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.

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

ObjectivePoint-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non-specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D).MethodsSural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with ≥ 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves.ResultsT1D were 53% female, aged 66±8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65±8yr(p = 0.36). Mean AMPPOCD and CVPOCD for the 139 participants was 7.4±5.8μV and 45.7±11.2m/s and mean AMPNCS and CVNCS was 7.2±6.1μV and 43.3±8.3m/s. Mean difference of AMPPOCD−AMPNCS was 0.3±3.8μV and was 2.3±8.5m/s for CVPOCD−CVNCS. A AMPPOCD of ≤6μV had 80% sensitivity and 80% specificity for identifying abnormal AMPNCS, while a CVPOCD of ≤44m/s had 81% sensitivity and 82% specificity to identify abnormal CVNCS. Abnormality in AMPPOCD or CVPOCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification.ConclusionsThe POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high-risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction.

Increased protein glycation, oxidation and nitration is linked to the development of diabetic nephropathy. We reported levels of serum protein glycation, oxidation and nitration and related hydrolysis products, glycation, oxidation and nitration free adducts in patients with type 1 diabetes (T1DM) during onset of microalbuminuria (MA) from the First Joslin Kidney Study, a prospective case-control study of patients with T1DM with and without early decline in GFR. Herein we report urinary excretion of the latter analytes and related fractional excretion values, exploring the link to MA and early decline in GFR. We recruited patients with T1DM and normoalbuminuria (NA) (n = 30) or new onset MA with and without early GFR decline (n = 22 and 33, respectively) for this study. We determined urinary protein glycation, oxidation and nitration free adducts by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) and deduced fractional excretion using reported plasma levels and urinary and plasma creatinine estimates. We found urinary excretion of pentosidine was increased ca. twofold in patients with MA, compared to normoalbuminuria (0.0442 vs 0.0103 nmol/mg creatinine, P < 0.0001), and increased ca. threefold in patients with early decline in GFR, compared to patients with stable GFR (0.0561 vs 0.0176 nmol/mg creatinine, P < 0.01). Urinary excretion of all other analytes was unchanged between the study groups. Remarkably, fractional excretions of 6 lysine and arginine-derived glycation free adducts were higher in patients with early decline in GFR, compared to those with stable GFR. Impaired tubular reuptake of glycation free adducts by lysine and arginine transporter proteins in patients with early GFR decline is likely involved. We conclude that higher fractional excretions of glycation adducts are potential biomarkers for early GFR decline in T1DM and MA. Measurement of these analytes could provide the basis for identifying patients at risk of early decline in renal function to target and intensify renoprotective treatment. Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) and severely decreases likelihood of long-term survival of patients with diabetes 1. It has high occurrence linked to a high global prevalence of diabetes, 5% type 1 diabetes mellitus (T1DM) and 95% type 2 diabetes mellitus (T2DM), with ca. 40% of patients with diabetes developing diabetic nephropathy 2,3. Approximately half of patients with diabetic nephropathy progress to diabetic kidney disease and ESRD with increased risk of potentially fatal cardiovascular disease. Current treatment guidelines address modifiable risk factors through intensification of control of glycemic status, blood

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