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Aims: Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes. The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking. Studies on the posterior interosseous nerve (PIN) have proposed PIN a useful indicator of DPN., Methods: A quantitative mass spectrometry-based proteomics analysis was made of peripheral nerves from age- and gender-matched living human male tissue donors; nine type 2 diabetes subjects, with decreased sural nerve action potentials indicating DPN, and six controls without type 2 diabetes, with normal electrophysiology results., Results: A total of 2617 proteins were identified. Linear regression was used to discover which proteins were differentially expressed between type 2 diabetes and controls. Only soft signals were found. Therefore, clustering of the 500 most variable proteins was made to find clusters of similar proteins in type 2 diabetes subjects and healthy controls., Conclusions: This feasibility study shows, for the first time, that the use of quantitative mass spectrometry enables quantification of proteins from nerve biopsies from subjects with and without type 2 diabetes, which may aid in finding biomarkers of importance to DPN development., (© 2021 Diabetes UK.)

Objective: The relationship between retinal vascular calibres (RVCs) and diabetic neuropathy is unclear. We investigated associations between RVCs and sensory nerve abnormality in adolescents with type 1 diabetes., Research Design and Methods: In a prospective longitudinal study of 889 adolescents with type 1 diabetes with baseline mean (±SD) age 14.1 ± 1.5 years and HbA 1c IFCC 69.4 ± 14.1 mmol/mol (8.6 ± 1.3%), RVCs were assessed from baseline retinal photographs: 'central zone' calibres, summarized as central retinal arteriolar (CRAE) and venular equivalents (CRVE) and 'extended zone' calibres: mean width of arterioles (MWa) and venules (MWv). Sensory nerve abnormality was defined as at least one abnormal sensory quantitative testing from two thermal and two vibration threshold tests measured at foot every 1-2 years. Associations between baseline RVC and sensory nerve function were examined using generalized estimating equations and cumulative risk by Cox regression analyses., Results: During a median study follow-up of 6.2 [IQR 3.7-10.4] years, sensory nerve abnormality was found in 27% of adolescents. Narrower extended zone calibre quartiles but not CRAE or CRVE quartiles were independently associated with sensory nerve abnormality: MWa (Q1 vs. Q2-4: OR 1.35 (95% CI 1.02, 1.61) and MWv (Q1 vs. Q2-4: 1.31 (1.03, 1.7)), after adjusting for HbA 1c , duration and blood pressure. Similarly, in Cox regression, the narrowest quartiles were associated with sensory nerve abnormality: MWa hazard ratio (HR) 1.5 (1.3, 1.8) and MWv 1.6 (1.4, 1.9)., Conclusions: Narrower extended zone retinal calibres were associated with sensory nerve abnormality in adolescents with type 1 diabetes and may present useful biomarkers to understand the pathophysiology of neuropathy., (© 2021 Diabetes UK.)

Aims: Microvascular complications' risk differs between people with latent autoimmune diabetes in adults (LADA) and people with type 2 diabetes. We aimed to investigate whether the prevalence of cardiac autonomic neuropathy, a life-threatening complication of diabetes, also varies depending on diabetes type., Methods: In this cross-sectional study, 43 adults with LADA, 80 with type 1 diabetes and 61 with type 2 diabetes were screened for cardiac autonomic neuropathy with recommended tests. Logistic regression models were used to test differences between diabetes types adjusting for confounders., Results: Cardiac autonomic neuropathy was diagnosed in 17 (40%) participants with LADA, 21 (26%) participants with type 1 diabetes and 39 (64%) participants with type 2 diabetes (p < 0.001). The odds ratio (OR) for cardiac autonomic neuropathy in type 1 diabetes and in type 2 diabetes compared to LADA were 0.54 (95% CI: 0.25-1.20, p-value: 0.13) and 2.71 (95% CI: 1.21-6.06, p-value 0.015) respectively. Smoking ( adj OR 3.09, 95% CI: 1.40-6.82, p-value: 0.005), HDL cholesterol ( adj OR 0.29, 95% CI: 0.09-0.93, p-value: 0.037) and hypertension ( adj OR 2.11, 95% CI: 1.05-4.24, p-value: 0.037) were independent modifiable risk factors for cardiac autonomic neuropathy. Differences among diabetes types did not change after correction for confounders., Conclusions: This is the first study offering a comparative evaluation of cardiac autonomic neuropathy among LADA, type 1 and type 2 diabetes, showing a lower risk of cardiac autonomic neuropathy in LADA compared to type 2 diabetes and similar compared to type 1 diabetes. This disparity was not due to differences in age, metabolic control or cardiovascular risk factors., (© 2020 Diabetes UK.)

Aim: To assess the prevalence of metabolic syndrome in type 1 diabetes, and its age-related association with diabetes complications., Methods: Australian National Diabetes Information Audit and Benchmarking (ANDIAB) was a well-established quality audit programme. It provided cross-sectional data on people attending specialist diabetes services across Australia. We determined the prevalence of metabolic syndrome (WHO criteria) in adults with type 1 diabetes and its associations with diabetes complications across age groups., Results: Metabolic syndrome prevalence was 30% in 2120 adults with type 1 diabetes. Prevalence increased with age: 21% in those aged <40 years, 35% in those aged 40-60 years, and 44% in those aged >60 years (P<0.001), which was driven by an increase in hypertension rate. Metabolic syndrome was associated with a higher prevalence of microvascular, macrovascular and foot complications, with the greatest impact at a younger age. The odds ratio for macrovascular complications with metabolic syndrome, compared with without, was 5.9 (95% CI 2.1-16.4) in people aged <40 years, 2.7 (95% CI 1.7-4.2) in those aged 40-60 years, and 1.7 (95% CI 1.1-2.7) in those aged >60 years (all P < 0.05). Metformin use was higher in those with metabolic syndrome (16% vs 4%; P<0.001)., Conclusions: In this large Australian cohort, metabolic syndrome was common in type 1 diabetes and identified people at increased risk of the spectrum of diabetes complications, particularly in young to middle-aged adults. Potential clinical implications are that therapies targeting insulin resistance in this high-risk group may reduce diabetes complications and should be explored., (© 2020 Diabetes UK.)

Aim: We aimed to explore the association between South Asian ethnicity and complications of type 1 diabetes, and whether this is affected by migration., Methods: In this retrospective cohort study, data on diabetes control and complications were obtained for South Asians in India (South Asians India , n = 2592) and the UK (South Asians UK , n = 221) and white Europeans in the UK (n = 1431). Multivariable logistic regression was used to identify associations between ethnicity and diabetic kidney disease, retinopathy and neuropathy adjusting for age, sex, BMI, disease duration, HbA 1c , blood pressure (BP) and cholesterol., Results: South Asians India had significantly greater adjusted odds of diabetic kidney disease [odds ratio (OR) 5.0, 95% confidence intervals (CI) 3.6-7.1] and retinopathy (OR 1.8, 95% CI 1.2-2.5), but lower odds of neuropathy (OR 0.5, 95% CI 0.4-0.6) than white Europeans. South Asians India had significantly greater adjusted odds of diabetic kidney disease (OR 3.0, 95% 1.8-5.3) than South Asians UK , but there was no significant difference in the odds of other complications., Conclusions: In this hypothesis-generating study, we report that South Asian ethnicity is associated with greater risk of diabetic kidney disease and retinopathy, and lower risk of neuropathy than white European ethnicity. Part of the excess diabetic kidney disease risk is reduced in South Asians UK . These associations cannot be accounted for by differences in vascular risk factors. Our findings in South Asians with type 1 diabetes mirror previous findings in type 2 diabetes and now need to be validated in a study of the effect of ethnicity on type 1 diabetes complications where healthcare is provided in the same setting., (© 2019 Diabetes UK.)

Aim: To compare clinical characteristics and outcomes in adults with type 1 diabetes aged ≥ 60 years using continuous subcutaneous insulin infusion (CSII) vs. insulin injection therapy. Further, to determine the percentage of older adults with type 1 diabetes using CSII., Research Design and Methods: Retrospective study using data of the Diabetes Prospective Follow-up Registry (DPV). Including percentage CSII use from 2008 to 2018, and the characteristics of 9547 individuals extracted from the DPV in March 2019 (N = 1404 CSII; N = 8143 insulin injection therapy). Wilcoxon rank sum tests were used for continuous variables and chi-square tests for categorical variables to compare clinical characteristics of people using CSII vs. insulin injection therapy. Adjusted analyses used generalized linear models to compare diabetes-related outcomes., Results: CSII usage has increased in older adults (from 12% in 2008 to 23% in 2018). After adjustment, CSII was associated with lower HbA 1c [60.7 mmol/mol (7.7 ± 0.1%) vs. 62.8% (7.9 ± 0.1%)], lower daily insulin dose (0.49 ± 0.02 vs. 0.61 ± 0.01 IU/kg), fewer days in hospital (8.1 ± 0.12 vs. 11.2 ± 0.11 days/person-year), fewer severe hypoglycaemic events (0.16 ± 0.02 vs. 0.21 ± 0.03 events/person-year) and fewer diabetic ketoacidosis (0.06 ± 0.01 vs. 0.08 ± 0.01 events/person-year). Individuals on CSII showed lower rates of microalbuminuria and also have a diagnosis of depression and neuropathy., Conclusions: A growing number of older adults are using insulin pumps. Older age in itself should not be seen as a contraindication for CSII., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aim: India contributes towards a large part of the worldwide epidemic of diabetes and its associated complications. However, there are limited longitudinal studies available in India to understand the occurrence of diabetes complications over time. This pan-India longitudinal study was initiated to assess the real-world outcomes of diabetes across the country., Methods: The LANDMARC study is the first prospective, multicentre, longitudinal, observational study investigating a large cohort of people with type 2 diabetes mellitus across India over a period of 3 years. The primary objective of this ongoing study is to determine the proportion of people developing macrovascular diabetes complications over the duration of the study (36 months ± 45 days) distributed over seven visits; the secondary objective is to evaluate microvascular diabetes complications, glycaemic control and time-to-treatment adaptation or intensification. Overall, 6300 participants (aged 25-60 years) diagnosed with type 2 diabetes for at least 2 years will be included from 450 centres across India. Data will be recorded for baseline demographics, comorbidities, glycaemic measurements, use of anti-hyperglycaemic medications and any cardiovascular or other diabetes-related events occurring during the observational study period., Conclusions: The LANDMARC study is expected to reveal the trends in complications associated with diabetes, treatment strategies used by physicians, and correlation among treatment, control and complications of diabetes within the Indian context. The findings of this study will help to identify the disease burden, emergence of early-onset complications and dose titration patterns, and eventually develop person-centred care and facilitate public health agencies to invest appropriate resources in the management of diabetes. (Trial Registration No: CTRI/2017/05/008452)., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Diabetic peripheral neuropathy in people with type 2 diabetes is poorly managed because of its insidious onset, delayed diagnosis and more complex aetiology resulting from the contribution of not only hyperglycaemia, but also ageing, hyperlipidaemia, hypertension and obesity. Because there is no US Food and Drug Adminstration-approved disease-modifying therapy for diabetic peripheral neuropathy, the key to ameliorating it in type 2 diabetes has to be through earlier diagnosis and timely multi-factorial risk factor reduction. The management of painful diabetic peripheral neuropathy also requires a detailed appraisal of the choice of therapy, taking into account efficacy, patient wishes, comorbidities, side effect profile and potential for abuse., (© 2019 Diabetes UK.)

Aims: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements., Methods: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score., Results: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm 2 vs 7.2 ± 0.1 mm 2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm 2 vs 12.8 ± 0.5 mm 2 ; P < 0.05) compared with controls., Conclusion: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction., (© 2019 Diabetes UK.)

Aim: To study cell-mediated immunity in the feet of people with type 2 diabetes with polyneuropathy., Methods: In a cohort comprising people with type 2 diabetes with polyneuropathy (n = 17) and without polyneuropathy (n = 12) and a healthy control group (n = 12) indurations due to delayed-type hypersensitivity responses to intracutaneous Candida albicans antigen were determined in the foot and compared with those in the arm (an area relatively spared in diabetic polyneuropathy). The sizes of indurations on the foot were correlated with electromyographic measurements in the participants with diabetes., Results: No differences were observed in the median size of indurations between the foot and arm in healthy controls and participants without polyneuropathy; in participants with polyneuropathy, induration sizes on the foot were smaller than on the arm: 0 (95% CI 0 to 1) vs 5 (95% CI 2 to 6) mm (P < 0.01). In participants with diabetes, larger indurations correlated with better nerve function (Spearman's rho 0.35 to 0.39)., Conclusion: Our findings suggest that diabetic peripheral polyneuropathy negatively affects cell-mediated immunity in the foot. (Clinical Trials registry no.: NCT01370837)., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims: To investigate changes in corneal nerve morphology in Type 2 diabetes and to establish relationships between in vivo corneal confocal microscopy and markers of peripheral nerve structure and function., Participants and Methods: We recruited 57 participants with Type 2 diabetes and 26 healthy controls of similar age and sex distribution. We also recruited a disease control group of 54 participants with Type 1 diabetes. All participants were assessed for distal symmetrical polyneuropathy using the Total Neuropathy Score. In vivo corneal confocal microscopy was used to assess corneal nerve fibre length, corneal nerve fibre density, corneal nerve branch density and inferior whorl length. Peripheral nerve structure was assessed using median nerve ultrasonography. Large fibre function was assessed according to median nerve axonal excitability. Small fibre function was assessed using Sudoscan TM and the Survey of Autonomic Symptoms., Results: Corneal nerve fibre length, fibre density and branch density and inferior whorl length were significantly lower in individuals with Type 2 diabetes compared to controls (P<0.001 for all). In the Type 2 diabetes cohort, correlations were observed between neuropathy severity and corneal nerve fibre density (P=0.004), corneal nerve branch density (P=0.003), corneal nerve fibre length (P=0.002) and inferior whorl length (P=0.01). Significant correlations were observed between corneal confocal outcomes and axonal excitability measurements. No association was found between corneal confocal microscopy and median nerve cross-sectional area, Sudoscan measurements or the Survey of Autonomic Symptoms., Conclusions: This study demonstrated significant changes in corneal nerves in individuals with Type 2 diabetes. Reductions in corneal nerve measures correlated with increasing neuropathy severity. Associations were found between corneal confocal microscopy and markers of voltage-gated potassium channel function., (© 2019 Diabetes UK.)

Aim: To assess if latent autoimmune diabetes of adulthood (LADA) is associated with small fibre neuropathy., Methods: Participants with LADA (n=31), Type 2 diabetes (n=31) and healthy control participants without diabetes (n=31) underwent a detailed assessment of neurologic deficits, quantitative sensory testing, electrophysiology, skin biopsy and corneal confocal microscopy., Results: The groups were matched for age (healthy control without diabetes: 53.5±9.1 vs. Type 2 diabetes: 58.0±6.5 vs. LADA: 53.2±11.6 years), duration of diabetes (Type 2 diabetes: 10.0±8.3 vs. LADA: 11.0±9.1 years) and blood pressure. However, BMI (P=0.01) and triglycerides (P=0.0008) were lower and HbA 1c (P=0.0005), total cholesterol (P=0.01) and HDL (P=0.002) were higher in participants with LADA compared with Type 2 diabetes. Peroneal motor nerve conduction velocity (P=0.04) and sural sensory nerve conduction velocity (P=0.008) were lower in participants with latent autoimmune diabetes in adults compared with Type 2 diabetes. Intra-epidermal nerve fibre density (P=0.008), corneal nerve fibre density (P=0.003) and corneal nerve branch density (P=0.006) were significantly lower in participants with LADA compared with Type 2 diabetes. There were no significant differences in the other neuropathy parameters., Conclusions: Despite comparable age and duration of diabetes, participants with LADA demonstrate more severe neuropathy and particularly small fibre neuropathy, compared with participants with Type 2 diabetes., (© 2018 Diabetes UK.)

Aim: Recent studies have reported an association between low vitamin D levels and diabetic peripheral neuropathy. However, many of these did not differentiate between people with painful diabetic peripheral neuropathy and those with painless diabetic peripheral neuropathy, or assess major confounding factors including sunlight exposure and daily activity. Our study addressed these limitations and evaluated vitamin D levels in people with carefully phenotyped diabetic peripheral neuropathy and controls., Methods: Forty-five white Europeans with Type 2 diabetes and 14 healthy volunteers underwent clinical and neurophysiological assessments. People with Type 2 diabetes were then divided into three groups (17 with painful diabetic peripheral neuropathy, 14 with painless diabetic peripheral neuropathy and 14 with no diabetic peripheral neuropathy). All had seasonal sunlight exposure and daily activity measured, underwent a lower limb skin biopsy and had 25-hydroxyvitamin D measured during the summer months, July to September., Results: After adjusting for age, BMI, activity score and sunlight exposure, 25-hydroxyvitamin D levels (nmol/l) (se) were significantly lower in people with painful diabetic peripheral neuropathy [painful diabetic peripheral neuropathy 34.9 (5.8), healthy volunteers 62.05 (6.7), no diabetic peripheral neuropathy 49.6 (6.1), painless diabetic peripheral neuropathy 53.1 (6.2); ANCOVAP = 0.03]. Direct logistic regression was used to assess the impact of seven independent variables on painful diabetic peripheral neuropathy. Vitamin D was the only independent variable to make a statistically significant contribution to the model with an inverted odds ratio of 1.11. Lower 25-hydroxyvitamin D levels also correlated with lower cold detection thresholds (r = 0.39, P = 0.02) and subepidermal nerve fibre densities (r = 0.42, P = 0.01)., Conclusions: We have demonstrated a significant difference in 25-hydroxyvitamin D levels in well-characterized people with painful diabetic peripheral neuropathy, while accounting for the main confounding factors. This suggests a possible role for vitamin D in the pathogenesis of painful diabetic peripheral neuropathy. Further prospective and intervention trials are required to prove causality between low vitamin D levels and painful diabetic peripheral neuropathy., (© 2018 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims: To identify awareness of potential brain complications of diabetes among individuals with diabetes and the public., Methods: For this observational, cross-sectional survey study, we recruited consecutive adult attendees of a specialist diabetes clinic and two primary care practices. Primary care attendees represented members of the general population of Ireland. An interviewer-administered questionnaire was used to gather data on respondents' awareness of brain complications of diabetes and modifiable risk factors for dementia. Multivariable logistic regression was undertaken to identify variables independently associated with awareness., Results: Respondents included a total of 502 adults: 250 in the diabetes group (37% women, mean age 63 ± 14 years, 88% with Type 2 diabetes) and 252 in the general population group (51% women, mean age 47 ± 17 years, 7% with Type 2 diabetes). The diabetes group had significantly greater awareness of diabetes complications, except for depression, compared with the general population group. In the group as a whole, respondent awareness of dementia (35%) and memory problems (47%) as potential complications of diabetes was poor compared with awareness of kidney (84%) and eye damage (84%). Respondents were 1.5 times more likely to identify that individuals can modify their risk of developing Type 2 diabetes than their risk of dementia., Conclusions: This study shows that there is poor awareness of brain complications of diabetes among individuals with diabetes and the general population in Ireland. The results suggest a need for expansion of public awareness campaigns and diabetes education programmes to promote awareness of the brain complications of diabetes and of the modifiable risk factors for dementia, as part of a life-course approach to dementia prevention., (© 2018 Diabetes UK.)

Aim: To investigate the possible association between vitamin D deficiency and cardiovascular autonomic neuropathy in people with diabetes., Methods: A total of 113 people with Type 1 or Type 2 diabetes [mean (interquartile range) diabetes duration 22.0 (12-31) years, mean (sd) age 56.2 (13.0) years, 58% men] underwent vitamin D (D2 and D3) assessment, and were screened for cardiovascular autonomic neuropathy using three cardiovascular reflex tests [heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva manoeuvre] and assessment of 5-min resting heart rate and heart rate variability indices., Results: We found an inverse U-shaped association between serum vitamin D level and E/I ratio, 30/15 ratio and three heart rate variability indices (P < 0.05). Vitamin D level was non-linearly associated with cardiovascular autonomic neuropathy diagnosis (P < 0.05 adjusted for age and sex). Linear regression models showed that an increase in vitamin D level from 25 to 50 nmol/l was associated with an increase of 3.9% (95% CI 0.1;7.9) in E/I ratio and 4.8% (95% CI 4.7;9.3) in 30/15 ratio. Conversely, an increase from 125 to 150 nmol/l in vitamin D level was associated with a decrease of 2.6% (95% CI -5.8;0.1) and 4.1% (95% CI -5.8;-0.5) in the respective outcome measures., Conclusions: High and low vitamin D levels were associated with cardiovascular autonomic neuropathy in people with diabetes. Future studies should explore this association and the efficacy of treating dysvitaminosis D to prevent cardiovascular autonomic neuropathy., (© 2016 Diabetes UK.)

In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin-induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored using metabolic cages. Potential effect of agomelatine on diabetes-induced mechanical and thermal allodynia was evaluated using dynamic plantar aesthesiometer and warm plate (38 °C) tests, respectively. Additionally, influence of agomelatine on hyperalgesia occurring in connection with diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold plate (4 °C, thermal nociceptive stimulus) tests. Obtained data indicated that, in diabetic rats, agomelatine significantly improved hyperalgesia and allodynia responses, without no effect on hyperglycemia or the associated polydipsia, polyuria, and hyperphagia. Therapeutic potential of agomelatine on neuropathic pain was suppressed with α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis), phentolamine (a nonselective α-adrenoceptor antagonist), and propranolol (a nonselective β-adrenoceptor antagonist) administrations. However, p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis) pretreatment could not be achieved to reverse these antihyperalgesic and antiallodynic effects. These results suggest that the curative effect of agomelatine on neuropathic pain is mediated through rising synaptic catecholamine levels as well as through interactions with both α- and β-adrenoceptors. To our knowledge, this is the first study to show findings that indicate catecholaminergic system mediated antihyperalgesic and antiallodynic effects of agomelatine., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

Aims: To examine QT intervals corrected for heart rate (QTc) in adolescents with Type 1 diabetes compared with control subjects, and to determine associations with metabolic control and autonomic function., Methods: Resting electrocardiogram recordings of 142 adolescents with Type 1 diabetes [mean (sd) age 15.3 (2.0) years, diabetes duration 9.0 (3.5) years, HbA1c 71 (17) mmol/mol or 8.7 (1.6)%] and 125 control subjects [mean (sd) age 15.7 (2.5) years] were used to calculate QTc duration and derive mean heart rate and heart rate variability (HRV) values. Linear and logistic regression models were used to examine the associations between QTc, metabolic control and autonomic function (HRV and pupillary function)., Results: QTc duration was not significantly different between subjects with Type 1 diabetes and control subjects (mean duration 392 vs 391 ms; P = 0.65). In the Type 1 diabetes group, QTc was positively associated with HbA1c [β = 4 (95% CI 2, 6); P < 0.001] and inversely associated with severe hypoglycaemic events [β = -10 (95% CI -20,-2); P = 0.01], less insulin/kg [β = -12 (95% CI -22, -2); P = 0.024] and less HRV. In the Type 1 diabetes group, QTc in the highest quintile (≥409 ms) vs quintiles 1-4 had more pupillary abnormalities (83 vs 56%; P = 0.03), lower pupillary maximum constriction velocity (4.8 vs 5.3 mm/s; P = 0.04), higher heart rate (78 vs 72 beats per min; P = 0.02) and lower HRV (standard deviation of mean NN intervals 4.0 vs 4.3 ms, P = 0.004 and root-mean-square difference of successive NN intervals 3.7 vs 4.1 ms; P = 0.004)., Conclusions: Although there are concerns about hypoglycaemia in general in people with Type 1 diabetes, chronic hyperglycaemia, rather than intermittent hypoglycaemia, appears to be more deleterious to autonomic cardiac function, even in adolescence. Longer QTc was associated with higher HbA1c concentration, lower risk of hypoglycaemia and autonomic dysfunction. Longitudinal studies are warranted., (© 2016 Diabetes UK.)

Aim: Hearing loss (as reflected by abnormal sound detection) is a frequently reported consequence of Type 1 diabetes mellitus. We sought to evaluate sound detection, auditory neural function and binaural processing ability in a group of school-aged participants with Type 1 diabetes and to assess their functional hearing and general communication ability., Methods: A range of electroacoustic, electrophysiological and behavioural test techniques were used to evaluate both cochlear and auditory neural function in 19 affected children. A cohort of matched controls was also assessed., Results: Although all of the participants with Type 1 diabetes enjoyed normal sound detection, 9 of the 19 (47%) showed evidence of auditory pathway abnormality with evoked potential latencies and/or amplitudes beyond age-related norms. Auditory brainstem response interpeak latencies (wave I-V) were longer than in matched controls [ 95% confidence interval (95% CI); 0.10, 0.28 ms: P < 0.001] and wave V amplitudes were reduced (95% CI; -0.21, 0.00 μV: P = 0.02). Binaural speech perception in noise was also impaired (95% CI; 0.82, 3.17 dB: P = 0.002) and perceptual ability was correlated with degree of neural disruption in the auditory brainstem (r = 0.662, P = 0.003)., Conclusions: Hearing deficits severe enough to restrict communication and threaten academic progress were common on our group of school-aged children with Type 1 diabetes. Evaluation of both cochlear and auditory neural function may form an important part of the standard management regime for children with diabetes., (© 2016 Diabetes UK.)

Aims: Few studies have analysed the presence of hearing abnormalities in diabetes. We assessed the presence of subclinical auditory alterations and their possible association with early vascular and neurological dysfunction in young adults with Type 1 diabetes of long duration., Methods: Thirty-one patients with Type 1 diabetes (mean age 33 ± 2.3 years, disease duration 25.7 ± 4.2 years) and 10 healthy controls underwent pure tone audiometry (PTA), distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) analyses. Associations with metabolic variables and chronic complications were explored., Results: Compared with healthy controls, patients with diabetes had significantly higher mean hearing thresholds, although still within the normoacusic range. DPOAE intensities at medium frequencies (2.8-4 kHz) were significantly lower in patients with diabetes. In ABR, in addition to waves I, III and V, we observed the appearance of a visible wave IV in patients with diabetes compared with controls (prevalence 61% vs. 10%, P < 0.05), and its appearance was related to a prolonged I-V interval (4.40 ± 0.62 ms vs. 4.19 ± 0.58 ms, P < 0.05). Diastolic blood pressure was higher in people with abnormal DPOAE (P < 0.05), whereas systolic blood pressure correlated with wave V and interpeak I-V interval latencies. A trend towards an association between evidence of wave IV and the presence of somatic neuropathy or abnormal cardiovascular autonomic tests was observed., Conclusions: Young adults with long-term Type 1 diabetes have subclinical abnormalities in qualitative auditory perception, despite normal hearing thresholds, which might reflect neuropathic and/or vascular alterations., (© 2015 Diabetes UK.)

Aims: Diabetic kidney disease independently predicts cardiovascular disease and premature death. We examined the burden of chronic kidney disease (CKD, defined as an estimated GFR < 60 ml/min/1.73 m(2) ) and quality of care in a cross-sectional survey of adults (age ≥ 18 years) with Type 2 diabetes across Asia., Methods: The Joint Asia Diabetes Evaluation programme is a disease-management programme implemented using an electronic portal that systematically captures clinical characteristics of all patients enrolled. Between July 2007 and December 2012, data on 28 110 consecutively enrolled patients (China: 3415, Hong Kong: 15 196, India: 3714, Korea: 1651, Philippines: 3364, Vietnam: 692, Taiwan: 78) were analysed., Results: In this survey, 15.9% of patients had CKD, 25.0% had microalbuminuria and 12.5% had macroalbuminuria. Patients with CKD were less likely to achieve HbA1c < 53 mmol/mol (7.0%) (36.0% vs. 42.3%) and blood pressure < 130/80 mmHg (20.8% vs. 35.3%), and were more likely to have retinopathy (26.2% vs. 8.7%), sensory neuropathy (29.0% vs. 7.7%), cardiovascular disease (26.6% vs. 8.7%) and self-reported hypoglycaemia (18.9% vs. 8.2%). Despite high frequencies of albuminuria (74.8%) and dyslipidaemia (93.0%) among CKD patients, only 49.0% were using renin-angiotensin system inhibitors and 53.6% were on statins. On logistic regression, old age, male gender, tobacco use, long disease duration, high HbA1c , blood pressure and BMI, and low LDL cholesterol were independently associated with CKD (all P < 0.05)., Conclusions: The poor control of risk factors, suboptimal use of organ-protective drugs and high frequencies of hypoglycaemia highlight major treatment gaps in patients with diabetic kidney disease in Asia., (© 2015 Diabetes UK.)

Aim: To identify impairment in functional capacity associated with complicated and non-complicated diabetes using the 6-min walk distance test., Methods: We enrolled 111 adults, aged ≥40 years, with Type 2 diabetes from a hospital facility and 150 healthy control subjects of similar age and sex from a community site in Lima, Peru. All participants completed a 6-min walk test., Results: The mean age of the 261 participants was 58.3 years, and 43.3% were male. Among those with diabetes, 67 (60%) had non-complicated diabetes and 44 (40%) had complications such as peripheral neuropathy, retinopathy or nephropathy. The mean unadjusted 6-min walk distances were 376 m and 394 m in adults with and without diabetes complications, respectively, vs 469 m in control subjects (P<0.001). In multivariable regression, the subjects with diabetes complications walked 84 m less far (95% CI -104 to -63 m) and those without complications walked 60 m less far (-77 to -42 m) than did control subjects. When using HbA1c level as a covariate in multivariable regression, participants walked 13 m less far (-16.9 to -9.9 m) for each % increase in HbA1c ., Conclusions: The subjects with diabetes had lower functional capacity compared with healthy control subjects with similar characteristics. Differences in 6-min walk distance were even apparent in the subjects without diabetes complications. Potential mechanisms that could explain this finding are early cardiovascular disease or deconditioning., (© 2015 Diabetes UK.)

Aims: Few reports have assessed the relationship between Type 1 diabetes and sleep disorders. The purposes of our study were to determine the prevalence of obstructive sleep apnoea in Type 1 diabetes and to compare the clinical profile of people with Type 1 diabetes with or without obstructive sleep apnoea., Methods: In this cross sectional study of 67 consecutive people with Type 1 diabetes, we performed polysomnography as part of their yearly check-ups., Results: In our cohort, with a mean BMI of 25.8 ± 4.7 kg/m(2), the prevalence of obstructive sleep apnoea [apnoea-hypopnoea index (AHI) > 10/h] was 46%. Severe obstructive sleep apnoea (AHI ≥ 30/h) was present in 19% of the patients. We found no significant differences in age, sex, body mass index, HbA1c or Epworth sleepiness scale score between people with or without obstructive sleep apnoea. People with obstructive sleep apnoea had a longer course of diabetes mellitus (P < 0.01) and a higher prevalence of retinopathy (P < 0.01), neuropathy (P = 0.05), cardiovascular disease (P < 0.01) and hypertension (P < 0.01). The occurrence of macrovascular complications was independently associated with the presence of OSA [odds ratio (OR) 8.28; 95% confidence interval (CI), 1.56-43.97; P = 0.013] and the duration of diabetes (OR 1.08; 95% CI, 1.02-1.15; P = 0.01). Moreover, retinopathy was independently associated with OSA (OR 4.54; 95% CI, 1.09-18.82; P = 0.04) and the duration of diabetes (OR 1.09; 95% CI, 1.04-1.15; P = 0.001)., Conclusions: The prevalence of obstructive sleep apnoea was high in people with Type 1 diabetes. Obstructive sleep apnoea was independently associated with macrovascular complications and retinopathy. Obesity and excessive daytime sleepiness were uncommon in this population., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Aims: Neuropad is a simple visual indicator test, with moderate diagnostic performance for diabetic peripheral neuropathy. As it assesses sweating, which is a measure of cholinergic small nerve fibre function, we compared its diagnostic performance against established measures of both large and, more specifically, small fibre damage in patients with diabetes., Methods: One hundred and twenty-seven participants (89 without diabetic peripheral neuropathy and 38 with) aged 57 ± 9.7 years underwent assessment with Neuropad, large nerve fibre assessments: Neuropathy Disability Score, vibration perception threshold, peroneal motor nerve conduction velocity; small nerve fibre assessments: neuropathy symptoms (Diabetic Neuropathy Symptoms score) corneal nerve fibre length and warm perception threshold., Results: Neuropad has a high sensitivity but moderate specificity against large fibre neuropathy assessments: Neuropathy Disability Score (> 2) 70% and 50%, vibration perception threshold (> 14 V) 83% and 53%, and peroneal motor nerve conduction velocity (< 42 m/s) 81% and 54%, respectively. However, the diagnostic accuracy of Neuropad was significantly improved against corneal nerve fibre length (< 14 mm/mm2) with a sensitivity and specificity of 83% and 80%, respectively. Furthermore, the area under the curve for corneal nerve fibre length (85%) was significantly greater than with the Neuropathy Disability Score (66%, P = 0.01) and peroneal motor nerve conduction velocity (70%, P = 0.03). For neuropathic symptoms, sensitivity was 78% and specificity was 60%., Conclusions: The data show the improved diagnostic performance of Neuropad against corneal nerve fibre length. This study underlines the importance of Neuropad as a practical diagnostic test for small fibre neuropathy in patients with diabetes., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Aims: Although severe hyperbilirubinaemia causes kernicterus in neonates, normal to modestly elevated bilirubin concentrations have been reported to be neuroprotective. However, the relationship between serum bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes is currently unknown. This study assessed the relationships between physiological serum total bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes., Methods: A total of 2991 patients with Type 2 diabetes were investigated in this cross-sectional study. Cardiovascular autonomic neuropathy was diagnosed by a cardiovascular reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded into normal, early, definite and severe. Cardiovascular autonomic neuropathy was either definite or severe in the present study. An analysis of covariance after adjustment for other covariates was performed. A logistic regression model was used to assess an association of cardiovascular autonomic neuropathy with serum total bilirubin tertiles., Results: Serum total bilirubin concentrations were significantly lower in subjects with cardiovascular autonomic neuropathy. The mean total bilirubin values differed significantly according to the severity of cardiovascular autonomic dysfunction (normal 13.0 μmol/l; early 12.3 μmol/l; definite 11.8 μmol/l; severe 10.1 μmol/l; P for trend < 0.001) after adjustment for other covariates. In multivariate analysis, serum total bilirubin levels were significantly associated with cardiovascular autonomic neuropathy (odds ratio 0.36; 95% CI 0.21-0.63 for the highest vs. the lowest bilirubin tertile, P < 0.001)., Conclusions: Serum total bilirubin concentrations within the physiologic range are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes., (© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.)

Aim: To investigate the relationship between small dense LDL cholesterol and cardiac autonomic neuropathy among patients with Type 2 diabetes., Methods: A total of 175 patients who had not taken lipid-lowering agents previously were enrolled consecutively in this study. Small dense LDL cholesterol level was measured using polyacrylamide tube gel electrophoresis, which fractionates LDL cholesterol into seven components according to particle size and charge. We analysed the mean LDL cholesterol particle size and the proportion of small dense LDL cholesterol., Results: The mean (± sd) patient age was 56 (± 14) years, the mean (± sd) duration of diabetes was 10.3 (± 8.3) years, the mean (± sd) proportion of small dense LDL cholesterol was 21.3 (± 17.6)% and the mean (± sd) LDL cholesterol size was 26.33 (± 0.8) nm. Men with cardiac autonomic neuropathy had a longer duration of diabetes compared with those without cardiac autonomic neuropathy. Women with cardiac autonomic neuropathy had a larger waist circumference, higher plasma triglyceride levels, smaller mean (± sd) LDL cholesterol size [26.8 (± 4.3) nm vs 26.4 (± 6.9) nm; P < 0.01] and larger mean (± sd) proportion of small dense LDL cholesterol [10.1 (± 9.9)% vs 19.1 (± 16.8)%; P < 0.01] compared with those without cardiac autonomic neuropathy. After adjusting for other confounding risk factors, the triglyceride/ HDL cholesterol ratio (odds ratio = 1.698, 95% CI: 1.07-2.69; P = 0.025) and mean LDL cholesterol size (odds ratio = 0.873, 95% CI: 0.77-0.99; P = 0.038) remained as independent risk factors for cardiac autonomic neuropathy in women., Conclusions: A more atherogenic lipid profile such as the triglyceride: HDL cholesterol ratio and a smaller mean LDL cholesterol particle size were related to the prevalence of cardiac autonomic neuropathy in women with Type 2 diabetes., (© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.)

Aim: To evaluate the prognosis of diabetic gastroparesis., Methods: Eighty-six patients with diabetes had measurements of gastric emptying of a mixed meal using a dual isotope test of solid and liquid meal components, mean blood glucose levels, HbA1c , upper gastrointestinal symptoms and autonomic nerve function performed in 1984-1989. These patients were followed up in 2011, after a mean period of ~25 years., Results: Of the 86 patients, gastric emptying of solid (the percentage remaining in the stomach at 100 min) was delayed in 35 (41%), and of liquid (the time taken for 50% of the liquid to empty) was delayed in 38 (44%). In 2011, 53 patients were known to be alive, 29 had died and four were lost to follow-up. In those who had died, both age at baseline (P < 0.001) and the score for autonomic nerve dysfunction (P < 0.001) were greater than those who were alive, while there was no difference in emptying of either the solid or liquid between the two groups. When patients with delayed gastric emptying were divided according to the median value ('delayed' and 'markedly delayed'), mortality tended to be greater in the 'markedly delayed' group for both solids (P = 0.12) and liquids (P = 0.09). Of the 82 patients who could be followed up, 23 of the 35 (66%) with delayed gastric emptying of solid and 25 of 38 (66%) with delayed gastric emptying of liquid were alive. After adjustment for age and autonomic dysfunction, there was no association between gastric emptying of either solid or liquid and death., Conclusions: Over a period of ~25 years, diabetic gastroparesis is apparently not usually associated with a poor prognosis, or increased mortality., Abbreviations: T100 min, the percentage remaining in the stomach at 100 mins; T50%, the time taken for 50% of the liquid to empty., (© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.)

Aim: Sensory diabetic neuropathy, determined by nerve conduction studies, is common in children with Type 1 diabetes. Diabetic neuropathy diagnoses are rarely made in paediatric daily care because they are asymptomatic, vibration detection is mostly normal and nerve-conduction testing is impractical. The present study aims to: (1) describe somatosensory dysfunction in children with diabetes, (2) test whether diabetes duration and HbA(1c) are related to somatosensory dysfunction and (3) identify the best screening test for large-fibre dysfunction, as indicated by nerve conduction studies., Methods: Forty-five children (age 13.2 ± 2.5 years) with Type 1 diabetes for 6.7 ± 2.5 years and matched control subjects were assessed by neurological examinations, nerve conduction tests and quantitative sensory testing on the feet using the protocol of the German Research Network on Neuropathic Pain. Abnormal nerve conduction was used as gold standard to define neuropathies., Results: We found a high prevalence of mechanical (38%) and thermal (24%) hypoesthesia often associated with hyperalgesia (47%). Tactile hypoesthesia (33%) was more frequent than pallhypaesthesia (11%). Only cold detection and mechanical pain thresholds were related to HbA(1c). Tactile hypoesthesia had the highest sensitivity (75%), specificity (89%) and positive (75%) and negative (89%) predictive values for neuropathies defined by nerve conduction tests (31% abnormal)., Conclusions: Almost half of the children with diabetes have subclinical large- and small-fibre neuropathies. Tactile detection was better than vibration for neuropathy assessment. Quantitative sensory testing is a valuable tool for assessment of neuropathy as well as a target of interventional studies in children with diabetes., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Aims: To further characterize the distal sensory neuropathy in subjects with unilateral diabetic Charcot foot neuroarthropathy., Methods: A retrospective cohort study to assess the level to which the sensory modalities of pinprick, light touch, vibration, joint position and temperature were attenuated in the affected and unaffected limbs in subjects with unilateral Charcot. The level to which the sensory modality was attenuated in each limb was assigned a score. The Wilcoxon signed rank test was used to compare the scores in the affected and unaffected limbs and also to compare the scores of the different sensory modalities in the affected and unaffected limbs., Results: Fifty subjects with unilateral Charcot foot neuroarthropathy were assessed. Mean age was 45 ± SD 6 years for the 17 subjects with Type 1 diabetes and 62 ± 10 years for the 33 subjects with Type 2 diabetes. Duration of diabetes was 21 ± 13 years, HbA(1c) was 70 ± 19 mmol/mol [8.6 ± 1.8 %] and 15 subjects (30%) required renal replacement therapy. The level of attenuation of vibration sensation was more proximal in the affected compared with the unaffected limbs (P = 0.002). Pinprick, light touch, joint position and temperature sensations were not different. Joint position sensation was less attenuated bilaterally than the other sensory modalities., Conclusions: Asymmetrical attenuation of vibration sensation may predict the side that will develop a Charcot joint and may suggest a more important role for vibration sense loss than loss of other sensory modalities in the pathophysiology of Charcot., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Aims: Heart rate variability may be used to assess diabetic cardiac autonomic neuropathy. The aim of the present study was to determine the reliability of standard short-term clinical measurements of heart rate variability in patients with Type 2 diabetes., Methods: In 24 patients with Type 2 diabetes (11 male, age 61 ± 9 years), parameters of heart rate variability in the time domain (standard deviation of RR intervals, coefficient of variation of RR intervals and root mean square of successive RR interval differences) and frequency domain (very low frequency, low frequency, high frequency and total spectral power) were derived from a 5-min electrocardiograph recorded during two laboratory visits separated by 16 ± 8 days. Absolute and relative reliability were assessed by 95% limits of random variation and the intraclass correlation coefficient, respectively. Categorical agreement of classifications of heart rate variability and sample size estimates for clinical trials were calculated., Results: Despite no significant difference in mean heart rate variability between tests, 95% limits of random variation indicated that repeated measurements were between 58% higher/37% lower (most reliable parameter; coefficient of variation of RR intervals) and 443% higher/82% lower (least reliable parameter; very low frequency power) than the first measure. The intraclass correlation coefficient ranged from 0.58 to 0.90 and sample size requirements from 20 to 93 patients per group. Agreement of categories of heart rate variability ranged from 79 to 96%., Conclusions: Short-term clinical measurements of heart rate variability in patients with Type 2 diabetes are characterized by poor absolute reliability, but substantial to good relative reliability, suggesting greater clinical utility in diagnosis than in sequential follow-up., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Background: The acute Charcot foot is thought to occur in people who have a number of predisposing factors, of which distal neuropathy is the most important. But while occurrence in the contralateral foot is not infrequent, recurrence in the same foot seems to be very rare., Case Report: A case is described in which discrete episodes of inflammation of the midfoot occurred in the same foot over a period of 14 years, and were attributed to acute Charcot neuroarthropathy (Charcot foot). There was coincidental evidence of osteomyelitis of the 4(th) toe but there was no suspicion that the inflammatory episodes of the midfoot were the result of bone infection and they settled without treatment with antibiotics., Conclusion: This case had clinically diagnosed recurrences of inflammation and destruction typical of the acute Charcot foot over an extended period, and this is most unusual. The implications of the rarity of such recurrences are discussed., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aims: Skin autofluorescence, a non-invasive measure of the accumulation for advanced glycation end products, has been reported to be a useful marker for diabetic vascular risks in the Caucasian population. The aim of this study was to evaluate associations between skin autofluorescence and vascular complications in non-Caucasian patients with Type 2 diabetes., Methods: Subjects in this cross-sectional study comprised 130 Japanese patients with Type 2 diabetes. Skin advanced glycation end products were assessed by skin autofluorescence using an autofluorescence reader. Association between skin autofluorescence and severity of vascular complications was evaluated., Results: Of the 130 patients, 60 (46.2%) had microvascular complications such as diabetic retinopathy, neuropathy and nephropathy, 10 (7.7%) had macrovascular complications and 63 (48.5%) had micro- and/or macrovascular complications. Skin autofluorescence increased with severity of vascular complications. Independent determinants of skin autofluorescence were age (β = 0.24, P < 0.01), mean HbA(1c) in previous year (β = 0.17, P = 0.03), microvascular complications (β = 0.44, P < 0.01) and macrovascular complications (β = 0.27, P < 0.01). Multiple logistic regression analysis revealed that diabetes duration (odds ratio 1.15, P < 0.01), systolic blood pressure (odds ratio 1.04, P = 0.01), skin autofluorescence (odds ratio 3.62, P = 0.01) and serum albumin (odds ratio 0.84, P < 0.01) were independent factors for the presence of vascular complications in these patients., Conclusions: Skin autofluorescence had independent effects on vascular complications in Japanese patients with Type 2 diabetes. This indicates that skin advanced glycation end products are a surrogate marker for vascular risk and a non-invasive autofluorescence reader may be a useful tool to detect high-risk cases in non-Caucasian patients with diabetes., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aim: Despite recent reports linking vitamin D deficiency with increased risk of diabetes mellitus and complications, there is limited data on patients with diabetic peripheral neuropathy. We aimed to evaluate the incidence and associations of vitamin D deficiency in 210 patients with Type 2 diabetes with and without diabetic peripheral neuropathy., Methods: Renal, liver, lipid profile and HbA(1c) were measured. Vitamin D status was determined by measuring 25-dihydroxyvitamin D. Presence or absence of coronary heart disease was determined and early-morning urine microalbumin:creatinine ratio was measured. All patients were assessed clinically using neuropathy symptom score, neuropathy disability score and nerve conduction study., Results: Eighty-seven patients had diabetic peripheral neuropathy and these patients had significantly longer duration of diabetes and higher HbA(1c). Age, gender, incidence of retinopathy and coronary heart disease were not significantly different from those without neuropathy. Mean (SD) vitamin D was significantly lower in those with neuropathy [36.9 (39.9) nmol/l] compared with those without [58.32 (58.9) nmol/l] and 81.5% of patients with neuropathy had vitamin D deficiency compared with 60.4% of those without. Vitamin D showed significant (P < 0.05) correlations with total cholesterol, LDL-cholesterol and urine microalbumin:creatinine ratio. Binary logistic regression analysis showed that diabetic peripheral neuropathy was significantly associated with vitamin D deficiency (odds ratio = 3.47; 95% CI = 1.04-11.56, P = 0.043) after inclusion of potential confounders such as duration of diabetes, HbA(1c) and LDL-cholesterol., Conclusion: Vitamin D deficiency is an independent risk factor for diabetic peripheral neuropathy, and further studies are required to confirm if Vitamin D supplementation could prevent or delay the onset., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aims: To evaluate the association between vitamin D insufficiency and peripheral neuropathy in a nationally representative sample of adults with diagnosed diabetes., Methods: Vitamin D concentrations, medical examination variables and questionnaire results from the 2001-2004 National Health and Nutrition Examination Survey were analysed for adults ≥ 40 years old with diagnosed diabetes (unweighted n = 591, weighted n = 8.82 million). Neuropathy was defined as self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling in hands or feet. Additionally, Semmes-Weinstein monofilament test results were used as an indicator of neuropathy. Insufficient vitamin D was characterized as < 30 ng/ml., Results: In the weighted population, 81% of adults with diabetes had vitamin D insufficiency. Vitamin D insufficiency was more common among Hispanics (92%) and non-Hispanic black people (98%) than among non-Hispanic white people (76%). Within the 3 months preceding the questionnaire, 50% reported experiencing pain or numbness (paresthesia) in their hands or feet; 37% reported pain or tingling in hands or feet; and 38% reported numbness or loss of feeling in hands or feet. Eight per cent had 4-6 insensate areas on their feet as determined by the Semmes-Weinstein monofilament test. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95% CI 1.17-3.85) and the adjusted numbness measure (odds ratio 2.04; 95% CI 1.18-3.52)., Conclusions: Vitamin D insufficiency is associated with self-reported peripheral neuropathy symptoms even after adjusting for demographic factors, obesity, co-morbidities, use of medications for neuropathy and diabetes duration and control., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aim: To evaluate vibration perception thresholds of patients with and without diabetes, before and after surgical carpal tunnel release., Methods: In a prospective study, 35 consecutive patients with diabetes and carpal tunnel syndrome were age and gender matched with 31 patients without diabetes having idiopathic carpal tunnel syndrome. Preoperatively, 6, 12 and 52 weeks after surgery, the vibration perception threshold of the index and little finger (median and ulnar nerve, respectively) was measured at seven different frequencies (8, 16, 32, 64, 125, 250 and 500 Hz)., Results: At several frequencies, patients with diabetes and carpal tunnel syndrome demonstrated significantly impaired vibration perception thresholds of both the index and the little finger, before as well as after carpal tunnel release, compared with patients without diabetes with idiopathic carpal tunnel syndrome. After surgery, the overall sensibility index improved for the index finger [patients with diabetes and carpal tunnel syndrome (0.79 to 0.91, P < 0.001), patients without diabetes with idiopathic carpal tunnel syndrome (0.91 to 0.96, P > 0.05)] as well as for the little finger [patients with diabetes and carpal tunnel syndrome (0.82 to 0.90, P < 0.008), patients without diabetes with idiopathic carpal tunnel syndrome (0.95 to 0.99, P < 0.05)]. For the index finger, the sensibility index improved to a significantly higher degree for patients with diabetes and carpal tunnel syndrome not having signs of peripheral neuropathy (0.83 to 0.95, P < 0.001) compared with those with neuropathy (0.74 to 0.84, P < 0.02). Vibration perception threshold correlates with age of both patients with diabetes and carpal tunnel syndrome and patients without diabetes with idiopathic carpal tunnel syndrome, while no relationship was found based on duration of diabetes., Conclusions: Vibrotactile sense is significantly impaired in patients with diabetes before and after carpal tunnel release compared with patients without diabetes. However, patients with diabetes obtained significant recovery of vibration perception threshold, particularly those without peripheral neuropathy., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aims: Decreased chemosensitivity to hypercapnia, a common finding in Type 1 diabetes mellitus, seems related to autonomic neuropathy. We proposed to verify whether simple neuroautonomic cardiovascular tests or indexes of severity of diabetes and respiratory impairment can identify patients with such a dysfunction, but no clinical evidence of autonomic neuropathy., Methods: Forty patients with Type 1 diabetes, 20 with autonomic neuropathy according to the results of a standardized test battery, were studied and compared with 40 normal subjects matched by age and sex. Spirometry and pulmonary diffusing capacity for carbon monoxide were performed. The chemosensitivity to hypercapnia was tested by the rebreathing method., Results: There was no significant difference between patients with and without autonomic neuropathy in chemosensitivity to hypercapnia, as expressed by the ventilation response to increasing end-tidal pressure of carbon dioxide; however, it was lower in the whole group of patients with diabetes than in control subjects (1.71 ± 0.80 vs. 2.45 ± 1.11 l⁻¹ min⁻¹ mmHg, respectively, P=0.002). No significant correlation was found between ventilation response to increasing end-tidal pressure of carbon dioxide and the results of autonomic tests. In patients with diabetes mellitus, the ventilatory response to hypercapnia significantly correlated with pulmonary diffusing capacity for carbon monoxide (Spearman's rho=0.387, P=0.013) and this was the only variable significantly associated with ventilation response to increasing end-tidal pressure of carbon dioxide in a multiple regression model., Conclusions: Chemosensitivity to hypercapnia was depressed in patients with diabetes mellitus, irrespective of autonomic neuropathy, in comparison with control subjects. The correlation with pulmonary diffusing capacity for carbon monoxide suggests that microcirculatory damage might contribute to depress the central chemosensitivity., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aims: The aim of this study was to investigate the prevalence of cardiovascular autonomic neuropathy in persons with previously diagnosed impaired glucose tolerance and to characterize associations between components of metabolic syndrome and cardiovascular autonomic neuropathy in the Finnish Diabetes Prevention Study cohort., Methods: Two hundred and sixty-eight individuals with impaired glucose tolerance at baseline in the Finnish Diabetes Prevention Study, but not diagnosed with diabetes during follow-up, were studied for cardiovascular autonomic neuropathy. At the second annual follow-up visit after the end of lifestyle intervention, we performed deep-breathing and active orthostatic tests to detect possible parasympathetic and sympathetic dysfunction. To describe metabolic characteristics, anthropometric measurements, an oral glucose tolerance test and assessments for HbA(1c,) serum lipids and blood pressure were carried out., Results: Prevalence of parasympathetic dysfunction was 25% and prevalence of sympathetic dysfunction was 6%, with no difference between the former intervention and control group participants or between men and women. Subjects with parasympathetic dysfunction were older, more obese (weight, waist circumference, body mass index) and had higher triglyceride concentration compared with those with normal parasympathetic function (P<0.01 for all). Parasympathetic dysfunction was not significantly associated with other characteristics of metabolic syndrome; for example, high cholesterol, glucose and insulin levels or HbA(1c) . Correlations between the Expiration/Inspiration (E/I) ratio (the longest heart beat duration in expiration divided by the shortest heart beat duration in inspiration) and measures reflecting obesity were statistically significant in the pooled population and in men but not in women., Conclusions: Cardiovascular autonomic neuropathy is common in persons with impaired glucose tolerance. Obesity, especially among men, seems to play an important role in the early pathogenesis of cardiovascular autonomic neuropathy., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

It has long been recognized that cardiac autonomic neuropathy increases morbidity and mortality in diabetes and may have greater predictive power than traditional risk factors for cardiovascular events. Significant morbidity and mortality can now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation of cardiovascular function. New and emerging syndromes include orthostatic tachycardia, orthostatic bradycardia and an inability to use heart rate as a guide to exercise intensity because of the resting tachycardia. Recent studies have shown that autonomic imbalance may be a predictor of risk of sudden death with intensification of glycaemic control. This review examines an association of autonomic dysregulation and the role of inflammatory cytokines and adipocytokines that promote cardiovascular risk. In addition, conditions of autonomic imbalance associated with cardiovascular risk are discussed. Potential treatment for restoration of autonomic balance is outlined., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Aims: The impact of depression on patients with chronic medical illnesses such as diabetes is well documented. Depression is relatively common in diabetes patients with diabetes-related complications and they are more likely to be referred to specialized outpatient facilities. Only a few studies have addressed the association between depression and multiple diabetes-related complications at these specialized outpatient facilities. The aim of this study was to determine the association between diabetes with multiple complications and depression in patients with Type 2 diabetes at a specialized outpatient clinic., Methods: After giving informed consent, 1194 patients were screened for depression using the Patient Health Questionnaire (PHQ-9). Additional data on the type of diabetes and complications were taken from the medical records. Logistic regression analysis was conducted, with complications as the predictor variable and the probability of depression as the dependent variable., Results: A total of 596 (63%) patients with Type 2 diabetes participated in the study. The presence of two or more complications (OR 2.23, 95% CI 1.02–2.94) was significantly associated with depression. Neuropathy (OR 1.7, 95% CI 1.10–2.77) and nephropathy (OR 1.68, 95% CI 1.00–2.48) were especially related to depression., Conclusions: Patients with Type 2 diabetes with two or more complications, especially neuropathy or nephropathy, are at high risk of depression. Knowing this can help clinicians identify patients at risk for depression and facilitate timely and adequate treatment.

Aims: To examine differences in the spatial QRS-T angle in patients with Type 2 diabetes mellitus with and without cardiac autonomic neuropathy., Methods: Two hundred and thirty-two patients with diabetes mellitus (105 with cardiac autonomic neuropathy and 127 without cardiac autonomic neuropathy) and 232 control subjects, matched by gender and age, were studied. Diagnosis of cardiac autonomic neuropathy was based on the classic autonomic function tests. All subjects underwent a digital electrocardiographic recording. Electrocardiographic parameters were measured using the Modular Electrocardiographic Analysis (MEANS) program. Left ventricular mass index (LVMi) and global myocardial performance index (Tei index) of the left ventricle were assessed by ultrasonography., Results: The spatial QRS-T angle was higher in the patients with diabetes in comparison with the control subjects (24.5 ± 10.7 vs. 9.7 ± 4.5°, P < 0.001) and in the patients with diabetes and cardiac autonomic neuropathy than in those without cardiac autonomic neuropathy (30.1 ± 11.3 vs. 19.5 ± 7.1, P < 0.001). No differences were found in the QT interval between the studied groups. Multivariate linear regression analysis in subjects with diabetes after controlling for age, gender, BMI, blood pressure, diabetes duration, HbA(1c) , lipids, microalbuminuria and insulin resistance, demonstrated significant and independent associations between the spatial QRS-T angle with presence and severity of cardiac autonomic neuropathy, all parameters of heart rate variability, LVMi and Tei index., Conclusions: The spatial QRS-T angle is increased in patients with Type 2 diabetes who have cardiac autonomic neuropathy, suggesting increased ventricular arrhythmogenicity, and is associated with the structural and functional properties of the myocardium. Further research is warranted to evaluate its role in cardiovascular risk stratification of patients with diabetes., (© 2010 The Authors. Diabetic Medicine © 2010 Diabetes UK.)

Aims: To establish the longitudinal relationship of foot complications to neuropathy based on a 4-year follow-up of diabetic patients stratified by sudomotor dysfunctions., Methods: One hundred and nineteen Type 2 diabetic patients and 36 non-diabetic subjects were initially registered in the prospective cohort study. Plantar skin temperature and sympathetic skin response (SSR) were used to monitor sympathetic mediated thermoregulation and sudomotor function. Peripheral somatic and central autonomic functions were studied using clinical, nerve conduction and cardiovascular reflex tests. At enrolment, the diabetic patients were classified into one of three groups by the progressive stages of sudomotor dysfunction: SSR+ (SSR present; 49 patients), SSR- (SSR absent; 41 patients) and at-risk group (SSR absent but with cracked skin involving partial thickness of the dermis; 29 patients)., Results: The at-risk group had 13.4 times (95% confidence interval 1.4-125.7) higher plantar ulceration rates than the other two patient groups during the 4 years. Skin temperature elevation occurred in parallel with development of foot sweating problems. There were no significant differences between the three patient groups in the ratios of abnormal heart rate variation, orthostatic test and clinical neuropathy score at follow-up. After 4 years of follow-up, nerve conduction abnormalities were more frequent in the at-risk and SSR- groups than in the SSR+ group., Conclusions: Early deterioration of small sympathetic fibres could not be quantified accurately by the clinical, somatic and autonomic tests. Assessing skin integrity and sudomotor function in at-risk individuals identifies early peripheral sympathetic neuropathy, even if the patients have no overt clinical symptoms.

Background: Erectile dysfunction (ED) in diabetes is related to autonomic neuropathy and endothelial dysfunction. We studied the relative importance of these factors in diabetic and non-diabetic men with ED and determined if they predict responses to treatment with sildenafil., Methods: Thirty-three men, aged 35-65 years, with ED (20 diabetic, 13 non-diabetic), 15 of whom were sildenafil responders and 18 non-responders, were compared with 30 age and risk-matched control subjects (15 diabetic, 15 non-diabetic). Subjects with ED completed the International Index of Erectile Function (IIEF) questionnaire. Endothelial function was assessed by changes in brachio-radial and femoro-tibial arterial pulse-wave velocity (pulse-wave velocity) during reactive hyperaemia, expressed as percentage endothelium-dependent dilatation. Autonomic function was assessed by heart rate variation during expiration and inspiration (E/I ratio) and during the valsalva manoeuvre., Results: The respective changes in pulse-wave velocity, in the arm and leg [mean (sd)] were 0.71 (6.5)% and 3.5 (6.4)% in the impotent diabetic men, 0.7 (7.6)% and 2.4 (5.9)% in the non-diabetic impotent men, -0.68 (5.7)% and -1.31 (7.2)% in the non-impotent diabetic men and 7.7 (3.7)% and 7.6 (3.4)% in the control subjects. There was a significant interaction between ED and diabetic status such that there was significantly impaired vascular response in the diabetic group (both with and without ED) and in the non-diabetic group with ED compared with the non-diabetic control group (P = 0.01 and P = 0.001 for brachio-radial and femoro-tibial measures, respectively). The E/I ratios of the diabetic men were significantly lower than those of the control subjects [1.17 (0.14) vs. 1.33 (0.16), P < 0.02), but there were no differences in the measures of autonomic neuropathy between the groups with ED and those with normal erectile function. Amongst diabetic men, the initial IIEF scores (maximum score 30, low score indicates more severe ED) were significantly higher in sildenafil-responders than non-responders [16.3 (8.4), vs. 6.8 (7 1), P < 0.02]. The rate of sildenafil response was not significantly affected by the measures of endothelial or autonomic function., Conclusions: ED in both diabetic and non-diabetic men is characterized by marked endothelial dysfunction in comparison with non-diabetic control subjects. Response to sildenafil is not predicted by either endothelial function or autonomic function, but in diabetic men appears to be related to the initial degree of erectile dysfunction.

Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin II, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na+ reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin II and insulin in PTC may enhance hypertrophy of PTC and/or Na+ reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.

Aims: Prospective studies of autonomic nerve function are rare. We have followed the progression of autonomic dysfunction in relation to nephropathy over 14 years in Type 1 diabetic patients., Methods: Autonomic nerve function was assessed by heart-rate responses to deep breathing (E/I ratio) and tilting (acceleration and brake indices) and by the postural blood pressure reaction in 58 patients, 43 of whom were reassessed after 14 years. Nephropathy was evaluated by the degree of albuminuria (albuminuria > 20 micro g/min or > 0.03 g/24 h) and glomerular filtration rate ((51)Cr-EDTA plasma clearance). The acceleration index had deteriorated after 7 years (P = 0.0155), whereas the E/I ratio (P = 0.0070) and the diastolic postural blood pressure reaction (P = 0.0054) had deteriorated 14 years after the baseline examination (age-corrected values). All those with albuminuria at the third examination showed signs of autonomic neuropathy at baseline (10 of 10) compared with only nine of 22 without (P = 0.0016). Multiple regression analysis showed that the association between autonomic dysfunction and future albuminuria was due to the E/I ratio. In addition, individuals with an abnormal postural diastolic blood pressure fall (n = 7) at baseline showed a greater fall in glomerular filtration rate more than others 7-14 years later [29 (16.5) ml/min/1.72 m(2) vs. 11 (9) ml/min/1.72 m(2); P = 0.0074]., Conclusion: Autonomic nerve function had deteriorated after 14 years. Autonomic neuropathy and abnormal postural diastolic blood pressure falls at baseline were associated with future renal complications., (Copyright 2004 Diabetes UK)

Painful diabetic neuropathy has always been a challenging complication of diabetes mellitus. Emerging theories suggest that early dysaesthesia associated with painful neuropathy may act as a marker for the development of the 'at risk' foot, allowing preventative clinical strategies to be undertaken. The mechanisms of neuropathic pain are complex. The authors' intentions are to help members of the diabetes care team better understand and appreciate the diverse symptoms reported by patients. The various treatments available for painful neuropathy are discussed in detail. Robust comparative studies on such treatments are, however, unavailable and the authors have designed a logical approach to management based on best current evidence and their own clinical experience.