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Purpose: To explore variations in systemic and ocular parameters among patients with diabetes, both with and without diabetic peripheral neuropathy (DPN) and to identify sensitive indicators for DPN diagnosis., Methods: Ninty-five patients with type 2 diabetes mellitus (T2DM) were involved in this cross-sectional study, including 49 without DPN and 46 with DPN. Ocular parameters were obtained using optical coherence tomography angiography (OCTA) and corneal confocal microscopy (CCM)., Result: Patients with DPN presented with significantly higher HbA1c (p < 0.05) and glycated albumin (GA, p < 0.01) levels, increased prevalence of diabetic retinopathy (DR, p < 0.05), and lower serum albumin (ALB, p < 0.01) and red blood cell (RBC, p < 0.05) levels. Ocular assessments revealed reduced corneal nerve fiber length (CNFL, p < 0.001) and enlarged foveal avascular zone (FAZ) area (p < 0.05) in DPN group. Logistic regression analysis indicated a significant association of presence of DR, RBC, GA, ALB, CNFL and DPN (p < 0.05, respectively). In the binary logistic regression for DPN risk, all three models including the presence of DR and CNFL exhibited the area under the curve (AUC) exceeding 0.8., Conclusion: The study establishes a strong correlation between ocular parameters and DPN, highlighting CCM's role in early diagnosis. Combining systemic and ocular indicators improves DPN risk assessment and early management., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Aims: Diabetic peripheral neuropathy (DPN) is one of the most important complications of diabetes with a poor prognosis. Saikosaponin d (SSD) is a triterpenoid saponin isolated from Radix Bupleuri that has multiple pharmacological activities. However, whether SSD affects DPN is unclarified., Methods: Sprague Dawley rats were treated with streptozotocin (STZ) and high-fat diet (HFD) to induce DPN, in the presence or absence of SSD, with or without transfection of lentivirus vectors carrying siRNA targeting aquaporin 1 (si-AQP1). The body weight, plasma glucose levels, mechanical and thermal hyperalgesia, and nerve conductive velocity (NCV) of rats were measured. Hematoxylin-Eosin staining was used for histopathological observation of sciatic nerves. RT-qPCR and western blotting were utilized for measuring expression levels of AQP1 and ras homolog family member A/Rho-associated protein kinase (RhoA/ROCK) signaling pathway-related markers in dorsal root ganglion (DRG) of rats., Results: SSD increased the body weight, decreased plasma glucose levels, attenuated mechanical and thermal hyperalgesia, enhanced NCV and reduced proinflammatory cytokine levels in DPN rats. AQP1 displayed a high level in DPN rats and SSD treatment repressed the expression of AQP1. SSD enhanced the protective effect of AQP1 knockdown on the pathological changes of DPN. AQP1 depletion suppressed the activation of RhoA/ROCK signaling pathway in DPN rats., Conclusion: SSD alleviates STZ/HFD-induced DPN in rats by inhibiting the AQP1/RhoA/ROCK signaling pathway., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Aims: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements., Methods: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination., Results: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%., Conclusion: This study suggests that CAN predominantly co-exists with concomitant DPN., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Aims: Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy and are currently poorly studied. We designed an eye-tracking-based test to evaluate oculomotor function in patients with type 1 diabetes., Methods: We used the SRLab-Tobii TX300 Eye tracker®, an eye-tracking device, coupled with software that we developed to test abnormalities in the oculomotor system. The software consists of a series of eye-tracking tasks divided into 4 classes of parameters (Resistance, Wideness, Pursuit and Velocity) to evaluate both smooth and saccadic movement in different directions. We analyzed the oculomotor system in 34 healthy volunteers and in 34 patients with long-standing type 1 diabetes., Results: Among the 474 parameters analyzed with the eye-tracking-based system, 11% were significantly altered in patients with type 1 diabetes (p < 0.05), with a higher proportion of abnormalities observed in the Wideness (24%) and Resistance (10%) parameters. Patients with type 1 diabetes without diabetic neuropathy showed more frequently anomalous measurements in the Resistance class (p = 0.02). The classes of Velocity and Pursuit were less frequently altered in patients with type 1 diabetes as compared to healthy subjects, with anomalous measurements mainly observed in patients with diabetic neuropathy., Conclusions: Abnormalities in oculomotor system function can be detected in patients with type 1 diabetes using a novel eye-tracking-based test. A larger cohort study may further determine thresholds of normality and validate whether eye-tracking can be used to non-invasively characterize early signs of diabetic neuropathy., Trial: NCT04608890., (© 2022. The Author(s).)

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.)

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).)

Aims: Cardiovascular autonomic neuropathy (CAN) is one of the most serious types of diabetic autonomic neuropathy and is a class of small fibre neuropathy. Among many inspection methods, quantitative sensory testing is an effective and convenient method for diagnosing diabetic small fibre neuropathy. This cross-sectional study aimed to identify the correlation between the development of cardiovascular autonomic neuropathy and quantitative sensory testing parameters in patients with type 2 diabetes mellitus., Methods: A total of 266 participants with type 2 diabetes mellitus from Nanjing Drum Tower Hospital were enrolled in this study, and each of them received cardiovascular reflex tests (CARTs) and quantitative sensory testing, including testing of cold, warm, cold pain, and heat pain detection thresholds (CDT, WDT, CPT, and HPT, respectively). The results of CARTs were compared with the thermal detection thresholds in quantitative sensory testing by using SPSS 26.0., Results: A total of 266 participants were divided into the CAN group, early CAN (ECAN) group, and without CAN (NCAN) group. There were significant differences in quantitative sensory testing parameters among three groups, and CARTs presented a positive correlation with the WDT and HPT and a negative correlation with the CDT. Moreover, after adjusting for age, sex, diabetes duration, and other influencing factors, WDT, HPT, and CDT were independent risk factors for cardiovascular autonomic neuropathy., Conclusions: The thermal detection thresholds, including cold, warm, and heat pain detection thresholds, in quantitative sensory testing were found to be significantly related to the results of CARTs. Some thermal detection thresholds were independent risk factors for cardiovascular autonomic neuropathy. Therefore, this study showed that quantitative sensory testing has a reliable predictive ability for the occurrence and development of cardiovascular autonomic neuropathy., (© 2021. Springer-Verlag Italia S.r.l., part of Springer Nature.)

The first reports of a link between thiamine and diabetes date back to the 1940s. Some years later, a role for thiamine deficiency in diabetic neuropathy became evident, and some pilot studies evaluated the putative effects of thiamine supplementation. However, the administration of thiamine and its lipophilic derivative benfotiamine for the treatment of this complication gained consensus only at the end of the '90 s. The first evidence of the beneficial effects of thiamine on microvascular cells involved in diabetic complications dates to 1996: from then on, several papers based on in vitro and animal models have addressed the potential use of this vitamin in counteracting diabetic microangiopathy. A few pilot studies in humans reported beneficial effects of thiamine administration on diabetic nephropathy, but, despite all promising proofs-of-concept, the possible role of thiamine in counteracting development or progression of retinopathy has not been addressed until now. Thiamine is a water-soluble vitamin, rapidly expelled from the body, with no issues of over-dosage or accumulation; unfortunately, it is non-patentable, and neither industry nor independent donors are interested in investing in large-scale randomized controlled clinical trials to investigate its potential in diabetes and its complications. Consequently, science will not be able to disprove a promising hypothesis and, more importantly, diabetic people remain deprived of a possible way to ameliorate their condition., (© 2021. The Author(s).)

Aims/hypothesis: Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes., Methods: We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic-euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years., Results: In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = -0.242 to r = -0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered., Conclusions/interpretation: Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes. Graphical abstract.

Aims/hypothesis: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes., Methods: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593)., Results: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001)., Conclusions/interpretation: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract.

This study aims to investigate the impact of type 2 diabetes (T2D) and diabetic peripheral neuropathy (DPN) on pinch proprioception and to establish the correlations with sensory impairments. We collected data from a total of 36 participants (healthy, n = 12; T2D without DPN, n = 11; and T2D + DPN, n = 13), all matched for age, 60 ± 6 years. Pinch proprioception was determined through 3 trials of attempts to actively reproduce 15° of pinch position without visual feedback. Target accuracy and precision was compared between groups using Kruskal-Wallis test. Sensation was tested through the two-point discrimination and Semmes-Weinstein monofilaments applied on the fingers. Sensory measures were correlated with pinch proprioception measures via Spearman's rank test. The T2D + DPN group showed significant decrements in accuracy and precision as compared to the T2D-only (p = 0.003 and p = 0.006, respectively) and the healthy groups (both p = 0.002); no significant differences were found between T2D-only and healthy. Spearman's rank showed moderate (r = 0.45-0.66, p < 0.001) correlations between pinch proprioception and sensory measures. Our results showed pinch proprioception disruption in people with T2D + DPN, but not in people with T2D-only. The awareness of pinch proprioceptive deficits is paramount for the safety of individuals with T2D and DPN. Moderate correlations between sensory impairments and pinch proprioceptive deficits suggest that not only superficial/discriminative sensation is implicated in proprioceptive decrements. Other mechanisms such as damage to muscle spindles or central nervous system associated with T2D + DPN warrant further investigations.

Diabetes mellitus is an independent risk factor for falling, particularly in the elderly. Due to chronic hyperglycemia and hyperinsulinemia patients with diabetes mellitus may have neurological deficits as peripheral neuropathy that is a debilitating micro-vascular complication affecting the proximal and distal peripheral sensory and motor nerves. Sensory neuropathy is prominent and represents the chief contributor to postural instability in diabetic subjects. Diabetic retinopathy is another complication consequent to a breakdown of the inner blood-retinal barrier with accumulation of extracellular fluids in the macula and growth of new vessels causing retinal detachment. Together peripheral neuropathy and retinopathy contribute to increase the risk of falls in diabetic patients, but a certain vestibular organs impairment should not be underestimated. Nevertheless, the exact mechanism and localization of peripheral vestibular damage consequent to chronic hyperglycemia and hyperinsulinemia are currently not still understood. Moreover it is not defined the possible role of these two blood conditions in worsening the prognosis of typical vestibular pathologies like "benign paroxysmal positional vertigo" and "Meniere disease". The aim of this review was to retrieve all studies investigating about the balance system alterations in patients suffering of diabetes. A search thorough Ovid MEDLINE was performed to enroll all eligible articles. Fourteen studies comprising a total of 1364 patients were included and analyzed in detail. On the basis of data reported in our review it appears plausible to hypothesize a direct connection among chronic hyperglycemic/hyperinsulinemic damage and peripheral vestibular organ dysfunction.

In parallel with the growing diabetes pandemic, there is an increasing burden of micro- and macrovascular complications, occurring in the majority of patients. The identification of a number of synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma samples are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a diverse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research.

Aims: Recently, the association between anemia and diabetic microvascular complications has been studied. Diabetic peripheral neuropathy (DPN) is also a common complication of type 2 diabetes mellitus (T2DM), while the relationship between anemia and DPN is rarely investigated. The aim of this study is to evaluate the association between anemia and DPN in T2DM., Methods: In this cross-sectional study, 1134 T2DM inpatients were enrolled. The diagnosis of DPN was based on neuropathy system score (NSS) and neuropathy disability score (NDS). Logistic regression was conducted to analyze the association between anemia and DPN., Results: The proportions of anemia in DPN and non-DPN group were 25.4 and 15.2%, respectively. Compared with non-anemia group, the proportions of moderate/severe NSS (42.7 vs. 24.5%, P < 0.001) and moderate/severe NDS (51.5 vs. 38.0%, P < 0.001) were higher while the nerve conduction velocity (NCV) was lower in anemia group. Univariate logistic regression analysis showed patients with anemia possessed an increased risk of DPN [OR = 1.906, 95%CI: 1.416, 2.567, P < 0.001]. Multivariate logistic regression analysis suggested anemia was an independent risk factor of DPN in model 1 and model 2 [model 1: OR = 1.472, 95%CI: 1.047, 2.070, P = 0.026; model 2: OR = 1.448, 95%CI: 1.013, 2.071, P = 0.043]., Conclusions: Anemia is an independent risk factor of DPN in T2DM patients.

Aims: We investigated associations between serum levels of glycated albumin (GA) and glycated hemoglobin (HbA1c) and the presence of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes mellitus (T1DM)., Methods: Between September 2009 and April 2015, we evaluated 314 patients with T1DM in the Endocrinology Department of Shengjing Hospital of China Medical University. We divided the patients into the DPN group (n = 72) and the non-DPN group (n = 242), on the basis of the presence of DPN., Results: The DPN group had significantly higher GA values than the non-DPN group. After univariate logistic regression, we selected several factors for further analysis: HbA1c, GA, duration of T1DM, body mass index, smoking, hypertension, and the presence of diabetic complications, including nephropathy, retinopathy, and cardiovascular disease. We performed a multivariate logistic regression analysis to examine the association between the presence of DPN and each of these variables. We identified GA, HbA1c, hypertension, smoking, retinopathy, and cardiovascular disease as independent variables for indicating the presence of DPN. Results of a receiver operating characteristic curve analysis revealed that the area under the curve of GA (0.771) was larger than that of HbA1c (0.629). We defined the cutoff value of GA as 23.5 % (sensitivity 0.764, specificity 0.661) and the cutoff value of HbA1c as 8.45 % (sensitivity 0.667, specificity 0.595) for predicting DPN in patients with T1DM., Conclusions: GA may be a better indicative marker of DPN in patients with T1DM than HbA1c.

Aims: To investigate the associations of vitamin B12 (cobalamin and holotranscobalamin) status with depression, cognition and neuropathy in patients with type 2 diabetes using metformin., Methods: In an observational study, among 550 type 2 diabetes patients using metformin, cobalamin and holotranscobalamin (holoTCII) levels were measured at the annual diabetes checkup, and deficiencies were defined as <148 and <21 pmol/L, respectively. Depression and cognitive function were assessed with corresponding International Classification of Primary Care codes and questionnaires; neuropathy with medical record data and a questionnaire. Confounding variables were retrieved from medical records. Multivariable logistic and linear regressions were used with cobalamin status as independent variable; depression, cognition and neuropathy as dependent variables., Results: The mean duration of diabetes was 8.4 years (±5.8); mean duration of metformin use was 64.1 months (±43.2), with a mean metformin dose of 1,306 mg/day. A sufficient cobalamin level was independently associated with a decreased risk of depression (OR 0.42; 95 % CI 0.23-0.78) and better cognitive performance (β = 1.79; 95 % CI 0.07-3.52) adjusted for confounders. This indicates that cobalamin-deficient patients had a 2.4 times higher chance of depression and a 1.79 point lower cognitive performance score. HoloTCII was not associated with any outcome., Conclusions: Cobalamin deficiency was associated with an increased risk of depression and worse cognitive performance, while holoTCII was not. Screening for cobalamin deficiency may be warranted in diabetes patients using metformin. Physicians should consider a cobalamin deficiency in diabetes patients using metformin with a depression or cognitive decline.

Oxidative stress is implicated in the pathogenesis of experimental diabetic neuropathy, but prospective studies in diabetic patients are lacking. We aimed to evaluate whether the plasma levels of various biomarkers of oxidative stress predict the progression of diabetic neuropathy and mortality over 6 years. We followed 89 diabetic patients aged 54 ± 14 years (59 % with polyneuropathy), 72 of whom underwent nerve function reassessment after 6.2 ± 0.8 years, whereas 17 died after 4.2 ± 1.0 years. Plasma markers of oxidative stress at baseline included superoxide anion, hypochlorous acid, peroxynitrite, 8-iso-prostaglandin F2α, vitamin E/lipid ratio, and vitamin C. Neuropathy was assessed by symptoms and deficits, motor and sensory nerve conduction velocity (MNCV, SNCV), vibration perception thresholds (VPT), thermal detection thresholds, and heart rate variability (HRV). Despite a reduction in HbA1c by 1.4 ± 1.6 % (p < 0.001), median SNCV, sural SNCV, peroneal MNCV, malleolar VPT, and warm TDT deteriorated after 6 years (all p < 0.05). In multivariate models, increased superoxide generation was associated with a decline in median SNCV (β = -0.997; p = 0.036) and deterioration in HRV at rest (OR 1.63 [95 % CI 1.09-2.44]; p = 0.017) over 6 years. Low vitamin E/lipid ratio tended to predict a decrease in peroneal MNCV (β = 0.781; p = 0.057) and an increase in malleolar VPT (β = -0.725; p = 0.077). Plasma superoxide generation was associated with an increased risk of mortality (HR 23.2 [95 % CI 1.05-513]; p = 0.047). In conclusion, increased plasma superoxide generation predicted the decline in sensory and cardiac autonomic nerve function and mortality over 6 years in diabetic patients, but larger studies are required for confirmation.

Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are common type 2 diabetes complications with a large inter-individual variability in terms of clinical manifestations and severity. Our aim was to evaluate a possible involvement of genetic polymorphisms in miRNA regions in the susceptibility to DPN and CAN. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetes patients (T2D) analysed for DPN and 128 T2D patients analysed for CAN. A genotype-phenotype correlation analysis was performed. The T allele of rs11888095 single nucleotide polymorphism (SNP) in MIR128a was significantly associated with a higher risk (ORadj = 4.89, P adj = 0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (ORadj = 0.49, P adj = 0.09), respectively. A multivariate logistic regression analysis confirmed that both SNPs contribute to DPN (p < 0.001 and p = 0.01 for MIR128a and MIR146a, respectively). MIR128a SNP significantly contributed also to DPN score (p = 0.026). Rs895819 SNP in MIR27a was significantly associated with a higher risk to develop early CAN (P adj = 0.023 and ORadj = 3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (P adj = 0.052, ORadj = 0.32) and to confirmed CAN (P adj = 0.041, ORadj = 0.13). The same SNP resulted significantly associated with a lower CAN score and a higher E/I (p = 0.002 and p = 0.003, respectively). In conclusion, we described associations of MIR128a and MIR146a SNPs with DPN susceptibility and of MIR146a and MIR27a SNPs with CAN susceptibility. This is the first study showing that genetic variability in miRNA genes could be involved in diabetic neuropathies susceptibility.

To look at the prevalence of phonatory symptoms in patients with type 2 diabetes mellitus. The correlation between these symptoms with duration of the disease, glycemic control, and neuropathy will be described. A total of 105 consecutive patients diagnosed with type 2 diabetes mellitus by their primary endocrinologist were evaluated. A control group consisting of 33 healthy subjects was recruited for this study. Demographic data included: age, gender, allergy, smoking, duration of the disease, glycemic control, and presence or absence of neuropathy. Subjects were also asked about the presence or absence of the following symptoms: hoarseness, vocal tiring or fatigue, vocal straining, and aphonia or complete loss of voice. Patients were also asked to fill out the Voice Handicap Index 10. The mean age of patients with diabetes was 53.21 + 9.68 years with male-to-female ratio of 2/3. The most common phonatory symptoms were vocal tiring or fatigue and hoarseness (34.3 and 33.3 %). There was a significant difference in the prevalence of hoarseness and vocal straining (p value 0.045 and 0.015, respectively) compared to controls. There was a significant correlation between glycemic control, neuropathy, and hoarseness (p value 0.030 and 0.001, respectively). Vocal straining and aphonia also correlated significantly with the presence of neuropathy. Close to 16 % of diabetic patients had a VHI-10 above or equal to 7. Diabetic patients are more likely to have phonatory symptoms compared to controls, namely straining and hoarseness. One out of seven patients with diabetes has reported that phonatory symptoms had a significant impact on their quality of life. The presence of neuropathy and poor glycemic control should alert the treating physician to these vocal complaints.

A threatening major amputation represents a fateful turning point for diabetics. This occurs in 50% of cases of amputations in diabetics. This increases the demand for another therapeutic route not only because of the limitations in quality of life but also due to substantially higher mortality. Even if an osteomyelitic ischemic situation is often present specialized centers have succeeded in substantially reducing the rate of major amputations in such patients. The term "minor amputation" commonly used in vascular surgery is not uniformly understood. Following the "vascular surgery working model" developed by Rümenapf, the significance of "minor amputations" for retention of extremities and the associated controversies have been shown. "Minor amputations" therefore represent a maxi-task if patients undergoing such a procedure are to be timely and competently treated. The necessary interdisciplinary cooperation with other specialists should in the future also include orthopedic surgeons.

In addition to chronic hyperglycemia, insulin resistance itself has been proposed to cause a diabetic neuropathy. We evaluated the role of insulin resistance in the pathogenesis of peripheral and autonomic neuropathy in patients with type 2 diabetes. Eighty-six patients with type 2 diabetes were evaluated for the anthropometric and biochemical profiles, and Kitt value was calculated from insulin tolerance test to assess the insulin resistance. Various autonomic function tests, nerve conduction velocity, and quantitative sensory tests were performed to assess autonomic and peripheral neuropathy. In univariate analysis, both autonomic and peripheral neuropathy were significantly associated with glycemic exposure index (GE index), HDL-cholesterol, duration of DM, and Kitt value. In stepwise linear regression analysis, GE index was an independent predictor of autonomic and peripheral neuropathy (β = 0.643, P < 0.001; β = 0.207, P = 0.013, respectively), and Kitt value was also an independent factor for the autonomic and peripheral neuropathy (β = - 0.306, P < 0.001; β = - 0.329, P < 0.001, respectively). Low HDL-cholesterol increased the odds ratio for peripheral neuropathy. Insulin resistance is independently associated with peripheral and autonomic neuropathy in Korean Type 2 diabetic patients along with hyperglycemia and HDL-cholesterol.

Painful diabetic neuropathy is one of the most common forms of neuropathic pain syndromes. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated as a key pain mediator in the development and maintenance of neuropathic pain conditions. Recent studies showed that endogenous TNF-alpha production was also accelerated in neural tissues and spinal cord under chronic hyperglycemia. Thus, in this study, we investigated whether pharmacological inhibition of TNF-alpha by etanercept, a TNF-alpha antagonist, could block behavioral sign of diabetic neuropathic pain. Diabetes was induced by streptozotocin (STZ) (200 mg/kg, i.p.) in Balb-c mice and behavioral tests were performed between 45 and 60 days after STZ administration. Mechanical and thermal sensitivities were measured by a series of calibrated Von Frey filaments and hot plate test, respectively. Etanercept was given by either intravenous (i.v.), intrathecal (i.th.) or intraplantar (i.pl.) routes to the diabetic mice. Tactile allodynia, but not thermal hyperalgesia, developed in diabetic mice. Both i.v. (1, 10 and 20 mg/kg) or i.th. (1, 5 and 10 μg/mouse) treatments with etanercept produced dose dependent reversal of tactile allodynia in diabetic mice. However, etanercept was found to be inactive against allodynia when given i.pl. (1, 5 and 10 μg/mouse). Our results suggest that etanercept has promising effects on diabetic neuropathic pain with antiallodynic effects when given systemically or intrathecally.

Aims/hypothesis: The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients., Methods: This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007-2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics., Results: Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29-3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59-6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70-1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications., Conclusions/interpretation: In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications.

Despite the fact that it is a frequent diabetic complication, the mechanisms underlying the manifestation of diabetic neuropathic pain remain poorly understood. In this study, we hypothesized that the depletion of peripheral macrophages with liposome-encapsulated clodronate (LEC) can prevent, at least delay, the progression of diabetes-induced neuropathic pain. Therefore, the aim of this study was to evaluate the effects of macrophage depletion on mechanical allodynia and thermal hyperalgesia in the streptozotocin (STZ)-induced rat model of diabetic neuropathy. LEC was intravenously administrated to rats three times with 5-day intervals. A single intravenous injection of STZ caused an increase in the average blood glucose levels and a decrease in body weight. Although LEC treatment did not affect the body weight gain, the blood glucose level was lower and serum insulin level higher in LEC-treated diabetic rats than in that of diabetic rats. In addition, LEC treatment alleviated the excessive damage in beta cells in diabetic rats. Diabetic animals displayed marked mechanical allodynia and thermal hyperalgesia. While the treatment of diabetic rats with LEC did not significantly change the thermal withdrawal latency, diabetes-induced decrease in mechanical paw withdrawal threshold was significantly corrected by the LEC treatment. The results of this study show that thermal hyperalgesia and mechanical allodynia induced by diabetes may be associated with alterations in blood glucose level. Depletion of macrophages with LEC in diabetic rats may reduce mechanical allodynia without affecting thermal hyperalgesia. Taken together, these results suggested that depletion of macrophages in diabetes may partially postpone the development of diabetic neuropathic pain.

There is concern that antipsychotic drugs cause diabetes. Although there has been an explosion in the quantity of literature about this subject, it remains confusing and inconsistent. To assess whether the association between antipsychotic drugs and diabetes is causative, we applied the Austin Bradford Hill criteria to the available evidence. In support of a causative relationship, there is temporality for some cases of diabetes, and there is a biologically plausible explanation. The causative link between antipsychotic drugs and diabetes is coherent with our understanding of diabetes and there are other analogies. However the strength of association is weak, there is lack of consistency or specificity, and there is little evidence to support a biological gradient. We should therefore conclude that the evidence surrounding a causative link between antipsychotic drugs and diabetes is inconclusive. Moreover, the risk is probably low and the attributable risk of developing diabetes is greater for traditional risk factors such as family history, ethnicity, obesity and ageing than it is for receiving an antipsychotic drug. Consequently, the majority of patients receiving second-generation antipsychotics will not develop diabetes as a result of their medication.

Aims/hypothesis: We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression., Methods: Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose., Results: AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase., Conclusions/interpretation: The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes.

Aims/hypothesis: A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary leakage., Methods: Three matched groups were studied: 18 diabetic patients with documented peripheral neuropathy (DN), 18 diabetic patients without peripheral neuropathy (D), and 18 healthy control subjects (C). Sensory and motor nerve function of the distal extremities were assessed by standard neurography, and expressed in a sensory-motor nerve function score. Sympathetic vasomotion of the skin microcirculation was assessed by determining the power of blood flow variability in the low-frequency (0.02-0.14 Hz) band by spectral analysis of laser Doppler flowmetry at the median ankle. Skin capillary leakage was evaluated by sodium fluorescein videodensitometry at the same site of the foot., Results: Sympathetically mediated vasomotion of the foot skin microcirculation was lower in diabetic patients with documented peripheral neuropathy compared with diabetic patients without peripheral neuropathy and control subjects (p<0.001). Capillary sodium fluorescein leakage was larger in 18 diabetic patients with documented peripheral neuropathy than in diabetic patients without peripheral neuropathy (p<0.02) and C (p<0.005). Multiple regression analysis disclosed that a reduced sympathetically mediated vasomotion, together with a lower sensory-motor nerve function score, independently contributed to the variance in sodium fluorescein leakage, for 30% (p<0.001) and 17% (p<0.01), respectively., Conclusions: A loss of sympathetic tone, apart from sensory-motor nerve dysfunction, seems to be a major determinant of an increased capillary permeability in diabetic patients with neuropathy.

Diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy. This review examines evidence for the importance of vascular factors and their metabolic substrate from human and animal studies. Diabetic neuropathy is associated with risk factors for macrovascular disease and with other microvascular complications such as poor metabolic control, dyslipidaemia, body mass index, smoking, microalbuminuria and retinopathy. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. Investigations on biopsy material from patients with mild to severe neuropathy show graded structural changes in nerve microvasculature including basement membrane thickening, pericyte degeneration and endothelial cell hyperplasia. Arterio-venous shunting also contributes to reduced endoneurial perfusion. These vascular changes strongly correlate with clinical defects and nerve pathology. Vasodilator treatment in patients and animals improves nerve function. Early vasa nervorum functional changes are caused by the metabolic insults of diabetes, the balance between vasodilation and vasoconstriction is altered. Vascular endothelium is particularly vulnerable, with deficits in the major endothelial vasodilators, nitric oxide, endothelium-derived hyperpolarising factor and prostacyclin. Hyperglycaemia and dyslipidaemia driven oxidative stress is a major contributor, enhanced by advanced glycation end product formation and polyol pathway activation. These are coupled to protein kinase C activation and omega-6 essential fatty acid dysmetabolism. Together, this complex of interacting metabolic factors accounts for endothelial dysfunction, reduced nerve perfusion and function. Thus, the evidence emphasises the importance of vascular dysfunction, driven by metabolic change, as a cause of diabetic neuropathy, and highlights potential therapeutic approaches.

Spontaneous diabetic WBN/Kob rats develop diabetic peripheral neuropathy characterized by primary segmental demyelination and secondary axonal degeneration. The objective of this study was to evaluate the histochemical and morphometric characteristics of the lesions of skeletal muscles innervated by the affected nerves in diabetic rats. The following groups of rats were investigated: 24-month-old males that had been diabetic for less than 12 months, 10-month-old pre-diabetic males, 24-month-old non-diabetic females, and 10-month-old nondiabetic females. The soleus (SOL), extensor digitorum longus (EDL) and biceps femoris (BF) muscles were studied by light and electron microscopy, including histochemical and morphometric analyses. Muscle weight was reduced with age to a remarkable degree in diabetic BF and EDL. Dispersed atrophy of muscle fiber was observed in type 2a fibers of BF and EDL, and type 2c fibers of SOL, and the incidence was higher in diabetic rats. Multi-core, myofibrillar disorientation and an increased number of central nucleus of SOL, along with connective tissue proliferation of BF perimysium were noted in diabetic rats. The fiber population and type of composition varied with age, but no remarkable changes attributable to diabetic conditions were observed. Electron microscopically, an abnormal arrangement of myofibrils, a number of myelin figures, mitochondrial swelling and lysis of mitochondrial cristae were seen in diabetic rats. However, the neuromuscular junction and capillaries were intact. These findings indicate that the diabetic skeletal muscle lesion in WBN/Kob rats was mainly myogenic in nature, and was aggravated by the age-related change.

Many patients with diabetes mellitus complain of early satiety and postprandial gastric fullness. In 1945, these symptoms were first found to result from a gastric motor dysfunction which makes the delivery of ingesta into the small intestine, the time of their absorption and the related blood-glucose rise unpredictable. Consequently, insulin or hypoglycaemic agents are administered at inappropriate time points and poor glycaemic control ensues. About 50% of patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus are affected. Hyperglycaemia may play an important role in the disorder: gastric emptying was found to be slower in states of induced hyperglycaemia than in euglycaemia. However, significantly reduced blood-glucose concentrations after therapy readjustment were not associated with an increase in emptying rate. Prolonged hyperglycaemia could alter nerve metabolism and contribute to the development of neuropathy. Severity of cardiovascular autonomic neuropathy, but not actual blood-glucose and glycated haemoglobin level, has been found to correlate with the degree of emptying impairment. Drugs enhancing gastric emptying could improve the coordination between insulin administration and the onset of nutrient absorption and thus glycaemic control. Disappointingly, trials to study the long-term effects of such drugs are scarce and their results predominantly negative. In conclusion, many diabetic patients have impaired gastric motor function which could contribute to poor glycaemic control. Evidence suggests that autonomic neuropathy is the main underlying factor. This review aims to offer a critical survey of all the data available at present on these topics.

Critical illness polyneuromypathy has not previously been reported as a complication of diabetic coma. We describe a patient with hyperosmolar non-ketotic coma (HONK) complicating gram-negative sepsis in whom persistent coma and profound tetraplegia caused considerable concern. Although, initially, it was feared that the patient had suffered a central neurological complication such as stroke or cerebral oedema, a diagnosis of critical illness motor syndrome (CIMS) was subsequently confirmed neurophysiologically. Profound limb weakness associated with HONK is not necessarily due to a catastrophic cerebral event, rather it may be a result of CIMS, which has an excellent prognosis for full neurological recovery.

Cross-sectional studies have shown plasma cell adhesion molecules (CAMs) to be increased in patients with diabetes-related complications. In the first prospective study of CAMs, we have shown that plasma CAMs may be a predictor of the development of diabetic neuropathy. We followed up 28 diabetic patients (13 neuropathic) over a 5 year period, starting from 1991. All patients had peroneal nerve conduction velocity (PNCV), vibration perception threshold and plasma CAMs measured at baseline and follow-up. We found P-selectin and intercellular adhesion molecule-1 (ICAM-1) to be increased at baseline in patients with neuropathy compared to non-neuropathic patients. P-selectin and E-selectin were also found to be significantly higher at baseline in patients who at follow-up showed deterioration in PNCV of more than 3 m/s (p<0.05; p=0.01; respectively). P-selectin and ICAM-1 strongly correlated with PNCV. Univariate and multivariate regression analyses showed a significant inverse association between increasing log P-selectin, log E-selectin and log ICAM-1 with decreasing PNCV, and remained significant even after adjustment for glycaemic control. P-selectin and E-selectin, odds ratios of 8.8 (95% CI: 1.1-68.8; p=0.038) and 12.5 (95% CI: 1.2-132.1; p=0.036), respectively, were significantly associated with the risk of deterioration of PNCV after 5 years. This study suggests that plasma cell adhesion molecules may play an important role in the development and progression of peripheral neuropathy in diabetes mellitus.

There is no information on the mutual occurrence and the development of autonomic and peripheral somatic neuropathies based on long-term follow-up of patients with non-insulin-dependent diabetes mellitus (NIDDM). We investigated the relation between the changes in autonomic function values and electrodiagnostic values, and the relation between the occurrence of autonomic neuropathy and peripheral somatic polyneuropathy in a group of patients with newly diagnosed NIDDM (n = 133, aged 45-65 years) at baseline and 5 and 10 years later. Parasympathetic autonomic neuropathy was diagnosed on the basis of heart rate variability during deep-breathing and sympathetic autonomic neuropathy on the basis of fall in systolic blood pressure while changing from supine to standing. Polyneuropathy was diagnosed on the basis of both clinical criteria and electrodiagnostic studies (nerve conduction velocity and response-amplitude values). In 10 years 36 patients died, mainly from cardiovascular causes. Altogether 78 patients completed the study. At 10 years, parasympathetic autonomic neuropathy was diagnosed in 61.3% of those with polyneuropathy and 66.7% of those without. Likewise, the frequency of sympathetic autonomic neuropathy was similar in those with polyneuropathy (21.9%) and those without (26.5%). The respective figures for combined (both parasympathetic and sympathetic) autonomic neuropathy were 10.0% and 18.8%. The worsening of parasympathetic and sympathetic autonomic function values was not related to the worsening in electrodiagnostic results with time. In conclusion, the development of autonomic and peripheral somatic neuropathies was divergent in patients with NIDDM suggesting different pathophysiological processes for these neuropathies.

Cardiac autonomic neuropathy (CAN) is a very frequent complication of insulin-dependent mellitus type 1, affecting the sympathetic or parasympathetic sections or both. The different impairment in the two sections might modify left ventricular function early. To evaluate this relationship, we studied 61 patients (mean age 39.6 +/- 7 years) with type 1 diabetes for more than 10 years, without coronary artery disease (CAD); negative ergometric stress test) and without other pathologies that could interfere with ventricular function. All patients underwent MONO-, 2-dimensional and Doppler echocardiographic examination and radionuclide angiography with 99Tc (RNA). According to the outcome of the Ewing tests, patients were divided into two groups: group A with two or more tests altered (26 patients with CAN) and group B with one or no tests altered (35 patients without CAN). No significant differences between the two groups were found in the systolic function parameters with either technique. In contrast, a pattern of abnormal relaxation was found for the diastolic function parameters: in group A a decrease in E-wave velocity and its time-velocity integral and an increase in A-wave and its time-velocity integral were detected with echocardiography. Moreover, RNA showed a reduced peak filling rate and an increased isovolumic relaxation time. When compared with normal values, an abnormal diastolic filling, defined as two independent echocardiography plus one RNA variable impairment, was found in 15 patients (57.6%) in group A and in only 4 patients (11.4%) in group B (P < 0.001). Our findings suggest an early involvement of diastolic function in patients with CAN.

The effects of aminoguanidine (AG) and L-carnitine (LC) on somatosensorial evoked potential (SEP) latency and neural levels of thiobarbituric acid reactive substances (TBARS), products of lipid peroxidation, were compared in alloxan-diabetic rats. AG and LC were given to diabetic rats starting from the 3rd week after the induction of diabetes and lasting for 4 weeks. SEP latency was measured by stimulating via caudal nerve and recording via cortex, once weekly during the treatments. Diabetes caused deficits in SEP (P < 0.05 vs non-diabetic control rats, respectively). AG and LC restored SEP latencies slightly but not significantly, with the exception of the prominent effect of AG at the first week and both treatments at the 4th week of the treatments (P < 0.05 vs untreated diabetic rats, respectively). Diabetes caused elevation in neural TBARS levels (P < 0.05 vs non-diabetic group), which was prevented by both AG and LC (P < 0.05 vs untreated diabetic rats, respectively). Weight and the glucose levels were not influenced by the treatments. Our results suggest that AG improves SEP latencies better than LC. Our results also suggest that the beneficial effects of both AG and LC on diabetic neuropathy are not associated with the regulation of glycemia, but these effects may be related in part with prevention of lipid peroxidation.

To investigate the presence of autoantibodies against sympathetic nervous tissue and their correlation with cardiac sympathetic dysinnervation in insulin-dependent diabetes mellitus (IDDM), 20 newly diagnosed (age 26 +/- 6 years) and 48 long-term IDDM patients (age 40 +/- 13 years, duration of diabetes 22 +/- 12 years) without myocardial perfusion abnormalities (normal 99mTC-methoxyisobutylisonitrile uptake) were assessed for myocardial 123I-metaiodo benzylguanidine (123I-MIBG) uptake and complement-fixing sympathetic ganglia (CF-SG) autoantibodies. Both groups of patients were also studied for islet cell antibodies (ICA) and ECG-based cardiac autonomic neuropathy. Eighty control subjects (age 18-49 years) were investigated for CF-SG autoantibodies. Eight newly diagnosed (40%) and 12 long-term (25%) IDDM patients exhibited CF-SG autoantibodies, compared to 4 control subjects (5%; p < 0.01, p < 0.05). In long-term diabetic patients, the reduction of global but not of regional myocardial 123I-MIBG uptake correlated with CF-SG autoantibodies (r = 0.34, p = 0.02). Newly diagnosed diabetic patients did not show an association between CF-SG autoantibodies and global or regional myocardial 123I-MIBG uptake. ECG-based cardiac autonomic neuropathy (> or = two of five cardiac reflex tests abnormal) was present in 22 and absent in 26 long-term IDDM patients, of whom 9 (41%) and 3 (12%), respectively were positive for CF-SG autoantibodies (p = 0.02). Only 1 newly diagnosed IDDM patient demonstrated ECG-based cardiac autonomic neuropathy and was also positive for CF-SG autoantibodies. Although they are somewhat suggestive, results concerning autoantibodies against sympathetic nervous tissue and cardiac sympathetic dysinnervation do not strongly support the view that autoimmune mechanisms play a major role in the pathogenesis of cardiac sympathetic neuropathy in IDDM.

Insulin neuritis, or painful neuropathy following rapid improvement in glycaemic control, is well recognised but its aetiology is unclear. An understanding of the processes involved in the genesis of acute painful neuropathy of rapid glycaemic control may give an insight into the early pathogenetic factors leading to diabetic nerve damage in general. We have identified five subjects with insulin neuritis including one who developed severe autonomic neuropathy following treatment with insulin. Subjects underwent: 1) assessment of neuropathic symptom and deficit scores; 2) quantitative sensory and electrophysiological studies and 3) sural nerve epineurial vessel photography and fluorescein angiography in vivo. The sural nerve photographs were independently graded by an ophthalmologist. All subjects with insulin neuritis presented with severe sensory symptoms but clinical examination and electrophysiological tests were normal except in the subject with the severe autonomic neuropathy in whom all the tests were abnormal. On nerve photography, there was an abundance of epineurial nutrient vessels although these showed severe abnormalities including arteriolar attenuation, tortuosity and arterio-venous shunting in all subjects. Proliferating neural 'new vessels' which bear striking similarities to those found in the retina and that were more leaky to fluorescein than normal vessels, were observed in three subjects. Venous distension and/or tortuosity was also observed in three subjects and this was most marked in the subject with severe autonomic neuropathy. This study shows that epineurial nutrient vessel anatomy is abnormal in subjects with acute painful neuropathy of rapid glycaemic control, a condition previously thought to be purely metabolic in origin. The presence of epineurial arterio-venous shunting and a fine network of vessels resembling the new vessels of the retina, may lead to a 'steal' effect rendering the endoneurium ischaemic. This process may be important in the genesis of neuropathic pain, and further supports the importance of vascular factors in the pathogenesis of diabetic neuropathy.

Foot disease in patients with diabetes mellitus is multifactorial and results from a combination of peripheral neuropathy, vascular compromise and superimposed infection. Foot complications in diabetic patients are common and account for more hospital days than any other aspects of their disease. Therefore, familiarity with the spectrum of findings in the different imaging modalities appears essential. Radiographically, significant changes include Charcot joints of the tarsus (destructive type) and bone absorption of the forefoot (mutilating type). In diabetic foot problems, magnetic resonance imaging and leukocyte scintigraphy appear to be the most effective tools for detection of osteomyelitis, and a negative study makes osteomyelitis unlikely. However, the findings of both techniques in active, noninfected neuropathic osteoarthropathy may be indistinguishable from those of osteomyelitis.

In this study we report a randomized double-blind, placebo-controlled trial to evaluate the effect of ORG 2766 in IDDM patients with peripheral neuropathy. Sixty-two patients were selected based on the following criteria: abnormal vibration perception threshold above the 95th-percentile adjusted for age and/or abnormal warm temperature threshold, both measured in the right hand. The patients were randomized into two treatment groups after baseline studies: Group 1 was treated with placebo and Group 2 was treated with 3 mg of the ACTH4-9 analogue ORG 2766 every 24 h. The total study period was 1 year. After 1 year of treatment there was a significant improvement in vibration threshold in Group 1 compared to Group 2. No other parameters improved in the study period. The number of patients selected may have been too small to detect a more important treatment effect. We conclude from this study that ORG 2766 can improve vibration threshold, indicating large myelinated fibre function, but does not affect any of the other neurophysiological function tests.

Transcutaneous oxygen, laser Doppler flowmetry, peroneal nerve motor conduction velocity and skin temperature were assessed in both legs of 34 diabetic patients, who had a mean age of 41 (range 29-77) years, and diabetes duration of 21 (3-34) years. Transcutaneous oxygen significantly correlated with peroneal nerve motor conduction velocity (r = 0.59 p < 0.001) and laser Doppler flowmetry (r = 0.7 p < 0.001). Laser Doppler flowmetry correlated weakly with peroneal motor conduction velocity, (r = 0.34 p < 0.05). In each patient the leg with the higher transcutaneous oxygen (mean 70.2 +/- 9.3 (SD) mmHg) had a significantly higher peroneal motor conduction velocity (45.3 +/- 7.1 vs 41.5 +/- 6.3 m/s, p < 0.01), than the leg with the lower transcutaneous oxygen (61.0 +/- 11.9 mmHg), though no difference in skin temperature was observed, 31.4 +/- 0.4 vs 31.1 +/- 0.5 degrees C. We then assessed the potential for reversibility of conduction velocity deficits in ten non-diabetic patients, aged 59 (52-77) years, undergoing unilateral femoro-popliteal bypass, measuring transcutaneous oxygen, peroneal nerve motor conduction velocity and skin temperature pre- and 6 weeks post-surgery. In the control leg (unoperated) there was no significant change in transcutaneous oxygen (63.2 +/- 8.8 vs 63.0 +/- 4.6 mm Hg), peroneal nerve motor conduction velocity (45.1 +/- 7.8 vs 43.4 +/- 7.2 m/s) or skin temperature (30.8 +/- 1.3 vs 30.2 +/- 1.2 degrees C) after surgery (all NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have suggested that nerve regeneration may be defective in patients with diabetic polyneuropathy. Since insulin-like growth factor I (IGF-I) has been shown to stimulate nerve regeneration, and IGF binding protein-1 is acutely regulated by plasma insulin we have investigated the relationships between plasma IGF-I, IGFBP-1, glucose and insulin in Type 1 (insulin-dependent) diabetic patients with peripheral polyneuropathy. Plasma samples were taken at hourly intervals over an 11-h period (08.00-19.00 hours) in order to characterise secretory profiles for 15 Type 1 diabetic patients (eight neuropathic and seven non-neuropathic) and eight non-diabetic control subjects. In the non-diabetic subjects, mean plasma IGF-I levels were stable throughout the 11-h period with a range of 97 micrograms/l-169 micrograms/l. In contrast, mean plasma IGFBP-1 levels declined steadily from a high level of 1.99 micrograms/l at 08.00 hours to approximately one half (0.86 microgram/l) at 15.00 hours. Comparison of areas under the curves revealed significant negative correlations between IGFBP-1 and glucose (-0.88, p = 0.01), IGFBP-1 and insulin (-0.75, p = 0.016), and IGFBP-1 and IGF-I (-0.68, p = 0.03). A significant positive correlation was found between insulin and IGF-I (+0.89, p = 0.001). The diabetic patients had markedly elevated plasma IGFBP-1 levels (area under curve, p = 0.01) and lower plasma IGF-I levels (p = 0.033) even though these patients were hyperinsulinaemic throughout the study period.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been shown that parameters of oxidative stress are increased in experimental diabetic neuropathy. The glutathione redox system is one of the intracellular scavenger systems for neutralizing free oxygen radicals. In this investigation we studied the effect of glutathione-treatment on the development of diabetic neuropathy in streptozotocin-induced diabetic rats by measuring sensory and motor nerve conduction velocities. The total study period was 10 weeks. Four groups of rats were studied: Group 1 consisted of non-diabetic, age-matched control rats; Group 2, of diabetic rats treated with placebo from week 0 to 10; Group 3, of diabetic rats treated with 200 mg glutathione/kg body weight i.v. two times per week from weeks 0 to 10; and Group 4, of diabetic rats treated with placebo from weeks 0 to 4 and as Group 3 from weeks 4 to 10. The sensory and motor nerve conduction velocity of rats treated prophylactically with glutathione (Group 3) were significantly different from those of rats treated with placebo (Group 2) or with glutathione administered at a later time point (Group 4). Complete restoration of sensory and motor nerve conduction velocity was not reached. There was a significant improvement in motor nerve conduction velocity from weeks 4 to 6 (p less than 0.005), but not in sensory nerve conduction velocity in the delayed treatment group (Group 4). In conclusion, treatment with glutathione, a free radical scavenger, is partially effective in the prevention of diabetic neuropathy in streptozotocin-induced diabetic rats, but is of limited value when the neuropathy is already present.

In 10 patients with Type 1 (insulin-dependent) diabetes mellitus gastric emptying of a digestible solid and liquid meal was measured during euglycaemia (blood glucose concentration 4-8 mmol/l) and during hyperglycaemia (blood glucose concentration 16-20 mmol/l). Gastric emptying was studied with a scintigraphic technique and blood glucose concentrations were stabilised using a modified glucose clamp. Patients were also evaluated for gastrointestinal symptoms, autonomic nerve function and glycaemic control. When compared to euglycaemia, the duration of the lag phase before any of the solid meal emptied from the stomach (p = 0.032), the percentage of the solid meal remaining in the stomach at 100 min (p = 0.032) and the 50% emptying time for the solid meal (p = 0.032) increased during hyperglycaemia. The 50% emptying time for the liquid meal (p = 0.042) was also prolonged during the period of hyperglycaemia. These results demonstrate that the rate of gastric emptying in Type 1 diabetes is affected by the blood glucose concentration.

The accumulation of 3H-fucose labelled glycoprotein and 35S-methionine labelled protein carried by the retrograde axonal transport in the sensory fibres of the sciatic nerve was examined on the day after injection of streptozotocin in rats. The accumulation of fucose-label was reduced (2.8 +/- 0.4 (SD) versus 2.1 +/- 0.5 (arbitrary units), 2p = 0.0044) indicating a decreased retrograde flux of glycoproteins. This early transport abnormality could have a key role in the development of peripheral neuropathy in diabetes.

The progression of subclinical polyneuropathy over 2.5 years has been studied in a representative group of 75 young patients with Type 1 (insulin-dependent) diabetes (initial age 16-19 years). The relationships between changes in nerve function, glycaemic control and concurrently developing microvascular complications (retinopathy, microproteinuria) were investigated. Deterioration of motor, sensory and autonomic nerve function, retinopathy and microproteinuria was related to poor glycaemic control. In addition, there was an association between developing neural and microvascular complications which was not diminished when their common relationship to hyperglycaemia was taken into account. These findings suggest that, although poor glycaemic control is an essential permissive factor in the early development of diabetic polyneuropathy, other influences, shared with microvascular complications, must also be important.

One thousand, two hundred and eighteen diabetic subjects living in and around country towns of Western Australia were screened for complications of diabetes. This population included 134 subjects of Aboriginal descent, who were compared with the Caucasoids taking part. In the Aboriginal group there was a greater proportion of Type 2 (non-insulin-dependent) diabetic patients, a relative female preponderance (69% compared with 51%) and a tendency to present at an earlier age of onset than their Caucasoid counterparts. Diabetic complications were at least as common in the Aboriginal group as in the Caucasoid patients. Indeed, retinopathy within 10 years of onset of diabetes was more common in the Aborigines. Peripheral neuropathy was more prevalent in Aborigines treated by diet alone or oral hypoglycaemic agents than in Caucasoids. A much greater prevalence of proteinuria was an additional feature of the Aboriginal subgroup (29% versus 4%).