynamic testing in people with T2DM. However, our findings suggest that people with T2DM and severe DSP have limited responses to SLR neurodynamic testing, and thus may be at risk for harm from nerve overstretch and the information gathered will be of limited clinical value.

Background: The pathophysiological basis of diabetic gastroparesis is poorly understood, in large part due to the almost complete lack of data on neuropathological and molecular changes in the stomachs of patients. Experimental models indicate various lesions affecting the vagus, muscle, enteric neurons, interstitial cells of Cajal (ICC) or other cellular components. The aim of this study was to use modern analytical methods to determine morphological and molecular changes in the gastric wall in patients with diabetic gastroparesis., Methods: Full thickness gastric biopsies were obtained laparoscopically from two gastroparetic patients undergoing surgical intervention and from disease-free areas of control subjects undergoing other forms of gastric surgery. Samples were processed for histological and immunohistochemical examination., Results: Although both patients had severe refractory symptoms with malnutrition, requiring the placement of a gastric stimulator, one of them had no significant abnormalities as compared with controls. This patient had an abrupt onset of symptoms with a relatively short duration of diabetes that was well controlled. By contrast, the other patient had long standing brittle and poorly controlled diabetes with numerous episodes of diabetic ketoacidosis and frequent hypoglycemic episodes. Histological examination in this patient revealed increased fibrosis in the muscle layers as well as significantly fewer nerve fibers and myenteric neurons as assessed by PGP9.5 staining. Further, significant reduction was seen in staining for neuronal nitric oxide synthase, heme oxygenase-2, tyrosine hydroxylase as well as for c-KIT., Conclusion: We conclude that poor metabolic control is associated with significant pathological changes in the gastric wall that affect all major components including muscle, neurons and ICC. Severe symptoms can occur in the absence of these changes, however and may reflect vagal, central or hormonal influences. Gastroparesis is therefore likely to be a heterogeneous disorder. Careful molecular and pathological analysis may allow more precise phenotypic differentiation and shed insight into the underlying mechanisms as well as identify novel therapeutic targets.