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Body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality. Over the last few decades, we have witnessed a global rise in adult obesity of epidemic proportions. Similarly, there has been a parallel increase in the incidence of atrial fibrillation (AF), itself a significant cause of cardiovascular morbidity and mortality. This may be partly attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy, however, epidemiological studies have demonstrated an independent association between obesity, diabetes and AF, suggesting possible common pathophysiological mechanisms and risk factors. Indeed, cardiac remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction have been reported in obese and diabetic cohorts. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype, which may predispose to the development of AF. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and some of the challenges posed in the management of this high-risk group of individuals. [ABSTRACT FROM AUTHOR]

There is a need to accurately identify patients with diabetes at higher risk of developing and progressing diabetic peripheral neuropathy (DPN). Fifty subjects with Type 1 Diabetes Mellitus (T1DM) and sixteen age matched healthy controls underwent detailed neuropathy assessments including symptoms, signs, quantitative sensory testing (QST), nerve conduction studies (NCS), intra epidermal nerve fiber density (IENFD) and corneal confocal microscopy (CCM) at baseline and after 2 years of follow-up. Overall, people with type 1 diabetes mellitus showed no significant change in HbA1c, blood pressure, lipids or neuropathic symptoms, signs, QST, neurophysiology, IENFD and CCM over 2 years. However, a sub-group ( n = 11, 22%) referred to as progressors, demonstrated rapid corneal nerve fiber loss (RCNFL) with a reduction in corneal nerve fiber density (CNFD) ( p = 0.0006), branch density (CNBD) ( p = 0.0002), fiber length (CNFL) ( p = 0.0002) and sural ( p = 0.04) and peroneal ( p = 0.05) nerve conduction velocities, which was not related to a change in HbA1c or cardiovascular risk factors. The majority of people with T1DM and good risk factor control do not show worsening of neuropathy over 2 years. However, CCM identifies a sub-group of people with T1DM who show a more rapid decline in corneal nerve fibers and nerve conduction velocity.

To assess the impact of renal transplantation on peripheral nerve damage in patients with chronic kidney disease (CKD). Fifteen patients with CKD (eGFR <15 mL/min/1.73 m 2 ) underwent longitudinal assessment after renal transplantation (age: 56.88 ± 2.53 years, eGFR: 46.82 ± 4.86) and were compared with 15 age-matched controls (age: 58.25 ± 2.18 years, eGFR: 86.0 ± 2.0). The neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration perception threshold (VPT), cold and warm sensation threshold (CST and WST), cold and heat induced pain (CIP and HIP), deep breathing heart rate variability (DB-HRV), nerve conduction studies and corneal confocal microscopy (CCM) to quantify small nerve fibre pathology, were undertaken within 1-month of renal transplantation (baseline) and at 6, 12 and 24 months of follow up. There was no significant difference in NSP (P = .1), NDS (P = .3), VPT (P = .6), CST (P = .2), CIP (P = .08), HIP (P = .1), DB-HRV (P = .9) and sural (P = .4) and peroneal (P = .1) nerve amplitude between patients with CKD and controls at baseline. However, sural (P = .04), peroneal (P = .002) and tibial (P = .007) nerve conduction velocity and tibial nerve amplitude (P = .03) were significantly lower, WST (P = .02) was significantly higher and corneal nerve fibre density (P = .004) was significantly lower in patients with CKD compared with controls. There was no significant change in NSP, NDS, quantitative sensory testing, DB-HRV, nerve conduction or CCM parameters 24 months after renal transplantation. There is evidence of small and large fibre neuropathy in patients with CKD, but no change up to 24 months after successful renal transplantation., (© 2021 Peripheral Nerve Society.)

Purpose: Increased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA)., Methods: Patients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified., Results: Lower CNFD (P < 0.001), CNBD (P < 0.0001), and CNFL (P < 0.0001) and higher LC density (P = 0.03) were detected in patients with T1DM, T2DM, and LADA compared to controls. CNBD was inversely correlated with mature (r = -0.5; P = 0.008), immature (r = -0.4; P = 0.02) and total (r = -0.5; P = 0.01) LC density, and CNFL was inversely correlated with immature LC density (r = -0.4; P = 0.03) in patients with T1DM but not in patients with T2DM and LADA., Conclusions: This study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM.

Background and Aim: Damage to small nociceptive fibres may contribute to painful diabetic neuropathy. We aimed to compare large and small nerve fibre measurements together with skin biopsy and corneal confocal microscopy in patients with type 1 diabetes and painful or painless diabetic neuropathy., Methods: We have assessed the McGill pain questionnaire, neuropathy disability score, vibration perception threshold, warm and cold sensation thresholds, electrophysiology, corneal confocal microscopy and skin biopsy in participants with type 1 diabetes and painful (n = 41) or painless (n = 50) diabetic neuropathy and control subjects (n = 50)., Results: The duration of diabetes, body mass index, glycated haemoglobin (HbA1c), blood pressure and lipid profile did not differ between subjects with painful and painless neuropathy. Neuropathy disability score and vibration perception threshold were higher and sural nerve conduction velocity was lower, but sural nerve amplitude, peroneal nerve amplitude and conduction velocity and cold and warm sensation thresholds did not differ between patients with painful compared to painless diabetic neuropathy. However, intraepidermal nerve fibre density, corneal nerve fibre density, corneal nerve branch density and corneal nerve fibre length were significantly lower in subjects with painful compared to painless diabetic neuropathy., Conclusions: There is evidence of more severe neuropathy, particularly small fibre damage in the skin and cornea, of patients with painful compared to painless diabetic neuropathy., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

A proportion of individuals with type 1 diabetes mellitus for more than 50 years (medallists) may be protected from developing nephropathy, retinopathy and neuropathy. Detailed neuropathy phenotyping was undertaken in a cohort of 33 medallists aged 63.7 ± 1.4 years with diabetes for 58.5 ± 0.8 years and HbA1c of 65.9 ± 2.1 mmol/mmol. Medallists had a significantly higher HbA1c (P < .001), lower estimated glomerular filtration rate (eGFR) (P = .005) and higher albumin creatinine excretion ratio (ACR) (P = .01), but a lower total cholesterol (P < .001), triacylglycerols (P = .001), low density lipoprotein-cholesterol (P < .001) and higher high density lipoprotein-cholesterol (P = .03), compared to controls. Twenty-four percent of participants were identified as "escapers" without confirmed diabetic neuropathy. They had a lower neuropathy symptom profile (P = .002), vibration perception threshold (P = .02), warm threshold (P = .05), higher peroneal amplitude (P = .005), nerve conduction velocity (P = .03), heart rate variability (P = .001), corneal nerve fibre density (P = 0.001), branch density (P < .001) and length (P = .001), compared to medallists with diabetic neuropathy. Escapers had a shorter duration of diabetes (P = .006), lower alcohol consumption (P = .04), lower total cholesterol (P = .04) and LDL (P = .02), higher eGFR (P = .001) and lower ACR (P < .001). Patients with extreme duration diabetes without diabetic neuropathy have a comparable HbA1c, blood pressure and body mass index, but a more favourable lipid profile and consume less alcohol compared to those with diabetic neuropathy., (© 2020 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background: The aetiology of painful diabetic neuropathy is unclear. We have evaluated vitamin D levels in diabetic patients with and without painful neuropathy., Methods: Forty-three patients with type 1 diabetes and painless (DPN) (n = 20) or painful (PDN) (n = 23) neuropathy and 14 non-diabetic healthy control subjects (C) underwent assessment of neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal confocal microscopy (CCM) and measurement of serum 25(OH)D., Results: There were no significant differences for age, BMI, HbA 1c , lipids, neurological deficits, QST, electrophysiology, intra-epidermal nerve fibre density (IENFD) and corneal nerve morphology between patients with DPN and PDN. Both positive (hyperalgesia and allodynia) and negative symptoms (paraesthesia and numbness) of diabetic neuropathy were greater in PDN compared with DPN (P = .009 and P = .02, respectively). Serum 25(OH)D levels were significantly lower in PDN (24.0 ± 14.1 ng/mL) compared with DPN (34.6 ± 15.0 ng/mL, P = .01) and controls (34.1 ± 8.6 ng/mL, P = .03). The odds ratio in favour of painful diabetic neuropathy was 9.8 [P = .003 (95% CI, 2.2-76.4)] for vitamin D deficiency (<20 ng/mL) and 4.4 [P = .03 (95% CI, 1.1-19.8)] for vitamin D insufficiency (<30 ng/mL)., Conclusions: This study suggests that vitamin D deficiency and insufficiency are associated with painful diabetic neuropathy., (© 2020 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Objective: To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss., Research Design and Methods: A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors., Results: Corneal nerve fiber density (CNFD) ( P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) ( P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) ( P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD ( P < 0.0001), CNBD ( P < 0.0001), and CNFL ( P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (β = -0.27, P = 0.007), HbA 1c (β = -1.1; P = 0.01), and weight (β = -0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (β = -0.13; P = 0.02), LDL cholesterol (β = 1.8, P = 0.04), and triglycerides (β = -2.87; P = 0.009) in patients with type 1 diabetes., Conclusions: CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes., (© 2020 by the American Diabetes Association.)

Aims/hypothesis: The study aimed to assess the impact on neuropathy of simultaneous pancreas and kidney transplantation (SPK) in individuals with type 1 diabetes., Methods: This longitudinal observational study examined neuropathic symptoms, deficits, quantitative sensory testing, neurophysiology, corneal confocal microscopy and skin biopsy results in 32 healthy (non-diabetic) control participants, 29 individuals with type 1 diabetes and severe diabetic peripheral neuropathy [DPN] and 36 individuals with type 1 diabetes after SPK., Results: Following SPK, HbA 1c , eGFR, triacylglycerols and HDL improved significantly (all p < 0.05). Compared with the DPN group, which remained unchanged over the 36 month study period, corneal confocal microscopy assessments improved over 36 months following SPK, with increasing corneal nerve fibre density of 5/mm 2 (95% CI 1.8, 8.2; p = 0.003) and corneal nerve fibre length of 3.2 mm/mm 2 (95% CI 0.9, 5.5; p = 0.006). The Neuropathy Symptom Profile and peroneal nerve conduction velocity also improved significantly by 36 months compared with DPN (2.5; 95% CI 0.7, 4.3; p = 0.008 and 4.7 m/s; 95% CI 2.2, 7.4; p = 0.0004, respectively), but with a temporal delay compared with the corneal confocal microscopy assessments. Intraepidermal nerve fibre density did not change following SPK; however, mean dendritic length improved significantly at 12 (p = 0.020) and 36 (p = 0.019) months. In contrast, there were no changes in the Neuropathy Disability Score, quantitative sensory testing or cardiac autonomic function assessments. Except for a small decrease in corneal nerve fibre density in the healthy control group, there were no changes in any other neuropathy measure in the healthy control or DPN groups over 36 months., Conclusions/interpretation: SPK is associated with early and maintained small nerve fibre regeneration in the cornea and skin, followed by an improvement in neuropathic symptoms and peroneal nerve conduction velocity.

Background: Diabetic peripheral neuropathy (DPN) can lead to foot ulceration and amputation. There are currently no disease-modifying therapies for DPN. The aim of this study was to determine if hypertension contributes to DPN in patients with type 1 diabetes mellitus (T1DM)., Methods: Subjects with T1DM (n = 70) and controls (n = 78) underwent a comprehensive assessment of DPN., Results: Hypertension was present in 40 of 70 T1DM subjects and 20 of 78 controls. Hypertension was associated with abnormal nerve conduction parameters (P = 0.03 to <0.001), increased vibration perception threshold (P = 0.01) and reduced corneal nerve fiber density and length (P = 0.02) in subjects with T1DM. However, after adjusting for confounding factors only tibial compound motor action potential and nerve conduction velocity were associated with hypertension (P = 0.03) and systolic blood pressure (P < 0.01 to <0.0001). Hypertension had no effect on neuropathy in subjects without diabetes., Conclusions: This study shows that hypertension is associated with impaired nerve conduction in T1DM. It supports previous small trials showing that angiotensin-converting enzyme inhibitors improve nerve conduction and advocates the need for larger clinical trials with blood pressure lowering agents in DPN., (© The Author(s) 2019. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Background: The population of women of childbearing age palliated with a Fontan repair is increasing. The aim of this study was to describe the progress of pregnancy and its outcome in a cohort of patients with a Fontan circulation in the UK., Methods: A retrospective study of women with a Fontan circulation delivering between January 2005 and November 2016 in 10 specialist adult congenital heart disease centres in the UK., Results: 50 women had 124 pregnancies, resulting in 68 (54.8%) miscarriages, 2 terminations of pregnancy, 1 intrauterine death (at 30 weeks), 53 (42.7%) live births and 4 neonatal deaths. Cardiac complications in pregnancies with a live birth included heart failure (n=7, 13.5%), arrhythmia (n=6, 11.3%) and pulmonary embolism (n=1, 1.9%). Very low baseline maternal oxygen saturations at first obstetric review were associated with miscarriage. All eight women with saturations of less than 85% miscarried, compared with 60 of 116 (51.7%) who had baseline saturations of ≥85% (p=0.008). Obstetric and neonatal complications were common: preterm delivery (n=39, 72.2%), small for gestational age (<10th percentile, n=30, 55.6%; <5th centile, n=19, 35.2%) and postpartum haemorrhage (n=23, 42.6%). There were no maternal deaths in the study period., Conclusion: Women with a Fontan circulation have a high rate of miscarriage and, even if pregnancy progresses to a viable gestational age, a high rate of obstetric and neonatal complications., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD)., Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements., Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD., Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN.

Objectives: Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy., Methods: In this cross sectional study, thirty subjects with Type 1 diabetes without neuropathy (T1DM), thirty one T1DM subjects with neuropathy (DSPN) and twenty seven non-diabetic healthy control subjects underwent detailed assessment of neuropathic symptoms and neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy and corneal confocal microscopy (CCM)., Results: Subjects with DSPN were older (C vs T1DM vs DSPN: 41.0±14.9 vs 38.8±12.5 vs 53.3±11.9, P = 0.0002), had a longer duration of diabetes (P<0.0001), lower eGFR (P = 0.006) and higher albumin-creatinine ratio (P = 0.03) with no significant difference for HbA1c, BMI, lipids and blood pressure. Patients with DSPN were representative of subjects with diabetic neuropathy with clinical signs and symptoms of neuropathy and greater neuropathy deficits quantified by QST, electrophysiology, intra-epidermal nerve fibre density and CCM. Corneal nerve fibre density (CNFD) (Spearman's Rho = 0.60 P<0.0001) and IENFD (Spearman's Rho = 0.56 P<0.0001) were comparable when correlated with peroneal nerve conduction velocity. For the diagnosis of diabetic neuropathy the sensitivity for CNFD was 0.77 and specificity was 0.79 with an area under the ROC curve of 0.81. IENFD had a diagnostic sensitivity of 0.61, specificity of 0.80 and area under the ROC curve of 0.73., Conclusions: CCM is a valid accurate non-invasive method to identify small nerve fibre pathology and is able to diagnose DPN.

Aims/hypothesis: The aim of this study was to identify the contribution of small- and large-fibre neuropathy to erectile dysfunction in men with type 1 diabetes mellitus., Methods: A total of 70 participants (29 without and 41 with erectile dysfunction) with type 1 diabetes and 34 age-matched control participants underwent a comprehensive assessment of large- and small-fibre neuropathy., Results: The prevalence of erectile dysfunction in participants with type 1 diabetes was 58.6%. After adjusting for age, participants with type 1 diabetes and erectile dysfunction had a significantly higher score on the Neuropathy Symptom Profile (mean ± SEM 5.3 ± 0.9 vs 1.8 ± 1.2, p = 0.03), a higher vibration perception threshold (18.3 ± 1.9 vs 10.7 ± 2.4 V, p = 0.02), and a lower sural nerve amplitude (5.0 ± 1.1 vs 11.7 ± 1.5 mV, p = 0.002), peroneal nerve amplitude (2.1 ± 0.4 vs 4.7 ± 0.5 mV, p < 0.001) and peroneal nerve conduction velocity (34.8 ± 1.5 vs 41.9 ± 2.0 m/s, p = 0.01) compared with those without erectile dysfunction. There was also evidence of a marked small-fibre neuropathy with an impaired cold threshold (19.7 ± 1.4°C vs 27.3 ± 1.8°C, p = 0.003), warm threshold (42.9 ± 0.8°C vs 39.0 ± 0.9°C, p = 0.005) and heart rate variability (21.5 ± 3.1 vs 30.0 ± 3.7 beats/min, p = 0.001) and reduced intraepidermal nerve fibre density (2.8 ± 0.7 vs 5.9 ± 0.7/mm, p = 0.008), corneal nerve fibre density (12.6 ± 1.5 vs 23.9 ± 2.0/mm 2 , p < 0.001), corneal nerve branch density (12.7 ± 2.5 vs 31.6 ± 3.3/mm 2 , p < 0.001) and corneal nerve fibre length (8.3 ± 0.7 vs 14.5 ± 1.0 mm/mm 2 , p < 0.001) in participants with type 1 diabetes and erectile dysfunction. Erectile dysfunction correlated significantly with measures of both large- and small-fibre neuropathy., Conclusions/interpretation: Small-fibre neuropathy is prominent in patients with type 1 diabetes, and is associated with erectile dysfunction and can be objectively quantified using corneal confocal microscopy. This may allow the identification of patients who are less likely to respond to conventional therapies such as phosphodiesterase type 5 inhibitors.

Background: Global iodine-123 metaiodobenzylguanidine (I-MIBG) uptake is predictive of cardiovascular events and mortality in patients with heart failure. Normal variations in global and regional uptake, however, are not well defined and few studies have addressed the functional relevance of I-MIBG uptake and distribution in healthy individuals., Materials and Methods: We performed I-MIBG scintigraphy and cardiac autonomic function testing using the standardized methodology in 15 healthy individuals (mean age 54.6±5.3 years, male : female 10 : 5) with no evidence of previous myocardial infarction or ischaemic heart disease., Results: Early heart to mediastinum ratio (HMR) was 1.67±0.13, late HMR was 1.73±0.16 and washout rate was 19.09±7.63% (4.20-31.30). Regional analysis showed reduced tracer uptake at the apex, base and inferior wall in all individuals. Early and late HMR correlated negatively with RFa (r=-0.603; P=0.05 and r=-0.644; P=0.033) and expiration and inspiration ratio (r=-0.616; P=0.043 and r=-0.676; P=0.022) and positively with LFa/RFa (r=0.711; P=0.014 and r=0.784; P=0.004). Washout rate correlated only with RFa (r=0.642; P=0.033)., Conclusion: Healthy adults show a heterogeneous pattern of cardiac innervation with reduced regional uptake of I-MIBG. Furthermore, HMR correlates with indices of cardiac sympathetic function, suggesting that it might not only be a useful prognostic marker but may also provide insight into the functional integrity of the cardiac autonomic nervous system.

Background: Experimental and clinical studies suggest a possible association between vitamin D deficiency and both diabetic retinopathy and maculopathy., Methods: We have performed a cross-sectional study in adults with types 1 and 2 diabetes mellitus. The relationship between the presence and severity of diabetic retinopathy and maculopathy with serum 25-hydroxyvitamin D concentration was evaluated using logistic regression analyses in the presence of demographic and clinical covariates., Results: 657 adults with diabetes were stratified based on retinopathy grading: No Diabetic Retinopathy (39%), Background Diabetic Retinopathy (37%), Preproliferative Diabetic Retinopathy (21%), and Proliferative Diabetic Retinopathy (3%), respectively. There were no differences in serum 25-hydroxyvitamin D concentrations (25(OH)D) between the groups (15.3 ± 9.0 versus 16.4 ± 10.5 versus 15.9 ± 10.4 versus 15.7 ± 8.5 ng/mL, P = NS). Logistic regression analysis demonstrated no statistically significant relationship between the severity of retinopathy and serum 25(OH)D. Furthermore, there was no difference in serum 25(OH)D between those with (n = 94, 14%) and those without (n = 563, 86%) Diabetic Maculopathy (16.2 ± 10.0 versus 15.8 ± 9.8, P = NS) and no relationship was demonstrated by logistic regression analyses between the two variables., Conclusions: This study has found no association between serum 25(OH)D and the presence and severity of diabetic retinopathy or maculopathy.

Objective: Impaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management., Research Design and Methods: Thirty subjects with IGT and 17 age-matched control subjects underwent an oral glucose tolerance test, assessment of neuropathic symptoms and deficits, quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) at baseline and annually for 3 years., Results: Ten subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years., Conclusions: CCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)