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The objective of this pilot clinical study was to identify salivary biomarkers that are associated with periodontal disease and measures of diabetic autonomic dysfunction. Saliva samples from 32 participants were obtained from 3 groups: healthy (H), type 1 diabetes mellitus (DM), and type 1 diabetes mellitus with neuropathy (DMN). Based on the periodontal examination, individuals' mean Periodontal Screening and Recording scores were categorized into two groups (periodontally healthy and gingivitis), and correlated to specific salivary inflammatory biomarkers assessed by a customized protein array and enzyme assay. The mean salivary IgA level in DM was 9211.5 ± 4776.4 pg/ml, which was significantly lower than H (17,182.2 ± 8899.3 pg/ml). IgA in DMN with healthy periodontium was significantly lower (5905.5 ± 3124.8 pg/ml) compared to H, although IgA levels in DMN patients with gingivitis (16,894. 6 ± 7084.3) were not. According to the result of a logistic regression model, IgA and periodontal condition were the indicators of the binary response given by H versus DM, and H versus DMN, respectively. These data suggest that selected salivary biomarkers, such as IgA, combined with a periodontal examination prior to obtaining salivary samples can offer a non-invasive method to assess risk for developing diabetic neuropathy., (© 2022. The Author(s).)

Background: Diabetic microvascular complications, including diabetic kidney disease (DKD), retinopathy (DR), and neuropathy (DN), were major causes of morbidity and mortality in diabetic patients worldwide. It has been suggested that urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were not the only indicators of renal function impairment in DKD and that they were also associated with diabetic peripheral neuropathy (DPN) which might affect nerve conduction velocity (NCV). As 30-40% of DPN patients had no subjective symptoms, while current perception threshold (CPT) could detect sensory nerve damage at an early stage. As a result, we aimed to investigate correlation between UACR, eGFR and CPT in DKD patients., Methods: A total of 273 DKD patients from the First Affiliated Hospital of Kunming Medical University from January 2018 to June 2020 were enrolled to complete the CPT test. CPT values of the bilateral median nerve and superficial and deep peroneal nerves at 2000 Hz, 250 Hz, and 5 Hz were collected., Results: In normoesthesia and hypaesthesia patients with DKD, MDRD-eGFR correlated negatively with TC (r = -0.135, P = 0.037), left superficial peroneal and deep peroneal nerve 2000 Hz CPT (r = -0.205, P = 0.001) and right superficial peroneal and deep peroneal nerve 2000 Hz CPT (r = -0.154, P = 0.017). Besides, left and right superficial peroneal and deep peroneal nerve 2000 Hz CPT correlated with CKD-EPI-eGFR and UACR. Multivariate logistic regression analysis found left superficial peroneal and deep peroneal nerve 2000 Hz CPT was independently associated with both MDRD-eGFR and CKD-EPI-eGFR., Conclusion: Decreased MDRD-eGFR and CKD-EPI-eGFR were expected to be a predictor of peripheral nerve injury in normoesthesia and hypaesthesia patients with DKD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Clinical Relevance: There is potential benefit in analysing corneal nerve tortuosity as a marker for assessment and progression of systemic diabetic neuropathy., Background: The aim of this work was to determine whether tortuosity significantly differs in participants with type 1 (T1DM) and type 2 (T2DM) diabetes compared to controls and whether tortuosity differed according to neuropathy status., Methods: Corneal nerves of 164 participants were assessed across T1DM, T2DM and control groups. Images of corneal nerves were captured via in vivo corneal confocal microscopy. Diabetic neuropathy status was examined using the Total Neuropathy Score (TNS). Tortuosity was assessed with Cfibre v0.097. Results were compared between groups with a linear mixed model accounting for location of image and controlling for age, producing Tortuosity Factor (TF), an estimate of the marginal means of each group., Results: Tortuosity was significantly reduced in the T1DM group compared to controls (TF = 0.241, 95%CI = 0.225-0.257 vs. TF = 0.272, 95%CI = 0.252-0.292; mean difference = -0.031, p = 0.02) and in the T2DM group compared to controls (TF = 0.261, 95%CI = 0.244-0.278 vs. TF = 0.289, 95%CI = 0.270-0.308; mean difference = -0.029, p = 0.03). Tortuosity did not significantly differ between participants with T1DM and T2DM accounting for age and TNS (TF = 0.240, 95%CI = 0.215-0.265 vs. 0.269, 95%CI = 0.244-0.293, mean difference = -0.029, p = 0.11). Tortuosity was significantly reduced in participants with neuropathy (TNS≥2) compared to participants with no neuropathy (TNS< 2) (TF = 0.248, 95%CI = 0.231-0.265 vs. TF = 0.272, 95%CI = 0.260-0.283; mean difference = -0.024, p = 0.03)., Conclusions: Tortuosity is significantly reduced in participants with T1DM and T2DM compared to age matched controls and in participants with neuropathy compared to those without neuropathy.

Goals: Identify conditioning factors of the foot risk (FR) by comparing two evaluation methods (qualitative and quantitative) for neuropathy, arteriopathy, foot deformities. Concordance between detected the alterations and registered in clinical history (CH)., Material and Methods: It is an observational study. Ambit: in two primary care centers of the Catalan Health Institute., Population: Five hundred thirty-two patients with diabetes, both >18 years with FR records and informed consent., Measurements: Neuropathy: symptom assessment (NSS) and signs of disability (NDS). Arteriopathy: Index ABI. Edinburgh Questionnaire, fart pulses. Foot deformities: Pedigraphy. Quantitative reference: Values Defined neuropathy: NDS>6 points or 3-5 and NSS>5 points. ITB: Normal value (.90-1.30)., Results: Women, 46.42%. Middle ages, 67.29 years (SD 7.69). One hundred fifty-three patients did not present neurovascular alterations., Qualitative: Without differentiating clinical manifestations: 252, patients presented neuropathy; 99, altered ITB; 28, two complications and 101, Edinburgh Quiz: altered., Quantitative: Differentiating clinical manifestations: among the neuropathy group; 110, patients only presented symptoms; 46, definite neuropathy. In 96, NDS and NSS scores without defined neuropathy criteria., Altered Abi: 52, only ABI>1.30; 47, ABI<.90; 12, associated neuropathy and ABI>1.30 and 16, with ABI<.90. Edinburgh questionnaire: 47, presented atypical symptoms and 26, typical. Agreement, between quantitative and recorded neurovascular alterations r=.32 for neuropathy and r=.21 in arteriopathy. The pressure point on the 5th metatarsal, was associated with quantitative neuropathy: OR: 2.32 (1.188-4.546), P=.01., Conclusion: The evaluation, identifying clinical manifestations, improves the identification of FR, although we need more research., (Copyright © 2022 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

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

Aims: This three-year follow-up study aimed to elucidate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) have any protection against diabetic neuropathy and nephropathy in patients with type 2 diabetes via reducing variability in glycemia and extraglycemic factors or their averages., Methods: Two type 2 diabetic cohorts of 40 and 73 patients treated with or without SGLT2i along with 60 control subjects were recruited. Two diabetic cohorts matched for HbA1c levels and oral hypoglycemic agents other than SGLT2is underwent glycemic control with or without SGLT2is more than two years. The urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) every 3 months and neuropathy outcome measures and mean Z-score of 8 neurophysiological tests were determined at the baseline and endpoint. Glycemic variability, evaluated by the coefficient of variation of monthly measured HbA1c levels and casual postprandial plasma glucose (CPPG), and coefficient of variation and average of extraglycemic parameters in diabetic cohorts were determined., Results: The glycemic variability and variability of some extraglycemic factors in SGLT2i cohort were smaller than those in non-SGLT2i cohort. However, only smaller coefficient of variation of HbA1c improved some neuropathy outcome measures, and ameliorated eGFR decline. SGLT2i improved the Z-score of neurophysiological tests. The optimized changes in the blood pressure, HDL-cholesterol and uric acid by SGLT2i led to neurological and renal protection. SGLT2i decreased the prevalence of nephropathy significantly and the prevalence of neuropathy insignificantly., Conclusion: Over 3 years period, SGLT2i significantly improved some neuropathy outcome measures, mean Z-score of 8 neurophysiological tests, and attenuated nephropathy in modestly controlled type 2 diabetes by reducing glycemic variability and mean nonglycemic factors of diabetic microvascular complication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ishibashi, Kosaka and Tavakoli.)

Diabetic peripheral neuropathy (DPN) includes symptoms of thermosensory impairment, which are reported to involve changes in the expression or function, or both, of nociceptive TRPV1 and TRPA1 channels in rodents. In the present study, we did not find changes in the expression or function of TRPV1 or TRPA1 in DPN mice caused by STZ, although thermal hypoalgesia was observed in a murine model of DPN or TRPV1 -/- mice with a Plantar test, which specifically detects temperature avoidance. With a Thermal Gradient Ring in which mice can move freely in a temperature gradient, temperature preference can be analyzed, and we clearly discriminated the temperature-dependent phenotype between DPN and TRPV1 -/- mice. Accordingly, we propose approaches with multiple behavioral methods to analyze the progression of DPN by response to thermal stimuli. Attention to both thermal avoidance and preference may provide insight into the symptoms of DPN., (© 2022. The Author(s).)

Diabetic peripheral neuropathy (DPN), peripheral artery disease (PAD), and foot deformity are the most common causes of diabetic foot, which can considerably worsen the patient's quality of life. In this study, we aimed to investigate the prevalence and risk factors associated with DPN, PAD, and foot deformity among patients with diabetes living in Beijing, China. In total, 3,898 diabetes patients from 11 hospitals in Beijing were evaluated using questionnaires and physical examinations, and 3,758 patients were included in the analysis. We compared the demographic, clinical, biological characteristics, and comorbidities of patients with and without DPN, PAD, or foot deformity, and used binary logistic regression analysis to identify potential factors associated with these outcomes. Overall, 882 patients (23.5%) had DPN, 437 patients (11.6%) had PAD, and 1,117 patients (29.7%) had foot deformities, including callus. The risk factors for DPN included: age ≥40 years, a ≥10+year duration of diabetes, a body mass index of <18.5 kg/m 2 or ≥24 kg/m 2 , a systolic blood pressure (SBP) of ≥140 mm Hg, a hemoglobin A 1c (HbA 1c ) level of ≥7%, chronic kidney disease, and cerebrovascular disease. The risk factors for PAD included: a 15+ year diabetes duration, a body mass index of <18.5 kg/m 2 , a SBP of ≥140 mm Hg, a HbA 1c level of ≥7%, chronic kidney disease, coronary heart disease, and cerebrovascular disease. The risk factors for skeletal foot deformities included: women, age ≥40 years, a SBP ≥140 mm Hg, and hyperlipidemia. The risk factors for callus formation included: women, a SBP ≥140 mm Hg, and hyperlipidemia. In conclusion, the prevalence of foot deformities was higher than DPN and PAD in patients with diabetes. Managing the risk factors for DPN, PAD, and foot deformity is important for reducing the risk of diabetic foot., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Yuan, Liu, Yuan, Sun, Zhang, Qi, Li, Zhang, Wen and Guo.)

Aims/introduction: To assess the relationship between type 2 diabetes mellitus onset age and vascular complications in China., Materials and Methods: A retrospective review of 3,568 patients with type 2 diabetes mellitus using a propensity score-matched (PSM) cohort analysis was carried out in two different age of onset groups (age 40 and 60 years). These groups were then subdivided into two groups, early-onset diabetes (EOD40 and EOD60; the onset age before 40 and 60 years, respectively) and late-onset diabetes (LOD40 and LOD60: the onset age after 40 and 60 years, respectively). Macrovascular and microvascular complications were analyzed before and after PSM., Results: Patients categorized in both the early-onset disease (EOD) groups had a higher risk of developing macro- and microvascular complications before PSM. After PSM, no differences existed between the EOD and late-onset disease groups in the risk of macrovascular complications. Compared with the late-onset disease group, the odds ratio of having a microvascular complication of diabetic retinopathy, chronic kidney disease and diabetic peripheral neuropathy in the 40-year-old EOD group increased to 2.906, 1.967 and 1.672 (P < 0.05), respectively. The odds ratio of diabetic retinopathy and diabetic peripheral neuropathy in the 60-year-old EOD group was 1.763 and 1.675 (P < 0.05), respectively., Conclusions: The earlier the onset of type 2 diabetes mellitus, the higher risk of microvascular, but not necessarily macrovascular, complications. It is not too late to prevent diabetes at any age. Pre-emptive microvascular treatment or preventative measures in EOD patients who do not yet show symptoms, might be beneficial., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: Diabetic neuropathy leads to postural instability. This study compared longitudinal changes in neuropathy outcomes relative to long-term glycemic control in patients aged <60 years with uncontrolled type 2 diabetes with and without a short one-leg standing time (OLST <60 s)., Materials and Methods: In this retrospective study, 58 hospitalized patients with type 2 diabetes (glycated hemoglobin [HbA1c] >7.0%; aged 17-59 years), who underwent re-evaluation of neuropathic sensory symptoms, ankle reflexes and nerve conduction attributes, and cardiac autonomic function (R-R interval), >1 year after discharge were divided into OLST <60 and ≥60 s groups. Patients were followed up every 2-3 months for HbA1c levels for up to 8 years. Neuropathy outcomes relative to OLST and HbA1c levels at baseline and over follow up were compared., Results: Additional development of sensory symptoms (one patient) and abnormal ankle reflexes (five patients) were identified during follow up, and decreased peripheral and cardiac autonomic function at both baseline and follow up, only in patients with OLST <60 s. Mean HbA1c levels were significantly higher in patients with OLST <60 s versus ≥60 s (7.8 ± 0.9% vs 7.2 ± 1.2%; P = 0.022). Better glycemic control during follow up was associated with better neuropathy outcomes only in patients with OLST ≥60 s., Conclusion: Non-elderly type 2 diabetes patients with OLST <60 s and decreased peripheral nerve function at baseline are at increased risk for intractable diabetic neuropathy. Better glycemic control alone might not improve neuropathy outcomes in these patients., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy., (© 2022. The Author(s).)

This paper analyzes the factors of peripheral neuropathy in type 2 diabetes mellitus and puts forward a balanced analysis of peripheral neuropathy in type 2 diabetes mellitus based on logistic regression equation. A total of 1192 eligible patients were selected as the study subjects. All selected patients underwent 75 g oral glucose tolerance test to measure fasting blood glucose and insulin and 2-hour postprandial blood glucose and 2-hour postprandial insulin, as well as neuroelectrophysiological examination. The results showed that the OR values of age, course of disease, fingertip blood glucose immediately after admission, and 2-hour blood glucose were greater than 1, and the P values were all less than 0.05, which were the risk factors of diabetic peripheral neuropathy. OR value of β cell function index (HBCI) is less than 1. P is less than 0.05, and it is a protective factor of diabetic peripheral neuropathy. Laboratory indicators are as follows: 75 g OGTT: 0-hour blood glucose, 2-hour blood glucose, and glycosylated hemoglobin; serum creatinine; glutamate transaminase; fibrinogen; ten items of hemoglobin; and indexes reflecting islet function: islet β is thin, and there are significant differences in cell function index, insulin resistance index, and insulin secretion index between the non-DPN group and DPN group. Age, course of disease, fingertip blood glucose immediately after admission, and blood glucose within 2 hours after admission were the risk factors for diabetic peripheral neuropathy. Islet β cell function index (HBCI) is a protective factor of diabetic peripheral neuropathy., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Lixin Zhang et al.)

Purpose: Neuropathy is one of the most important complications of diabetes. According to recent advances, vitamin D deficiency might play a role in the development and progression of diabetic neuropathy. Moreover, therapeutic vitamin D supplementation has the potential to improve this condition. The aim of the present review was to summarize new data available in this area., Methods: The PubMed database was searched for articles written in English and published through September 2021, using combinations of the following key words: vitamin D, diabetes, diabetes mellitus, diabetic neuropathy, polyneuropathy, peripheral neuropathy, cardiac autonomic neuropathy, supplementation, and therapy., Findings: A number of studies have suggested that vitamin D deficiency can play a significant role in the development of peripheral neuropathy, diabetic foot ulcers, as well as cardiovascular autonomic neuropathy in patients with type 2 diabetes. Vitamin D supplementation might serve as an effective adjuvant therapy for neuropathic pain and may slow or stop the progression of neural damage., Implications: Vitamin D therapy for diabetic complications could be a reliable option; however, further studies are needed to confirm this notion., Competing Interests: DECLARATION OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that can predispose patients to higher risk for cardiovascular death. The aim of the present study was to evaluate the presence of cardiac autonomic neuropathy and sudomotor dysfunction in patients with newly diagnosed carbohydrate disturbances (prediabetes or diabetes) and to assess their relationship to metabolic disturbances and cardiovascular risk. In the present study, we included 160 patients -78 with obesity without carbohydrate disturbances, 52 with prediabetes, and 30 with newly diagnosed diabetes. CAN was diagnosed using cardiovascular reflex tests and sudomotor function was evaluated by SUDOSCAN. Cardiovascular risk was calculated using SCORE and FRMINGHAM risk scores. The prevalence of cardiac autonomic neuropathy was significantly higher in patients with newly diagnosed diabetes. Independently of their glycemic status, the patients who had blood glucose on the 60th-minute of OGTT>8.5 mmol/l had significantly higher prevalence of cardiac autonomic neuropathy (30.2% vs 15.6%, р=0.044). Patients with high cardiovascular risk according to FRAMINGHAM and SCORE had worse heart rate variability scores. Autonomic neuropathy risk assessed by SUDOSCAN was a good predictor for the presence of CAN. In conclusion, CAN has a higher prevalence on patients with newly diagnosed diabetes compared to prediabetic and normoglycemic subjects, while the patients with blood glucose>8.5 mmol/l on the 60th-minute of OGTT have higher prevalence of CAN independently of their glycemic status. SUDOSCAN testing can be used to assess the risk of CAN and to select patients that should undergo further testing., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: The aim of this study is to investigate a possible association between vitamin D deficiency and diabetic peripheral neuropathy in pediatric patients with type 1 diabetes mellitus., Materials-Methods: Twenty-nine patients with type 1 diabetes mellitus and 19 healthy controls were included to the study. All individuals were evaluated for diabetic peripheral neuropathy with nerve conduction studies. Complete blood cell count, biochemical investigations, serum vitamin D levels, hemoglobin A1c levels were recorded., Results: No statistically significant differences between the diabetes and control groups in terms of gender, age, body weight, height, body mass index, systolic and diastolic blood pressures, laboratory investigations, serum vitamin D levels and nerve conduction studies was found. Patients with diabetes were grouped as patients with normal serum vitamin D levels and patients with vitamin D deficiency. Sensory nerve action potential of sural nerve and motor peroneal nerve velocity were statistically significantly lower in diabetic patients with vitamin D deficiency compared to diabetic patients with normal vitamin D levels (p 0.009 and 0.005 respectively)., Conclusion: Our results suggested that hypovitaminosis D might lead to development of neuropathic changes particularly on the lower limb nerves even in the early stages of the disease. It should be kept in mind that patients with hypovitaminosis D should be elaborately examined and closely followed up for the development of diabetic neuropathic changes, even if glucose control is achieved., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Aims/introduction: To explore the relationship between heart rate-corrected QT (QTc) interval and diabetic peripheral neuropathy (DPN), and whether QTc interval has diagnostic utility for DPN beyond nerve conduction velocity., Materials and Methods: A total of 965 patients with diabetes, including 473 patients with DPN and 492 patients without DPN, underwent standard 12-lead electrocardiography and detailed assessments of peripheral neuropathy., Results: Patients with DPN had longer QTc intervals than those without. Among participants, from the first to fourth quartile of QTc interval, the proportion of patients with DPN appreciably increased and the nerve conduction velocity obviously decreased (P for trend <0.001). The univariate and multivariate analyses showed that prolonged QTc interval was closely associated with increased risk of DPN (univariable odds ratio 1.112, 95% confidence interval 1.097-1.127, P < 0.001; multivariable odds ratio 1.118, 95% confidence interval 1.099-1.137, P < 0.001). Receiver operating characteristic analysis for the diagnosis of DPN showed a greater area under the curve for QTc interval of 0.894 than the median nerve motor conduction velocity of 0.691, median nerve sensory conduction velocity of 0.664 and peroneal nerve motor conduction velocity of 0.692. The optimal cut-off point of QTc interval for DPN was 428.5 ms with sensitivity of 0.715 and specificity of 0.920 (P < 0.001). The combination of QTc interval and nerve conduction testing increased the area under the curve for the diagnosis of DPN (from 0.736 to 0.916; P < 0.001)., Conclusions: QTc interval with 428.5 ms has more reliable diagnostic utility for DPN than nerve conduction velocity, and prolonged QTc interval is closely associated with an increased risk of DPN., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Painful diabetic neuropathy is one of the most common complications of diabetes in humans. The current treatments are not completely effective, and the main mechanisms implicated in the development of diabetic neuropathy are not completely elucidated. Thus, in male db/db mice, a murine model of type 2 diabetes, we investigated the effects of treatment with a heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), on the 1) hyperglycemia and mechanical allodynia associated with type 2 diabetes and 2) molecular changes induced by diabetic neuropathy in the central nervous system (CNS). Thus, we evaluated the effects of CoPP on the protein levels of 4-HNE (oxidative stress), Nrf2, superoxide dismutase 1 (SOD1), NAD(P)H quinone oxidoreductase 1 (NQO1), HO-1, glutathione S-transferase Mu 1 (GSTM1) (antioxidant enzymes), phosphatidylinositol 3-kinase/protein kinase B (nociceptive pathway), CD11b/c (microglial activation), and BAX (apoptosis) in the amygdala and spinal cord of db/db mice. Our results showed the antihyperglycemic and antiallodynic effects of CoPP treatment as well as the potent antioxidant, antinociceptive, anti-inflammatory, and antiapoptotic properties of this HO-1 inducer in the CNS of type 2 diabetic mice. Treatment with CoPP also prevented the downregulation of several antioxidant proteins (Nrf2, SOD-1, and NQO1) and/or enhanced the protein levels of HO-1 and GSTM1 in the spinal cord and/or amygdala of db/db mice. These effects might be implicated in the antiallodynic actions of CoPP. Our findings revealed the modulatory effects of CoPP in the CNS of db/db mice and provide new prospects for novel type 2 diabetes-associated neuropathy therapies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Axon degeneration in diabetic peripheral neuropathy (DPN) is associated with impaired NAD + metabolism. We tested whether the administration of NAD + precursors, nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), prevents DPN in models of Type 1 and Type 2 diabetes. NMN was administered to streptozotocin (STZ)-induced diabetic rats and STZ-induced diabetic mice by intraperitoneal injection at 50 or 100 mg/kg on alternate days for 2 months. mice The were fed with a high fat diet (HFD) for 2 months with or without added NR at 150 or 300 mg/kg for 2 months. The administration of NMN to STZ-induced diabetic rats or mice or dietary addition of NR to HFD-fed mice improved sensory function, normalized sciatic and tail nerve conduction velocities, and prevented loss of intraepidermal nerve fibers in skin samples from the hind-paw. In adult dorsal root ganglion (DRG) neurons isolated from HFD-fed mice, there was a decrease in NAD + levels and mitochondrial maximum reserve capacity. These impairments were normalized in isolated DRG neurons from NR-treated mice. The results indicate that the correction of NAD + depletion in DRG may be sufficient to prevent DPN but does not significantly affect glucose tolerance, insulin levels, or insulin resistance.

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).)

Several studies have been conducted to investigate the relation between 25-hydroxyvitamin D [25(OH)D] level and diabetic neuropathy (DN). However, there is still no clear conclusion due to differences in study design and cut-off values used in the published work, in addition to the absence of a comprehensive meta-analysis (MA) on the topic. The present systematic review and MA therefore aims at clarifying the association between vitamin D level and peripheral DN in patients with type 2 diabetes mellitus. Primary research studies that explored the association between 25(OH)D level and diabetic peripheral neuropathy in type 2 diabetes were located from Medline, EMBASE, Web of Science, Cochrane Library, CINHAL and Google Scholar. Twenty-six studies met the inclusion criteria with 6277 participants where 2218 were diabetic with DN, 2959 were diabetic without DN and 406 were healthy. Diabetic patients with DN showed significantly lower serum 25(OH)D compared with patients without DN (standardised mean difference (SMD) of -0·92 (95 % CI -1·18, -0·65, I2 = 93·3 %, P < 0·0001). The pooled OR value of vitamin D deficiency was higher in patients with DN, 1·84 (95 % CI 1·46, 2·33, P < 0·0001) and 2·87 (95 % CI 1·10, 7·52, P = 0·03) when using fixed-effects and random-effects models, respectively. Vitamin D deficiency has been found to be highly prevalent among diabetic patients with neuropathy. Since 25(OH)D has been implicated in glucose haemostasis and showed benefit in reducing neuropathy symptoms, its supplementation is warranted for this population of patients.

Introduction: Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased mortality and morbidity. To explore metabolic mechanisms associated with CAN we investigated associations between serum metabolites and CAN in persons with type 1 diabetes (T1D)., Materials and Methods: Cardiovascular reflex tests (CARTs) (heart rate response to: deep breathing; lying-to-standing test; and the Valsalva maneuver) were used to diagnose CAN in 302 persons with T1D. More than one pathological CARTs defined the CAN diagnosis. Serum metabolomics and lipidomic profiles were analyzed with two complementary non-targeted mass-spectrometry methods. Cross-sectional associations between metabolites and CAN were assessed by linear regression models adjusted for relevant confounders., Results: Participants were median (IQR) aged 55(49, 63) years, 48% males with diabetes duration 39(32, 47) years, HbA 1c 63(55,69) mmol/mol and 34% had CAN. A total of 75 metabolites and 106 lipids were analyzed. In crude models, the CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4-deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and the amino acid methionine (p<0.05). Upon adjustment, positive associations with the CAN diagnoses were retained for hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, citric acid, and phenols (P<0.05)., Conclusion: Metabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives are associated with the CAN diagnosis in T1D. These pathway may be part of the pathogeneses leading to CAN and may be modifiable risk factors for the complication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hansen, Suvitaival, Theilade, Mattila, Lajer, Trošt, Ahonen, Hansen, Legido-Quigley, Rossing and Ahluwalia.)

SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease.

Autonomic neuropathy is a significant complication of long term Type 2 DM which contributes to the diurnal variation of BP. Non dipping pattern is when the nocturnal dipping is less than normal. Non dippers are associated with increased target organ damage and increased risk of cardiovascular mortality. The pattern of blood pressure variation and dipping is found using Ambulatory blood pressure monitor (ABPM). This study aims to study the variation in dipping pattern as recorded by ABPM in patients with Type 2 Diabetes., Material: 50 patients with a history of diabetes for at least 5 years patients were selected and subjected for ambulatory blood pressure monitoring and assessment of glycemic status.50 normal subjects were enrolled as controls., Observation: In our study we found that 22 (44%) of patients in the diabetic and 38 (76%) among patients in the normal group were normal dippers. 17(34%) patients in the diabetic group and 12 (24%) patients in the non diabetic group were non dippers. 11(22%) in the diabetic group were reverse dippers while none of the patients in the normal were reverse dippers. The difference between the distribution of the dippers, non dippers and reverse dippers between the two groups was statistically significant. (p&lt;0.001).Patients having diabetes for more than 10 years had increased incidences of abnormal dipping (77.8%) as compared to patients with diabetes of 5 to 10 years (43.8%). This difference showed a statistical significance(p=0.02).The incidence of reverse dipping was more in patients with a Hba1c of more than 9% (n=10, 34.5%) when compared to patients who had a Hba1c of 7-9% (n=1, 4.8%)., Conclusion: A majority of patients with diabetes were found to have an abnormal pattern of blood pressure that included non-dipping and reverse dipping patterns. Duration of diabetes and severity of Hba1C had a direct correlation with abnormal pattern of blood pressure variability that included non-dippers and reverse dippers. Thus, ambulatory blood pressure monitoring is an important tool to assess the blood pressure variability can be used regularly to assess the complications of diabetes namely autonomic neuropathy and renal dysfunction., (© Journal of the Association of Physicians of India 2011.)

Diabetic neuropathy is a chronic condition that affects a significant number of individuals with diabetes. Streptozotocin injection intraperitoneally to rodents produces pancreatic islet β-cell destruction causing hyperglycemia, which affect the brain leading to memory and cognition impairment. Dapagliflozin may be able to reverse beta-cell injury and alleviate this impairment. This effect may be via neuroprotective effect or possible involvement of the antioxidant, and anti-apoptotic properties. Forty rats were divided into four groups as follows: The normal control group, STZ-induced diabetes group, STZ-induced diabetic rats followed by treatment with oral dapagliflozin group and normal rats treated with oral dapagliflozin. Behavioral tests (Object location memory task and Morris water maze) were performed. Serum biomarkers (blood glucose and insulin) were measured and then the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. In the hippocampus the followings were determined; calmodulin, ca-calmodulin kinase Ⅳ (CaMKIV), protein kinase A (PKA) and cAMP-responsive element-binding protein to determine the transcription factor CREB and its signaling pathway also Wnt signaling pathway and related parameters (WnT, B-catenin, lymphoid enhancer binding factor LEF, glycogen synthase kinase 3β). Moreover, nuclear receptor-related protein-1, acetylcholine and its hydrolyzing enzyme acetylcholine esterase, oxidative stress parameter malondialdehyde (MDA) and apoptotic parameter caspase-3 were determined. STZ was able to cause destruction to pancreatic β-cells which was reflected on glucose levels causing diabetes. Diabetic neuropathy was clear in the rats performing the behavioral tests. Memory and cognition parameters in the hippocampus were negatively affected. Oxidative stress and apoptotic parameter were elevated while the electrical activity was declined. Dapagliflozin was able to reverse the previously mentioned parameters and behavior. Thus, to say dapagliflozin significantly showed neuroprotective action along with antioxidant, and anti-apoptotic properties., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Autonomic dysfunction associated with Type 2 Diabetes Mellitus is a well known entity, of which cardiac autonomic neuropathy deserves a special mention due to its propensity to cause major cardiac events in a seemingly asymptomatic individual. The incidence of Cardiac autonomic neuropathy among newly diagnosed Diabetes patients is less studied, with most of the current studies done in Western populace who have a different metabolic milieu compared to Indians. This study aims to find the prevalence of cardiac autonomic neuropathy in the Central Indian population, presenting to our center who are diagnosed to be having Diabetes Mellitus within one year., Material: 35 patients, of the age group (18-45 years), who were diagnosed to have Type 2 Diabetes Mellitus within the last one year were taken, after excluding any other chronic illness, like CKD, CLD, CVA, etc. and after getting consent. 35 healthy age and sex-matched controls were included in the study. Cardiac Autonomic Testing was done for all of them, using the measurement of Heart Rate Variability (HRV), Deep Breathing Test (DBT), Cold Pressor Test (CPT), and Lying to Standing Test (LST). The experimental data was analyzed using Labchart Software for autonomic dysfunction., Observation: On preliminary analysis, around 40% of the patients enrolled in the study had cardiac autonomic dysfunction, predominantly parasympathetic dysfunction, compared to the controls. There was no significant age-wise difference in cardiac autonomic dysfunction. There was also no statistically significant correlation with the HbA1c of the patient at presentation and their cardiac autonomic dysfunction., Conclusion: There is significant cardiac autonomic dysfunction among newly diagnosed Diabetes patients. This reaffirms the fact that early screening and diagnosis of this disease is paramount to prevent significant morbidity and mortality associated with the complications of the disease., (© Journal of the Association of Physicians of India 2011.)

The relationship between renal impairment and diabetic peripheral neuropathy (DPN) remains inconclusive. We aim to investigate the risk factors for the occurrence of DPN in Taiwanese adults with type 2 diabetes mellitus (T2DM) and focus on renal impairment. A hospital-based study was conducted from 2013 to 2019 and 552 Taiwanese people who had T2DM without DPN at baseline were enrolled. DPN was diagnosed using the Michigan Neuropathy Screening Instrument. Potential risk factors were recorded, including patient's sociodemographic factors, current medication usage and biochemical markers. As of 2019, 73 developed DPN and 479 had no DPN. The cumulative incidence during the 6-year period was 13.22%. Multivariable logistic regression analysis revealed that lower estimated glomerular filtration rate (eGFR) (odds ratio [OR] 0.98, p = 0.005), advanced age (OR 1.06, p = 0.001), increased body weight (OR 1.04, p = 0.018), duration of DM (OR 1.05, p = 0.036) and male gender (OR 3.69, p = 0.011) were significantly associated with future DPN. In addition, patients with T2DM under the age of 65 with higher serum creatinine concentration (OR 8.91, p = 0.005) and higher baseline HbA1C (OR 1.71, p < 0.001) revealed significantly associated with future DPN. In conclusion, this is the first large scaled hospital-based study with long term follow-up to investigate risk factors for DPN in Taiwanese. Lower eGFR and higher serum creatinine concentration, particularly in people under the age of 65, are predictors of future DPN in Taiwanese people with T2DM. Other predictors included advanced age, increased body weight, duration of DM, male gender for all ages and HbA1c in enrolled patients under the age of 65. Our study not only confirms the association between renal impairment and future DPN but also provides a commonly available assessment to predict the future DPN., (© 2022. The Author(s).)

Background: As one of the most challenging complications in the management of diabetes mellitus, painful diabetic peripheral neuropathy (PDPN) is accompanied by various clinical manifestations, including numbness, burning, coldness, and other sensory abnormalities in the extremities. Meanwhile, PDPN seriously affects the life quality of patients and causes great pain. Western medicine mostly provides symptomatic treatments, such as antioxidants, aldose reductase inhibitors, nerve nutrition, microcirculation improvement, and analgesic drugs on the basis of blood sugar control. Although certain efficacy has been achieved, the problem has not been solved at root. Mudan granules have some advantages in the treatment of PDPN, but there is insufficient high-quality clinical studies to verify this. Therefore, the purpose of this study was to evaluate the efficacy and safety of Mudan granules in treating PDPN., Methods: A randomized, double-blind, placebo, and parallel-controlled trial design was used to study the efficacy and safety of Mudan granules in the treatment of PDPN. In this study, 93 patients with painful diabetic neuropathy were recruited and randomly divided into a treatment group and a placebo group based on 1:1. The treatment group was given Mudan granules and the control group accepted placebo treatment, and the basic treatment was performed according to the recommended guidelines. During the treatment period, the patients' visual analog scores, clinical efficacy, Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) scores, nerve conduction velocity, and drug-induced adverse reactions were observed at baseline after 8 and 10 weeks., Discussion: This study will evaluate the efficacy and safety of Mudan granules in treating PDPN. The experimental results will provide evidence support to treat PDPN with Mudan granules., Trial Registration: DOI 10.17605/OSF.IO/5CE32., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Diabetic neuropathy (DN) is a late complication of diabetic mellitus and may rise into painful and painless variants. Limited studies have looked at nociceptive mechanisms of painless DN variant. The study aimed to determine phosphorylation and total NR2B subunit of N-methyl-D-aspartate receptor in the spinal cord of painless DN rat during early phase following formalin injection. Thirty-six Sprague-Dawley male rats were randomly assigned into three groups: control, painful, and painless DN (n = 12). The rats were developed into the early phase of DN for 2 weeks following diabetic induction. Two weeks later, the rats were injected with 5% formalin solution and flinching and licking responses were recorded for 60 min. The rats were sacrificed 3 days later, and the spinal cord enlargement region was collected. Immunohistochemistry and Western blot procedures were conducted to determine the phosphorylated and total NR2B subunit expressions. The results showed reduced flinching and licking responses in painless DN rats compared to control and painful DN groups, followed by a significant reduction in phosphorylated and total NR2B expression at both ipsilateral and contralateral regions of the spinal cord. In conclusion, reduced pain behavior responses in painless DN rats following formalin injection is possibly contributed by the reduced expression of phosphorylated and total NR2B subunit in the spinal cord., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To assess the point prevalence of peripheral neuropathy (PN) in children with type 1 diabetes mellitus (T1DM) and to determine their predictors., Methods: In this cross-sectional study, children aged 8-18 y with T1DM on insulin therapy for > 2 y and free from acute complications were enrolled. All participants were evaluated for symptoms of PN with diabetic neuropathy symptom (DNS) score and underwent a detailed neurological examination. Assessment of nerve dysfunction was done using nerve conduction studies (NCS). The disease-related factors that increase the risk of PN were determined., Results: Fifty children (52% boys) were enrolled with mean age of 12.2 ± 2.8 y and duration of diabetes 5.1 ± 2.1 y. No subject had clinical evidence or DNS score suggestive of PN. Twenty-eight (56%) children demonstrated subclinical neuropathy on NCS. Proportion of children with pure motor, pure sensory, and mixed motor-sensory neuropathy was 40%, 2%, and 14%, respectively. The peroneal nerve was the most common motor nerve affected. Poor glycemic control (HbA1c > 9%) and longer duration of diabetes (> 5 y) were significantly associated with the risk of PN (p value < 0.05)., Conclusion: A large proportion of children with T1DM have subclinical PN. Poor glycemic control and longer duration of diabetes are risk factors for nerve dysfunction. Neurophysiological studies should be performed in these children to facilitate early detection., (© 2021. Dr. K C Chaudhuri Foundation.)

Background: A risk assessment tool has been developed for automated estimation of level of neuropathy based on the clinical characteristics of patients. The smart tool is based on risk factors for diabetic neuropathy, which utilizes vibration perception threshold (VPT) and a set of clinical variables as potential predictors., Methods: Significant risk factors included age, height, weight, urine albumin-to-creatinine ratio, glycated hemoglobin, total cholesterol, and duration of diabetes. The continuous-scale VPT was recorded using a neurothesiometer and classified into three categories based on the clinical thresholds in volts (V): low risk (0-20.99 V), medium risk (21-30.99 V), and high risk (≥31 V)., Results: The initial study had shown that by just using patient data ( n = 5088) an accuracy of 54% was achievable. Having established the effectiveness of the "classical" method, a special Neural Network based on a Proportional Odds Model was developed, which provided the highest level of prediction accuracy (>70%) using the simulated patient data ( n = 4158)., Conclusion: In the absence of any assessment devices or trained personnel, it is possible to establish with reasonable accuracy a diagnosis of diabetic neuropathy by means of the clinical parameters of the patient alone.

Aims: We aimed to estimate the prevalence of Diabetic peripheral neuropathy (DPN) and Cardiac autonomic neuropathy (CAN) in youth with type 1 diabetes; identify key risk factors; identify the most useful tests for the diagnostic evaluation of DPN and CAN; identify key treatment options for DPN and CAN., Methods: A systematic search was performed including studies published in the last 15 years. PICO framework was used in the selection process and evidence was assessed using the GRADE system., Results: A total of 758 studies were identified and a final number of 49 studies were included in this systematic review. According to moderate-high level quality studies, the prevalence of probable DPN, ranged between 13.5 and 62%; subclinical DPN between 22 and 88%; confirmed DPN between 2.6 and 11%. The Michigan Neuropathy Screening Instrument was the tool with higher sensitivity and specificity for detecting DPN, which needs to be confirmed by nerve conduction velocity. The prevalence of CAN was 4-39%. Specific treatment options for DPN or CAN in patients younger than 25 years are not available. Key risk factors for DPN and CAN are hyperglycemia/HbA1c, age, diabetes duration, the presence of other microvascular complications, waist/height ratio, lipid profile and blood pressure. For CAN, additional risk factors were cigarette smoking, BMI and total daily insulin., Conclusions: Prevalence of neuropathy in youth with type 1 diabetes varies depending on different screening methods and characteristics of the study populations. However, the assessed studies confirmed a relatively high prevalence of subclinical neuropathy, reiterating the importance of early identification of risk factors to prevent this complication., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Diabetes polyneuropathy is an important complication of diabetes polyneuropathy, and its notable sequelae of foot ulceration, autonomic dysfunction, and neuropathic pain are associated with significant morbidity and mortality. Despite the major impact on quality of life and health economic costs, it remains underdiagnosed until late in its natural history, and there is lack of any intervention that can reverse its clinical progress. Assessment of small fiber neuropathy (SFN) in diabetes offers an opportunity to detect abnormalities at an early stage so that both interventional studies and preventative measures can be enacted to prevent progression to the devastating complications of foot ulceration and cardiac dysautonomic death. Over the last two decades, significant advances have been made in understanding the pathophysiology of diabetes neuropathy and its assessment. In this review, we discuss limitations of the screening methods recommended in current clinical guidelines which are based on large nerve fiber assessments. Thereafter, we discuss in detail the various methods currently available to assess small fiber structure and function and examine their individual strength and limitations. Finally, we discuss the reasons why despite the considerable body of evidence available, legislators and global experts have yet to incorporate the assessment of SFN as routine clinical surveillance in diabetes management. We hope that these insights will stimulate further discussion and be instrumental in the early adoption of these methods so as to reduce the burden of complications arising due to diabetes polyneuropathy.

Background: Diabetic neuropathy (DN) is the least recognized complication of diabetes mellitus and may start early in the course of the disease. Aldose reductase (AKR1B1) gene promoter Z-2/Z-2 polymorphism increases the expression of AKR1B1 enzyme and may contribute to DN., Subjects: We evaluated 108 Type 1 diabetes (T1D) children and adolescents (mean ± SD age: 13.5 ± 3.46 years, disease duration: 5.3 ± 3.4 years) and 150 healthy controls (age: 11.9 ± 2.7 years)., Methods: In both groups, pupillary dilation (PD) in darkness, postural blood pressure test (PBPT), and vibration sensation thresholds (VST) in upper and lower limbs were estimated as indices of autonomic and peripheral neuropathy, respectively. Nerve conduction studies (NCS) were performed in patients as peripheral neuropathy index. The polymorphisms of AKR1B1 gene were evaluated using microsatellite (AC)n sequence Z., Results: PBPT, PD, and VST impairments were more frequent in patient group compared with controls, while 38.6% of patients exhibited NCS abnormality. Gender, age, pubertal status, height, body mass index, diabetes duration, HbA1c, and anti-GAD titers were associated with neuropathy indices in patients. There was a strong correlation between PD and NCS in patients, while homozygous patients for Z-2 AKR1B1 gene polymorphism had higher prevalence of abnormal NCS (83.3% vs. 34.6%), PD (62.5% vs. 31.5%), and PBPT values compared with heterozygous or negative patients. Homozygous AKR1B1 status predicted PD, NCS, and PBPT variance, while PD, VST, NCS, and PBPT parameters accurately discriminated homozygous AKR1B1 patients., Conclusions: Impaired indices of peripheral and autonomic DN were present in a significant proportion of young T1D patients. PD, VST, NCS, and PBPT parameters were simultaneously associated with homozygous state of AKR1B1 Z-2 gene polymorphism, implicating polyol metabolism with both autonomic and peripheral neuropathies., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The effect of diabetic polyneuropathy (DPN) and autonomic neuropathy (AN) on bone turnover in type 2 diabetes mellitus (DM) is uncertain due to the lack of data. In this study, we tried to determine the effect of DPN and AN on bone metabolism. Materials and Methods: The study included patients with type 2 DM (aged 18-80 years) and age-matched healthy individuals who presented to the Departments of Metabolism and Diabetes, Geriatrics, and General Internal Medicine, Cerrahpaşa Medical School, Istanbul University. The patients were examined to find out whether they had AN, and neuropathy scores were recorded by exploring peripheral neuropathy. Bone mineral density was measured by dual-energy X-ray (DXA). Demographic characteristics, the presence of microvascular complications, and biochemical data were obtained from patients' files. Serum cross-linked C-telopeptide (Ctx), osteocalcin, and bone-specific alkaline phosphatase (B-ALP) were analyzed. Results: The study comprised a total of 64 patients: 23 had type 2 DM and osteoporosis (OP) (duration of diabetes 10.1 ± 7 years; mean age 63 ± 9.1 years; female/male 18/5; Group 1), 41 had type 2 DM and non-OP (duration of diabetes 10.3 ± 7.6 years; mean age 58 ± 7.4 years; female/male 30/11; Group 2), and 26 healthy volunteers made up the control group (mean age 62 ± 11.9 years; female/male 14/12; Group 3). The bone turnover parameters were lower in type 2 DM individuals. The levels of osteocalcin (13.3 ± 5.2 ng/mL) and B-ALP (44.7 ± 10.9 IU/L) in patients with type 2 DM were lower than those of healthy subjects: osteocalcin (20.6 ± 10 ng/mL) and B-ALP (111 ± 31.4 IU/L; P  = 0.001 and P  = 0.000, respectively). Ctx levels (193.5 ± 49.3; 207.6 ± 40 ng/mL) were recorded to be similar ( P  = 0.2). AN was also noted as a risk factor for OP. For patients without AN, the likelihood of developing OP (odds ratio) was 0.7. The corresponding ratio for patients with AN was 9.3. Conclusions: Among the independent variables, the neuropathy score was determined to have an impact on bone turnover. AN was identified to be a significant risk factor for OP.

Diabetes is the 4 th most common disease affecting the world's population. It is accompanied by many complications that deteriorate the quality of life. Painful diabetic neuropathy (PDN) is one of the debilitating consequences of diabetes that effects one-third of diabetic patients. Unfortunately, there is no internationally recommended drug that directly hinders the pathological mechanisms that result in painful diabetic neuropathy. Clinical studies have shown that anticonvulsant and antidepressant therapies have proven fruitful in management of pain associated with PDN. Currently, the FDA approved medications for painful diabetic neuropathies include duloxetine, pregabalin, tapentadol extended release, and capsaicin (for foot PDN only). The FDA has also approved the use of spinal cord stimulation system for the treatment of diabetic neuropathy pain. The drugs recommended by other regulatory bodies include gabapentin, amitriptyline, dextromethorphan, tramadol, venlafaxine, sodium valproate, and 5 % lidocaine patch. These drugs are only partially effective and have adverse effects associated with their use. Treating painful symptoms in diabetic patient can be frustrating not only for the patients but also for health care workers, so additional clinical trials for novel and conventional treatments are required to devise more effective treatment for PDN with minimal side effects. This review gives an insight on the pathways involved in the pathogenesis of PDN and the potential pharmacotherapeutic agents. This will be followed by an overview on the FDA-approved drugs for PDN and commercially available topical analgesic and their effects on painful diabetic neuropathies., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2022 Zunaira Qureshi et al.)

Aim: Type 2 Diabetes Mellitus (T2DM) is associated with microvascular complications, including diabetic retinopathy (DR), diabetic nephropathy (DNp), and diabetic peripheral neuropathy (DPN). In this study, we investigated genetic variations and Single Nucleotide Polymorphisms (SNPs) associated with DR, DNp, DPN and their combinations among T2DM patients of Arab origin from the United Arab Emirates, to establish the role of genes in the progression of microvascular diabetes complications., Methods: A total of 158 Emirati patients with T2DM were recruited in this study. The study population was divided into 8 groups based on the presence of single, dual, or all three complications. SNPs were selected for association analyses through a search of publicly available databases, specifically genome-wide association study (GWAS) catalog, infinome genome interpretation platform, and GWAS Central database. A multivariate logistic regression analysis and association test were performed to evaluate the association between 83 SNPs and DR, DNp, DPN, and their combinations., Results: Eighty-three SNPs were identified as being associated with T2DM and 18 SNPs had significant associations to one or more diabetes complications. The most strongly significant association for DR was rs3024997 SNP in the VEGFA gene. The top-ranked SNP for DPN was rs4496877 in the NOS3 gene. A trend towards association was detected at rs833068 and rs3024998 in the VEGFA gene with DR and rs743507 and rs1808593 in the NOS3 gene with DNp. For dual complications, the rs833061, rs833068 and rs3024997 in the VEGFA gene and the rs4149263 SNP in the ABCA1 gene were also with borderline association with DR/DNp and DPN/DNp, respectively. Diabetic with all of the complications was significantly associated with rs2230806 in the ABCA1 gene. In addition, the highly associated SNPs rs3024997 of the VEGFA gene and rs4496877 of the NOS3 gene were linked to DR and DPN after adjusting for the effects of other associated markers, respectively., Conclusions: The present study reports associations of different genetic polymorphisms with microvascular complications and their combinations in Emirati T2DM patients, reporting new associations, and corroborating previous findings. Of interest is that some SNPs/genes were only present if multiple comorbidities were present and not associated with any single complication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 ElHajj Chehadeh, Sayed, Abdelsamad, Almahmeed, Khandoker, Jelinek and Alsafar.)

Diabetic painless and painful peripheral neuropathy remains the most frequent complication of diabetes mellitus, but the pathophysiology remains undescribed, there are no robust clinical endpoints and no efficient treatment exists. This hampers good clinical practice, fruitful clinical research and successful pharmacological trials, necessary for the development of early detection, prevention and treatment. This chapter supplies an update on background and treatment of diabetic peripheral neuropathy. Goals and perspectives for future clinical and scientific approaches are also described., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Diabetic neuropathy is among the most frequent complications of both type 1 (T1DM) and type 2 diabetes (T2DM) and commonly manifests as a distal symmetrical polyneuropathy (DSPN). Despite evidence that T1DM- and T2DM-related DSPN are separate entities, most of our knowledge on diabetic DSPN derives from studies focused on type 2 diabetes. This systematic review provides an overview of current evidence on DSPN in T1DM, including its epidemiological, pathophysiological and clinical features, along with principal diagnostic tests findings. This review included 182 clinical and preclinical studies. The results indicate that DSPN is a less frequent complication in T1DM compared with T2DM and that distinctive pathophysiological mechanisms underlie T1DM-related DSPN development, with hyperglycemia as a major determinant. T1DM-related DSPN more frequently manifests with non-painful than painful symptoms, with lower neuropathic pain prevalence compared with T2DM-associated DSPN. The overt clinical picture seems characterized by a higher prevalence of large fiber-related clinical signs (e.g., ankle reflexes reduction and vibration hypoesthesia) and to a lesser extent small fiber damage (e.g., thermal or pinprick hypoesthesia). These findings as a whole suggest that large fibers impairment plays a dominant role in the clinical picture of symptomatic T1DM-related DSPN. Nevertheless, small fiber diagnostic testing shows high diagnostic accuracy in detecting early nerve damage and may be an appropriate diagnostic tool for disease monitoring and screening., (© 2021. The Author(s).)

Objective: To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes (T1D)., Research Design and Methods: Measurements of DPN at Epidemiology of Diabetes Intervention and Complications (EDIC) years 1, 14, and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 years, diabetes duration 29.5 years) and 371 women (mean age 50.6 years, diabetes duration 29.8 years) enrolled in the Diabetes Control and Complications Trial (DCCT)/EDIC study. DPN was defined by symptoms, signs, and abnormal electrophysiology or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores., Results: Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men and female sexual dysfunction (FSD), LUTS, and urinary incontinence (UI) in 16% of women. Adjusted for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides, and statin medication use, the odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17 were 3.52 (95% CI 1.69, 7.31) times greater in men with confirmed DPN at EDIC year 13/14 compared to men without confirmed DPN. Compared to men without DPN, men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared with those without FSD or LUTS/UI at EDIC year 17., Conclusions: In long-standing T1D, DPN is associated with the later development of urological complications in men., (© 2021 by the American Diabetes Association.)

Aims/introduction: To investigate the association between cardiovascular autonomic neuropathy (CAN) assessed by the coefficient of variation of the R-R interval and the reduction in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes., Materials and Methods: This retrospective observational cohort study enrolled type 2 diabetes patients who had their coefficient of variation of the R-R interval measured on an electrocardiogram from January 2005 to December 2018. CAN was defined using the reference coefficient of variation of the R-R interval value based on age and sex. The primary outcome was set as a 40% eGFR decline from baseline. Regression analyses using the Cox proportional hazards model were carried out to evaluate the association., Results: Of the 831 patients, 118 (14.2%) were diagnosed with CAN. In the analysis of the primary outcome, the median follow-up period was 5.3 years, and 25 (21.2%) patients with CAN and 78 (10.9%) patients without CAN developed a 40% eGFR decline. In the univariate regression analysis, CAN was significantly associated with a 40% eGFR decline (hazard ratio 2.42, 95% confidence interval 1.54-3.80). In the multivariate analysis, CAN remained almost significant after adjusting for the prognostic risk factors for CAN and the decline in the renal function, and an interaction with proteinuria was found. In analyses for the interaction effect between CAN and proteinuria, the presence of CAN synergistically increased the risk of an eGFR decline in patients with macroproteinuria., Conclusions: CAN strongly increased the risk of a 40% eGFR decline from baseline, especially in type 2 diabetes patients with macroproteinuria., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Despite the advent of novel therapies which manage and control diabetes well, the increased risk of morbidity and mortality in diabetic subjects is associated with the devastating secondary complications it produces. Long-standing diabetes majorly drives cellular and molecular alterations, which eventually damage both small and large blood vessels. The complications are prevalent both in type I and type II diabetic subjects. The microvascular complications include diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, while the macrovascular complications include diabetic heart disease and stroke. The current therapeutic strategy alleviates the complications to some extent but does not cure or prevent them. Also, the recent clinical trial outcomes in this field are disappointing. Success in the drug discovery of diabetic complications may be achieved by a better understanding of the underlying pathophysiology and by recognising the crucial factors contributing to the development and progression of the disease. In this review, we discuss the well-studied cellular mechanisms leading to the development and progression of diabetic complications. In addition, we also highlight the various therapeutic paradigms currently in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The association between nonalcoholic fatty liver (NAFL) or liver fibrosis and diabetic peripheral neuropathy (DPN) has not been well studied. We aimed to investigate the association of NAFL or liver fibrosis indices and DPN in individuals with type 2 diabetes. In this observational study, we included 264 individuals with type 2 diabetes, and calculated non-alcoholic fatty liver disease (NAFLD) liver fat score, NAFLD fibrosis score, and Fibrosis-4 (FIB-4) index to evaluate the status of NAFLD or liver fibrosis. DPN was diagnosed when the Michigan Neuropathy Screening Instrument-Physical Examination score was ≥ 2.5. The NAFLD fibrosis score and FIB-4 index were significantly higher in individuals with DPN than in those without DPN. Logistic analyses showed that the NAFLD fibrosis score and FIB-4 index were associated with DPN after adjustment for covariates (adjusted odds ratio 1.474 and 1.961, respectively). In the subgroup analysis, this association was only significant in the group with a high NAFLD liver fat score (> - 0.640). Serum levels of fetuin-A, a hepatokine, were decreased in individuals with abnormal vibration perception or 10-g monofilament tests compared with their counterparts. The present study suggests that liver fibrosis might be associated with DPN in individuals with type 2 diabetes., (© 2021. The Author(s).)

Diabetic neuropathy is one of the most prevalent chronic complications of diabetes, and up to half of diabetic patients will develop diabetic neuropathy during their disease course. Notably, emerging evidence suggests that glycemic variability is associated with the pathogenesis of diabetic complications and has emerged as a possible independent risk factor for diabetic neuropathy. In this review, we describe the commonly used metrics for evaluating glycemic variability in clinical practice and summarize the role and related mechanisms of glycemic variability in diabetic neuropathy, including cardiovascular autonomic neuropathy, diabetic peripheral neuropathy and cognitive impairment. In addition, we also address the potential pharmacological and non-pharmacological treatment methods for diabetic neuropathy, aiming to provide ideas for the treatment of diabetic neuropathy., (© 2021. The Author(s).)

Aim: To investigate the diagnostic utility of corneal confocal microscopy (CCM) for small fiber neuropathy in type 2 diabetes., Materials and Methods: There were 186 participants with type 2 diabetes enrolled in this cross-sectional research. Pure small fiber neuropathy and mixed fiber neuropathy were defined using clinical examination, electromyography, and quantitative sensory testing. Demographics and clinical data, corneal confocal microscopy parameters, and other neuropathy measures were compared among the groups. The diagnostic utility of corneal confocal microscopy for small fiber neuropathy was assessed by the receiver operating curve., Results: Of the 186 patients, 24.7% had a pure small fiber neuropathy and 17.2% of patients were diagnosed with mixed fiber neuropathy. The corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), and corneal nerve fiber length (CNFL) were significantly lower in subjects with pure small fiber neuropathy compared with those without diabetic peripheral neuropathy (all P < 0.05). The receiver operating curve analysis for corneal confocal microscopy diagnosing small fiber neuropathy demonstrated the area under the curve for CNFD of 0.791, CNFL of 0.778, CNBD of 0.710., Conclusions: Patients with type 2 diabetes with pure small fiber neuropathy showed more corneal nerve loss compared with those without diabetic peripheral neuropathy. It was revealed that corneal confocal microscopy can be a reasonable marker in the diagnosis of small fiber neuropathy in type 2 diabetes., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Previous studies exploring the influence of glycemic variability (GV) on the pathogenesis of distal symmetrical polyneuropathy (DSPN) in type 1 diabetes (T1DM) produced conflicting results. The aim of this study was to assess the relationship between GV and DSPN in T1DM. Adults with T1DM were included in this cross-sectional study and asked to undergo 3-day CGM. GV quantified by coefficient of variation (CV) and mean amplitude of glucose excursions (MAGE) were obtained from CGM. Clinical characteristics and biochemical assessments were collected for analysis. The study comprised 152 T1DM patients (53.9% males) with mean age of 44.2 year. Higher levels of age and duration of diabetes and lower levels of total cholesterol, LDL, fasting C-peptide and postprandial C-peptide were observed in DSPN subjects. DSPN groups displayed a higher blood glucose between 00:00 and 12:59 according to the CGM profile. Higher MAGE and CV were associated with increased risk of DSPN in the fully adjusted model. Meanwhile, a significant association between measurements of hypoglycemia, especially nocturnal hypoglycemia, and DSPN was found after multiple tests. CGM parameters describing the glycemic variability and hypoglycemia were potential risk factors for DSPN in adults with T1DM., (© 2021. The Author(s).)

Globally, diabetes has assumed epidemic proportions with the neuropathic complications attributed to the malady emerging as a substantial burden on patients and society. DNP has greatly affected the daily life of patients, the effect of traditional treatment methods is not ideal, and it is easy to produce drug resistance. This work is aimed at scrutinizing the effect of upregulating the expression of TNFAIP3 on diabetic neuralgia in mice. This work entailed ascertaining the effects of TNFAIP3 on a murine DNP system. This inspired us to observe the analgesic effect via high expression of lentivirus-mediated TNFAIP3 by intrathecal injection in the animal model to explore its regulatory impacts, symptom relief, and mechanistic role in pain. The results displayed an attenuation of hind paw pain hypersensitivity by LV-TNFAIP3 in the animals. The spinal cord and dorsal root ganglion of mice with neuropathic pain displayed an evident dip in TNFAIP3. Inhibition of the ERK/NF- κ B signaling pathway employing LV-TNFAIP3 conspicuously suppressed this pathway while the diabetic pain hypersensitivity was quelled. This effect was also seen with insulin treatment evidently. In conclusion, according to the above analyses, the interaction between DNP and extracellular signal-regulated kinase signal transduction pathway is one of the key factors of pathogenesis., Competing Interests: The author declares that there are no competing economic interests., (Copyright © 2021 Yang Liu et al.)

Background: The application of nanomedicine to antiretroviral drug delivery holds promise in reducing the comorbidities related to long-term systemic exposure to highly active antiretroviral therapy (HAART). However, the safety of drugs loaded with silver nanoparticles has been debatable. This study is aimed at evaluating the effects of HAART-loaded silver nanoparticles (HAART-AgNPs) on the behavioural assessment, biochemical indices, morphological, and morphometric of the hippocampus in diabetic Sprague-Dawley rats., Methods: Conjugated HAART-AgNPs were characterized using FTIR spectroscopy, UV spectrophotometer, HR-TEM, SEM, and EDX for absorbance peaks, size and morphology, and elemental components. Forty-eight male SD rats (250 ± 13 g) were divided into nondiabetic and diabetic groups. Each group was subdivided into ( n = 8) A (nondiabetic+vehicle), B (nondiabetic+HAART), C (nondiabetic+HAART-AgNPs), D (diabetic+vehicle), E (diabetic+HAART), and F (diabetic+HAART-AgNPs). Morris water maze, Y-maze test, and weekly blood glucose levels were carried out. Following the last dose of 8-week treatment, the rats were anaesthetized and euthanized. Brain tissues were carefully removed and postfixed for Nissl staining histology., Results: 1.5 M concentration of HAART-AgNPs showed nanoparticle size 20.3 nm with spherical shape. HAART-AgNPs revealed 16.89% of silver and other elemental components of HAART. The diabetic control rats showed a significant increase in blood glucose, reduced spatial learning, positive hippocampal Nissl-stained cells, and a significant decrease in GSH and SOD levels. However, administration of HAART-AgNPs to diabetic rats significantly reduced blood glucose level, improved spatial learning, biochemical indices, and enhanced memory compared to diabetic control. Interestingly, diabetic HAART-AgNP-treated rats showed a significantly improved memory, increased GSH, SOD, and number of positive Nissl-stained neurons compared to diabetic-treated HAART only., Conclusion: Administration of HAART to diabetic rats aggravates the complications of diabetes and promotes neurotoxic effects on the experimental rats, while HAART-loaded silver nanoparticle (HAART-AgNP) alleviates diabetes-induced neurotoxicity., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 Sodiq Kolawole Lawal et al.)

Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid-stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA-induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA-induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Jingwen Fan et al.)

Aims: Inflammatory osteolysis is sine-qua-non of active Charcot neuroarthropathy (CN) causing decreased foot bone mineral density (BMD) and fractures. We aimed to explore the effect of anti-inflammatory or anti-resorptive agents for effect on foot bone mineral content (BMC) and consequent long-term outcomes of foot deformities, fractures and amputation., Methods: Forty-three patients with active CN (temperature difference >2°C from normal foot) were evaluated. Patients were off-loaded with total contact cast and randomized to receive either methylprednisolone (1gm) (group A), zoledronate (5mg) (group B) or placebo (100ml normal saline) (group C) once monthly infusion for three consecutive months. Change in foot BMC was assessed at 6 months or at remission and followed subsequently up to 4 years for the incidence of new-onset fracture, deformities, or CN recurrence., Results: Thirty-six participants (24 male, 12 female) were randomized (11 in group A, 12 group B, 13 group C). The mean age was 57.7± 9.9 years, duration of diabetes 12.3± 5.8 years and symptom duration 6.5± 2.8 weeks. BMC increased by 36% with zoledronate (p = 0.02) but reduced by 13% with methylprednisolone (p = 0.03) and 9% (p = 0.09) with placebo at remission. There were no incident foot fractures, however, two patients sustained ulcers, and 3 had new-onset or worsening deformities and none required amputation during 3.36 ± 0.89 years of follow-up., Conclusion: Bisphosphonate for active CN is associated with an increase in foot bone mineral content as compared to decrease with steroids or total contact cast but long-term outcomes of foot deformities, ulceration and amputation are similar., Trial Registration: ClinicalTrials.gov: NCT03289338., Competing Interests: The authors have declared that no competing interests exist.