Aims/hypothesisSmall cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP.MethodsNine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard.ResultsType 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity.Conclusions/interpretationWe established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4653-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

JDRF operating grant 17-2013-312.

Type 1 diabetes carries a significant risk for cardiovascular mortality, but it is unclear how atherosclerosis associates with microvascular complications. We aimed to determine the relationships between atherosclerotic burden and neuropathy, retinopathy, and diabetic kidney disease (DKD) in adults with a ‡50-year history of type 1 diabetes. RESEARCH DESIGN AND METHODS Adults with type 1 diabetes (n = 69) underwent coronary artery calcification (CAC) volume scoring by wide-volume computerized tomography. Microvascular complications were graded as follows: neuropathy by clinical assessment, electrophysiology, vibration and cooling detection thresholds, heart rate variability, and corneal confocal microscopy; retinopathy by ultra-wide-field retinal imaging; and DKD by renal hemodynamic function measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II. The cohort was dichotomized to high (‡300 Agatston units [AU]) or low (<300 AU) CAC and was stratified by diabetes status. A comparator group without diabetes (n = 73) matched for age and sex also underwent all study procedures except for retinal imaging. RESULTS CAC scores were higher in participants with type 1 diabetes (median Agatston score 1,000 [interquartile range = 222, 2,373] AU vs. 1 [0.75] AU in comparators, P < 0.001). In participants with type 1 diabetes, high CAC scores associated with markers of neuropathy and retinopathy, but not with DKD, or renal hemodynamic function at baseline or in response to angiotensin II. CONCLUSIONS The presence of high CAC in adults with longstanding type 1 diabetes was associated with large nerve fiber neuropathy and retinopathy but not with renal hemodynamic function, suggesting that neuropathy, retinopathy, and macrovascular calcification share common risk factors. The pathophysiology of cardiovascular disease (CVD) in individuals with type 1 diabetes (T1D) is complex and remains incompletely understood. A combination of factors, including inflammation, endothelial dysfunction, and oxidative stress (1-3), leading to an increased atherosclerotic burden are implicated (4,5). In light of the diffuse and systemic nature of these pathogenic factors, it is not surprising that

Aim To assess whether adding empagliflozin to closed‐loop automated insulin delivery could reduce the need for carbohydrate counting in type 1 diabetes (T1D) without worsening glucose control. Materials and Methods In an open‐label, crossover, non‐inferiority trial, 30 adult participants with T1D underwent outpatient automated insulin delivery interventions with three random sequences of prandial insulin strategy days: carbohydrate counting, simple meal announcement (no carbohydrate counting) and no meal announcement. During each sequence of prandial insulin strategies, participants were randomly assigned empagliflozin (25 mg/day) or not, and crossed over to the comparator. Mean glucose for carbohydrate counting without empagliflozin (control) was compared with no meal announcement with empagliflozin (in the primary non‐inferiority comparison) and simple meal announcement with empagliflozin (in the conditional primary non‐inferiority comparison). Results Participants were aged 40 ± 15 years, had 27 ± 15 years diabetes duration and HbA1c of 7.6% ± 0.7% (59 ± 8 mmol/mol). The system with no meal announcement and empagliflozin was not non‐inferior (and thus reasonably considered inferior) to the control arm (mean glucose 10.0 ± 1.6 vs. 8.5 ± 1.5 mmol/L; non‐inferiority p = .94), while simple meal announcement and empagliflozin was non‐inferior (8.5 ± 1.4 mmol/L; non‐inferiority p = .003). Use of empagliflozin on the background of automated insulin delivery with carbohydrate counting was associated with lower mean glucose, corresponding to a 14% greater time in the target range. While no ketoacidosis was observed, mean fasting ketones levels were higher on empagliflozin (0.22 ± 0.18 vs. 0.13 ± 0.11 mmol/L; p < .001). Conclusions Empagliflozin added to automated insulin delivery has the potential to eliminate the need for carbohydrate counting and improves glycaemic control in conjunction with carbohydrate counting, but does not allow for the elimination of meal announcement.

Objective In vivo Corneal Confocal Microscopy (IVCCM) is a validated, non-invasive test for diabetic sensorimotor polyneuropathy (DSP) detection, but its utility is limited by the image analysis time and expertise required. We aimed to determine the inter- and intra-observer reproducibility of a novel automated analysis program compared to manual analysis.MethodsIn a cross-sectional diagnostic study, 20 non-diabetes controls (mean age 41.4±17.3y, HbA1c 5.5±0.4%) and 26 participants with type 1 diabetes (42.8±16.9y, 8.0±1.9%) underwent two separate IVCCM examinations by one observer and a third by an independent observer. Along with nerve density and branch density, corneal nerve fibre length (CNFL) was obtained by manual analysis (CNFLMANUAL), a protocol in which images were manually selected for automated analysis (CNFLSEMI-AUTOMATED), and one in which selection and analysis were performed electronically (CNFLFULLY-AUTOMATED). Reproducibility of each protocol was determined using intraclass correlation coefficients (ICC) and, as a secondary objective, the method of Bland and Altman was used to explore agreement between protocols.ResultsMean CNFLManual was 16.7±4.0, 13.9±4.2 mm/mm2 for non-diabetes controls and diabetes participants, while CNFLSemi-Automated was 10.2±3.3, 8.6±3.0 mm/mm2 and CNFLFully-Automated was 12.5±2.8, 10.9 ± 2.9 mm/mm2. Inter-observer ICC and 95% confidence intervals (95%CI) were 0.73(0.56, 0.84), 0.75(0.59, 0.85), and 0.78(0.63, 0.87), respectively (p = NS for all comparisons). Intra-observer ICC and 95%CI were 0.72(0.55, 0.83), 0.74(0.57, 0.85), and 0.84(0.73, 0.91), respectively (p<0.05 for CNFLFully-Automated compared to others). The other IVCCM parameters had substantially lower ICC compared to those for CNFL. CNFLSemi-Automated and CNFLFully-Automated underestimated CNFLManual by mean and 95%CI of 35.1(-4.5, 67.5)% and 21.0(-21.6, 46.1)%, respectively.ConclusionsDespite an apparent measurement (underestimation) bias in comparison to the manual strategy of image analysis, fully-automated analysis preserves CNFL reproducibility. Future work must determine the diagnostic thresholds specific to the fully-automated measure of CNFL.

Abbreviations CNBD Corneal nerve branch density CNFD Corneal nerve fibre density CNFL Corneal nerve fibre length IVCCM In vivo corneal confocal microscopy ROC Receiver operating characteristic ROC-AUC Area under the ROC curveTo the Editor: There exists an urgent need to better characterise and identify the presence of early-stage diabetic neuropathy when therapy is most likely to be effective. The lack of an objective endpoint for early neuropathy has seriously hindered the evaluation of disease-modifying therapies in clinical research and the prediction of neuropathy progression in clinical care [1,2]. There is considerable evidence that injury to small, thinly myelinated and unmyelinated nerve fibres precedes injury to large myelinated fibres in individuals with diabetic neuropathy [3].Morphological examination of the small nerve fibres of the cornea by in vivo corneal confocal microscopy (IVCCM) has emerged as an objective and non-invasive imaging technique for identifying diabetic neuropathy. Specifically, lower corneal nerve fibre length (CNFL) has been confirmed as a valid biomarker for neuropathy identification in younger adults with type 1 diabetes [4,5] and may represent a surrogate endpoint for trials of disease-modifying therapies for neuropathy. However, CNFL's diagnostic performance may be impaired with advanced age and diabetes duration owing to age-and extensive disease-related changes in corneal nerve morphology [6]. We aimed to determine whether CNFL retains its diagnostic validity in a unique cohort of older adults who have lived with type 1 diabetes for over 50 years.As part of the second phase of the Canadian Study of Longevity in Type 1 Diabetes [7], 67/75 (89%) participants with type 1 diabetes and 69/75 (92%) participants forming a non-diabetic control group from age/sex-matched subgroups underwent electrophysiology-based procedures to define neuropathy (reference standard) and evaluation of corneal morphology by IVCCM (index test) in a cross-sectional analysis of the baseline evaluation. All participants provided written informed consent and the study and its procedures were approved by the institutional ethics board at the University

Introduction Glomerular filtration rate (GFR) is routinely used for clinical assessment of kidney function. However, the accuracy of estimating equations in older adults is uncertain. Methods In 66 adults with ≥50 years type 1 diabetes (T1D) duration and 73 nondiabetic controls from age/sex-matched subgroups (65 ± 8 years old and 77[55%] were women) we evaluated the performance of estimated GFR (eGFR) by creatinine (Modification of Diet and Renal Disease [MDRD], Chronic Kidney Disease–Epidemiology [CKD-EPI] cr ), cystatin C (CKD-EPI cys , CKD-EPI cr-cys ), and β 2 -microglobulin (β2M) compared with measured GFR by inulin clearance (mGFR). Performance was evaluated using metrics of bias (mean difference), precision (SD), and accuracy (proportion of eGFR that differed by >20% of mGFR). Results Mean mGFR was 104 ± 18 ml/min per 1.73 m 2 (range: 70–154 ml/min per 1.73 m 2 ) and was not different between T1D and controls (103 ± 17 vs. 105 ± 19 ml/min per 1.73 m 2 , P = 0.39). All equations significantly underestimated mGFR (bias: −15 to −30 ml/min per 1.73 m 2 , P < 0.001 for all comparisons) except for β2M, which had bias of 1.9 ml/min per 1.73 m 2 ( P = 0.61). Bias was greatest in cystatin C–based equations. Precision was lowest for β2M (SD: 43.5 ml/min per 1.73 m 2 , P < 0.001 for each comparison). Accuracy was lowest for CKD-EPI cysC (69.1%, P < 0.001 for each comparison). Cystatin C–based equations demonstrated greater bias and lower accuracy in older age subgroups (<60, 60–69, ≥70 years). All equations demonstrated greater bias across higher ranges of mGFR (60–89, 90–119, ≥120 ml/min per 1.73 m 2 ). Results were similar between T1D and controls except that β2M had lower performance in T1D. Conclusion Better estimates of GFR in older adults are needed for research and clinical practice, as this subgroup of the population has an amplified risk for the development of chronic kidney disease (CKD) that requires accurate GFR estimation methods.

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