Steno Diabetes Center Copenhagen Research Articles

Frequency of Rebound Hyperglycemia in Adults with Type 1 Diabetes Treated with Different Insulin Delivery Modalities.

Background: For people with type 1 diabetes (T1D), ensuring fast and effective recovery from hypoglycemia while avoiding posthypoglycemic hyperglycemia (rebound hyperglycemia, RH) can be challenging. The objective of this study was to investigate the frequency of RH across different treatment modalities and its impact on glycemic control. Methods: This cross-sectional real-world study included adults with T1D using continuous glucose monitoring and attending the outpatient clinic at Steno Diabetes Center Copenhagen. RH was defined as ≥1 sensor glucose value (SG) >10.0 mmol/L (180 mg/dL) starting within 2 h of an antecedent SG <3.9 mmol/L (70 mg/dL). The severity of the RH events was calculated as area under the curve (AUC) and separately for users of multiple daily injections (MDIs), unintegrated insulin pumps, sensor augmented pumps (SAPs), and automated insulin delivery (AID), respectively. Results: Across the four groups, SAP and AID users had the highest incidence of RH (2.06 ± 1.65 and 2.08 ± 1.49 events per week, respectively) and a similar percentage of hypoglycemic events leading to RH events (41.3 ± 22.8% and 39.6 ± 20.1%, respectively). The AID users with RH events were significantly shorter compared with MDI users (122 ± 72 vs. 185 ± 135 min; P < 0.0001). Overall, severity of RH was inversely associated with more advanced technology (P < 0.001) and inversely associated (P < 0.001) with time in target range (TIR). Conclusions: Groups with insulin suspension features experienced the highest frequency of RH; however, AID users tended to experience shorter and less severe RH events. The association between the severity of RH events and TIR suggests that RH should be assessed and used in the guidance of hypoglycemia management.

Impact of Missed and Late Meal Boluses on Glycemic Outcomes in Automated Insulin Delivery-Treated Children and Adolescents with Type 1 Diabetes: A Two-Center, Population-Based Cohort Study.

Objective: To evaluate the impact of missed or late meal boluses (MLBs) on glycemic outcomes in children and adolescents with type 1 diabetes using automated insulin delivery (AID) systems. Research Design and Methods: AID-treated (Tandem Control-IQ or Medtronic MiniMed 780G) children and adolescents (aged 6-21 years) from Stanford Medical Center and Steno Diabetes Center Copenhagen with ≥10 days of data were included in this two-center, binational, population-based, retrospective, 1-month cohort study. The primary outcome was the association between the number of algorithm-detected MLBs and time in target glucose range (TIR; 70-180 mg/dL). Results: The study included 189 children and adolescents (48% females with a mean ± standard deviation age of 13 ± 4 years). Overall, the mean number of MLBs per day in the cohort was 2.2 ± 0.9. For each additional MLB per day, TIR decreased by 9.7% points (95% confidence interval [CI] 11.3; 8.1), and compared with the quartile with fewest MLBs (Q1), the quartile with most (Q4) had 22.9% less TIR (95% CI: 27.2; 18.6). The age-, sex-, and treatment modality-adjusted probability of achieving a TIR of >70% in Q4 was 1.4% compared with 74.8% in Q1 (P < 0.001). Conclusions: MLBs significantly impacted glycemic outcomes in AID-treated children and adolescents. The results emphasize the importance of maintaining a focus on bolus behavior to achieve a higher TIR and support the need for further research in technological or behavioral support tools to handle MLBs.

Extracellular matrix turnover proteins as risk markers in people with type 2 diabetes and microalbuminuria

BackgroundThis post-hoc study investigated whether biomarkers reflecting extracellular matrix (ECM) turnover predicted cardiovascular disease (CVD), mortality, and progression of diabetic kidney disease (DKD) in individuals with type 2 diabetes (T2D) and microalbuminuria. MethodsSerum levels of specific ECM turnover biomarkers were assessed in 192 participants with T2D and microalbuminuria from an observational study conducted at Steno Diabetes Center Copenhagen from 2007 to 2008. Endpoints included CVD events, mortality, and DKD progression, defined as decline in estimated glomerular filtration rate (eGFR) of >30 %. ResultsParticipants had a mean age of 59 years, with 75 % males. Over a median follow-up of 4.9 to 6.3 years, the study recorded 38 CVD events, 24 deaths, and 40 DKD events. Elevated levels of a degradation fragment of collagen type I (C1M) were associated with an increased risk of >30 % eGFR decline, although this association was not independent of other risk factors. No significant associations were found between other ECM turnover biomarkers and DKD progression, mortality, or CVD risk. ConclusionElevated C1M levels were linked to DKD progression in individuals with T2D and microalbuminuria, but not independently of other risk factors. None of the ECM turnover biomarkers were associated with CVD or mortality.

Effects of 3 months of 10-h per-day time-restricted eating and 3 months of follow-up on bodyweight and cardiometabolic health in Danish individuals at high risk of type 2 diabetes: the RESET single-centre, parallel, superiority, open-label, randomised controlled trial

Time-restricted eating (TRE) has been suggested to be a simple, feasible, and effective dietary strategy for individuals with overweight or obesity. We aimed to investigate the effects of 3 months of 10-h per-day TRE and 3 months of follow-up on bodyweight and cardiometabolic risk factors in individuals at high risk of type 2 diabetes. This was a single-centre, parallel, superiority, open-label randomised controlled clinical trial conducted at Steno Diabetes Center Copenhagen (Denmark). The inclusion criteria were age 30-70 years with either overweight (ie, BMI ≥25 kg/m2) and concomitant prediabetes (ie, glycated haemoglobin [HbA1c] 39-47 mmol/mol) or obesity (ie, BMI ≥30 kg/m2) with or without prediabetes and a habitual self-reported eating window (eating and drinking [except for water]) of 12 h per day or more every day and of 14 h per day or more at least 1 day per week. Individuals were randomly assigned 1:1 to 3 months of habitual living (hereafter referred to as the control group) or TRE, which was a self-selected 10-h per-day eating window placed between 0600 h and 2000 h. Randomisation was done in blocks varying in size and was open for participants and research staff, but outcome assessors were masked during statistical analyses. The randomisation list was generated by an external statistician. The primary outcome was change in bodyweight, assessed after 3 months (12 weeks) of the intervention and after 3 months (13 weeks) of follow-up. Adverse events were reported and registered at study visits or if participants contacted study staff to report events between visits. This trial is registered on ClinicalTrials.gov (NCT03854656). Between March 12, 2019, and March 2, 2022, 100 participants (66 [66%] were female and 34 [34%] were male; median age 59 years [IQR 52-65]) were enrolled and randomly assigned (50 to each group). Of those 100, 46 (92%) in the TRE group and 46 (92%) in the control group completed the intervention period. After 3 months of the intervention, there was no difference in bodyweight between the TRE group and the control group (-0·8 kg, 95% CI -1·7 to 0·2; p=0·099). Being in the TRE group was not associated with a lower bodyweight compared with the control group after subsequent 3-month follow-up (-0·2 kg, -1·6 to 1·2). In the per-protocol analysis, participants who completed the intervention in the TRE group lost 1·0 kg (-1·9 to -0·0; p=0·040) bodyweight compared with the control group after 3 months of intervention, which was not maintained after the 3-month follow-up period (-0·4 kg, -1·8 to 1·0). During the trial and follow-up period, one participant in the TRE group reported a severe adverse event: development of a subcutaneous nodule and pain when the arm was in use. This side-effect was evaluated to be related to the trial procedures. 3 months of 10-h per-day TRE did not lead to clinically relevant effects on bodyweight in middle-aged to older individuals at high risk of type 2 diabetes. Novo Nordisk Foundation, Aalborg University, Helsefonden, and Innovation Fund Denmark.

A comparative study of cardiovascular risk stratification methods in type 1 diabetes mellitus patients

The Steno Diabetes Center Copenhagen developed the Steno T1 Risk Engine (ST1RE) to predict cardiovascular events, encompassing fatal and nonfatal ischemic heart disease, ischemic stroke, heart failure, and peripheral arterial disease in type 1 diabetes mellitus(T1DM).The current study investigated the agreement between ST1RE and the Brazilian Society for Endocrinology and Metabology (SBEM) classification. Participants were included in the study if diagnosed with T1DM and had at least one outpatient visit in 2021. Patients with established cardiovascular disease and chronic kidney disease on dialysis were excluded. Clinical parameters were obtained from medical records, such as age, body mass index (BMI), blood pressure, physical activity, current smoking, microvascular target organ damage, levels of low-density lipoprotein cholesterol, creatinine, glycated hemoglobin (HbA1c), and albuminuria.Overall, 92 patients (38 males and 53 females) with an age median (P25; P75) of 33 years (25.5;42.5), BMI of 24.8 + 4.1 kg/m2, and duration of diabetes (mean ± SD) of 23.4 + 9.5 years were evaluated. There were no differences considering the gender for most analyzed variables, but a higher proportion of women exhibited microvascular complications such as microalbuminuria, macroalbuminuria, and retinopathy. Our results show a weak agreement in the 10-year cardiovascular risk estimation between SBEM and ST1RE classifications. According to SBEM criteria, 72.8% of patients were considered high-risk, while only 15.2% of patients received the same classification using ST1RE. The dissimilarities between these two classifications were also evident when age and gender factors were compared. While 60% of patients under 35 years were classified as high risk according to SBEM criteria, only 1.8% received this stratification risk in the ST1RE classification.The results indicate a low agreement between the 10-year cardiovascular event risk classification by SBEM and the classification by ST1RE for type 1 diabetes patients without established cardiovascular disease.

Randomized Trial of SGLT2 Inhibitor Identifies Target Proteins in Diabetic Kidney Disease

IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as novel therapeutics to treat diabetic kidney disease (DKD). Albeit the beneficial effects of SGLT2i have been demonstrated, their target mechanisms on kidney function are unknown. The current study aimed to elucidate these mechanisms by studying SGLT2i-induced changes in the urinary proteome of persons with type 2 diabetes (T2D) and DKD. Methods40 T2D participants were enrolled in a double blind randomized cross-over trial at the Steno Diabetes Center Copenhagen, Denmark. They were treated with 10 mg of dapagliflozin for 12 weeks. 32 participants with complete urinary proteomics measures before and after the trial were included. All participants received RAS blockade and had albuminuria, (UACR ≥ 30 mg/g). A type 1 diabetes cohort consisting healthy controls and persons with DKD was included for validation. Urinary proteome changes were analyzed using Wilcoxon signed-rank test. Functional enrichment analysis was conducted to discover affected biological processes. ResultsDapagliflozin treatment significantly (Padjusted < 0.05) affected 36 urinary peptide fragments derived from 19 proteins. 18 proteins were correspondingly reflected in the validation cohort. A multi-fold change in peptide abundance was observed in many proteins (A1BG, ALB, CALD1, COLCRNN, HSP90AB1, IGLL5, PI16, PTGDS, SERPINA1). These also included urinary biomarkers of kidney fibrosis and function (type I & III collagens and albumin). Biological processes relating inflammation, wound healing, and kidney fibrosis were enriched. ConclusionThe current study discovers the urinary proteome impacted by the SGLT2i providing new potential target sites and pathways especially relating to wound healing and inflammation.

129-LB: A Comparison of CGM Metrics in People with Type 1 Diabetes Treated with Different Insulin Modalities

Background: There is a lack of real-world data comparing CGM data across different insulin treatment modalities. This study examined the association between CGM-measured glycemic metrics and different insulin treatment modalities in a large type 1 diabetes clinic. Methods: Individuals with type 1 diabetes attending Steno Diabetes Center Copenhagen, Denmark, were eligible for inclusion if they had ≥70% CGM data available within a four-week period within the past year. Participants were divided into four groups based on their insulin treatment: multiple daily injections (MDI +/- alarms), sensor unintegrated insulin pumps (SUP +/- alarms), sensor-augmented insulin pumps (SAP), and automated insulin delivery systems (AID). The latest measured HbA1c and CGM were analyzed. Results: Of 6,319 attendees, 2,689 met the inclusion criteria: 1405 with MDI, 453 with SUP, 307 with SAP, and 524 with AID. Compared to the MDI - alarms group, a clinically relevant lower mean HbA1c was found in the SAP (0.5%; 95% CI:0.3-0.6) and the AID group (0.7%; 95% CI:0.6-0.9) (adjusted for sex, age and diabetes duration). CGM metrics for the four different treatment groups are presented. Conclusion: The results suggest that AID was superior to all other insulin delivering systems with CGM. Although results may be affected by bias due to indication, the expansion of AID use to a wider type 1 population should be considered. Disclosure K. Nørgaard: Advisory Panel; Medtronic, Novo Nordisk, Research Support; Medtronic, Dexcom, Inc., Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; Medtronic, Novo Nordisk, Stock/Shareholder; Novo Nordisk. B. Carstensen: Stock/Shareholder; Novo Nordisk. A. G. Ranjan: None. C. Laugesen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. K. G. Tidemand: None. H. U. Andersen: None. J. Svensson: Other Relationship; Medtronic, Sanofi, Rubin MEdical, Research Support; Novo Nordisk, Medtronic, Stock/Shareholder; Novo Nordisk. C. Selmer: Other Relationship; Boehringer-Ingelheim, Novo Nordisk. A. Green: None. D. Vistisen: Research Support; Bayer Inc., Sanofi, Boehringer-Ingelheim, Stock/Shareholder; Novo Nordisk A/S.

Marker for kidney fibrosis is associated with inflammation and deterioration of kidney function in people with type 2 diabetes and microalbuminuria.

Diabetic kidney disease is a major cause of morbidity and mortality. Dysregulated turnover of collagen type III is associated with development of kidney fibrosis. We investigated whether a degradation product of collagen type III (C3M) was a risk marker for progression of chronic kidney disease (CKD), occurrence of cardiovascular disease (CVD), and mortality during follow up in people with type 2 diabetes (T2D) and microalbuminuria. Moreover, we investigated whether C3M was correlated with markers of inflammation and endothelial dysfunction at baseline. C3M was measured in serum (sC3M) and urine (uC3M) in 200 participants with T2D and microalbuminuria included in an observational, prospective study at Steno Diabetes Center Copenhagen in Denmark from 2007-2008. Baseline measurements included 12 markers of inflammation and endothelial dysfunction. The endpoints were CVD, mortality, and CKD progression (>30% decline in eGFR). Mean (SD) age was 59 (9) years, eGFR 90 (17) ml/min/1.73m2 and median (IQR) urine albumin excretion rate 102 (39-229) mg/24-h. At baseline all markers for inflammation were positively correlated with sC3M (p≤0.034). Some, but not all, markers for endothelial dysfunction were correlated with C3M. Median follow-up ranged from 4.9 to 6.3 years. Higher sC3M was associated with CKD progression (with mortality as competing risk) with a hazard ratio (per doubling) of 2.98 (95% CI: 1.41-6.26; p = 0.004) adjusted for traditional risk factors. uC3M was not associated with CKD progression. Neither sC3M or uC3M were associated with risk of CVD or mortality. Higher sC3M was a risk factor for chronic kidney disease progression and was correlated with markers of inflammation.

Indicators of quality of diabetes care in persons with type 2 diabetes with and without severe mental illness: a Danish nationwide register-based cohort study.

This study aims to examine quality of diabetes care in persons with type 2 diabetes with and without severe mental illness (SMI). In a nationwide prospective register-based study, we followed persons with type 2 diabetes in Denmark with and without SMI including schizophrenia, bipolar disorder, or major depression. Quality of care was measured as receipt of care (hemoglobin A1c, low-density lipoprotein-cholesterol and urine albumin creatinine ratio assessment and eye and foot screening) and achievement of treatment targets between 2015 and 2019. Quality of care was compared in persons with and without SMI using generalized linear mixed models adjusted for key confounders. We included 216,537 persons with type 2 diabetes. At entry 16,874 (8%) had SMI. SMI was associated with lower odds of receiving care, with the most pronounced difference in urine albumin creatinine ratio assessment and eye screening (OR: 0.55, 95% CI: 0.53-0.58 and OR: 0.37 95% CI: 0.32-0.42, respectively). Among those with an assessment, we found that SMI was associated with higher achievement of recommended hemoglobin A1c levels and lower achievement of recommended low-density lipoprotein-cholesterol levels. Achievement of recommended low-density lipoprotein-cholesterol levels was similar in persons with versus without schizophrenia. Compared to persons without SMI, persons with SMI were less likely to receive process of care, with the most pronounced differences in urine albumin creatinine ratio assessment and eye screening. This study was funded by Steno Diabetes Center Copenhagen through an unrestricted grant from Novo Nordisk Foundation.

Diabetes Technology and the Human Factor.

Diabetes Technology and the Human Factor.

Multiomics signatures of type 1 diabetes with and without albuminuria.

To identify novel pathophysiological signatures of longstanding type 1 diabetes (T1D) with and without albuminuria we investigated the gut microbiome and blood metabolome in individuals with T1D and healthy controls (HC). We also mapped the functional underpinnings of the microbiome in relation to its metabolic role. One hundred and sixty-one individuals with T1D and 50 HC were recruited at the Steno Diabetes Center Copenhagen, Denmark. T1D cases were stratified based on levels of albuminuria into normoalbuminuria, moderate and severely increased albuminuria. Shotgun sequencing of bacterial and viral microbiome in stool samples and circulating metabolites and lipids profiling using mass spectroscopy in plasma of all participants were performed. Functional mapping of microbiome into Gut Metabolic Modules (GMMs) was done using EggNog and KEGG databases. Multiomics integration was performed using MOFA tool. Measures of the gut bacterial beta diversity differed significantly between T1D and HC, either with moderately or severely increased albuminuria. Taxonomic analyses of the bacterial microbiota identified 51 species that differed in absolute abundance between T1D and HC (17 higher, 34 lower). Stratified on levels of albuminuria, 10 species were differentially abundant for the moderately increased albuminuria group, 63 for the severely increased albuminuria group while 25 were common and differentially abundant both for moderately and severely increased albuminuria groups, when compared to HC. Functional characterization of the bacteriome identified 23 differentially enriched GMMs between T1D and HC, mostly involved in sugar and amino acid metabolism. No differences in relation to albuminuria stratification was observed. Twenty-five phages were differentially abundant between T1D and HC groups. Six of these varied with albuminuria status. Plasma metabolomics indicated differences in the steroidogenesis and sugar metabolism and circulating sphingolipids in T1D individuals. We identified association between sphingolipid levels and Bacteroides sp. abundances. MOFA revealed reduced interactions between gut microbiome and plasma metabolome profiles albeit polar metabolite, lipids and bacteriome compositions contributed to the variance in albuminuria levels among T1D individuals. Individuals with T1D and progressive kidney disease stratified on levels of albuminuria show distinct signatures in their gut microbiome and blood metabolome.

Non-dipping and higher nocturnal blood pressure are associated with risk of mortality and development of kidney disease in type 1 diabetes

AimsPeople with type 1 diabetes have increased risk of cardiovascular (CV) and kidney disease. A 24-hour ambulatory blood pressure (BP) measurement (ABPM) examines diurnal variations in BP. We aimed to determine the prognostic significance of blunted decrease in nocturnal systolic BP of <10 % (non-dipping of nocturnal BP) for CV- and kidney disease and all-cause mortality in type 1 diabetes. MethodsFrom 2009 to 2011, at Steno Diabetes Center Copenhagen, 654 participants with type 1 diabetes had 24-hour ABPM obtained with a tonometric wrist-watch device (BPro, HealthStats, Singapore). In 2017, outcomes (composite CV endpoint; all-cause mortality; decline in estimated glomerular filtration rate (eGFR) ≥30 %; end-stage kidney disease (ESKD); and a composite kidney endpoint including decline in eGFR ≥30 %, ESKD and all-cause mortality) were registered. Hazard Ratios (HR) were calculated using Cox regressions. ResultsParticipants were mean ± SD 55 ± 13 years old and had median (IQR) 35 (24–44) years diabetes duration. Mean daytime and nocturnal systolic BP were 133 ± 16 and 121 ± 16 mmHg while 337 (52 %) participants demonstrated non-dipping. After CV risk factor adjustments, non-dipping was associated with all-cause mortality (HR 2.12 (1.09–4.11), p = 0.03) and the composite kidney endpoint (HR 1.92 (1.23–3.00), p = 0.004). ConclusionsNon-dipping entailed increased risk of all-cause mortality and kidney disease in type 1 diabetes.

Improving the Patient Experience With Longer Wear Infusion Sets Symposium Report.

Continuous subcutaneous insulin infusion (CSII) therapy is becoming increasingly popular. CSII provides convenient insulin delivery, precise dosing, easy adjustments for physical activity, stress, or illness, and integration with continuous glucose monitors in hybrid or other closed-loop systems. However, even as insulin pump hardware and software have advanced, technology for insulin infusion sets (IISs) has stayed relatively stagnant over time and is often referred to as the "Achilles heel" of CSII. To discuss barriers to insulin pump therapy and present information about advancements in, and results from clinical trials of extended wear IISs, Diabetes Technology Society virtually hosted the "Improving the Patient Experience with Longer Wear Infusion Sets Symposium" on December 1, 2021. The symposium featured experts in the field of IISs, including representatives from Steno Diabetes Center Copenhagen, University of California San Francisco, Stanford University, Medtronic Diabetes, and Science Consulting in Diabetes. The webinar's seven speakers covered (1) advancements in insulin pump therapy, (2) efficacy of longer wear infusion sets, and (3) innovations to reduce plastics and insulin waste.

Advances in Insulin Pump Infusion Sets Symposium Report.

Continuous subcutaneous insulin infusion (CSII) is becoming increasingly used for achieving target glycemic control as well as providing flexibility in lifestyle. In a widely used version of CSII, the insulin pump itself is attached to one end of an insulin infusion set (IIS), which delivers insulin via a thin flexible plastic tube to the patient's body via a cannula or needle that is inserted under the skin at the other end of the IIS. Despite the increased use of CSII by patients with diabetes, there have been few recent advances in IIS technology, especially when compared to the many recent advances made in insulin pump technology and in insulin pharmacokinetics. To discuss recent developments in, and future plans for IIS development, Diabetes Technology Society virtually hosted the Advances in Insulin Pump Infusion Sets Symposium on December 1, 2020. This symposium featured experts in the field of IISs, including representatives from Medtronic and ConvaTec (which are two manufacturers that are currently developing IISs), Stanford University, Steno Diabetes Center Copenhagen, and Science Consulting in Diabetes. The webinar's six speakers covered (1) patient burden, (2) extended wear technology, and (3) future directions in IIS development.

Copeptin and renal function decline, cardiovascular events and mortality in type 1 diabetes.

Plasma copeptin is a surrogate of arginine vasopressin (AVP) secretion and is associated with a risk of renal and cardiovascular disease. We investigated associations between copeptin and renal events, cardiovascular events and mortality in type 1 diabetes (T1D). We conducted a prospective cohort study on 658 individuals with T1D from Steno Diabetes Center Copenhagen. Plasma copeptin concentrations and conventional risk factors were assessed at baseline. The five endpoints were traced through national registries and electronic laboratory records. Baseline mean age was 55 ± 13 years and estimated glomerular filtration rate (eGFR) was 81 ± 26 mL/min/1.73 m2. The median follow-up was 6.2 years (interquartile range 5.8-6.7); 123 participants reached a combined renal endpoint [decline in eGFR ≥30%, end-stage kidney disease (ESKD) or all-cause mortality], 93 had a decrease in eGFR ≥30%, 21 developed ESKD, 94 experienced a combined cardiovascular endpoint and 58 died from all causes. Higher copeptin was associated with all endpoints in unadjusted Cox regression analyses. Upon adjustment for baseline eGFR, the associations were attenuated and remained significant only for the combined renal endpoint and decrease in eGFR ≥30%. Results were similar upon further adjustment for other risk factors, after which hazard ratios for the two renal endpoints were 2.27 (95% confidence interval 1.08-4.74) and 4.49 (1.77-11.4), respectively, for the highest versus the lowest quartile of copeptin. Higher copeptin was an independent risk marker for a combined renal endpoint and decline in renal function. AVP may be a marker of renal damage or a factor whose contribution to renal and cardiovascular risk is partially mediated by renal damage.

Abstract 14182: Genome Wide Association Study for High Sensitive Cardiac Troponin T Levels Identifies a Novel Gene in Europeans With Type 1 Diabetes

Introduction: Adults with diabetes have a two to four folds increased risk of dying with heart disease compared to those without diabetes. Higher cardiac troponins, especially Troponin T (TnT) is a specific biomarker for cardiac injury also guiding management of chest pain and associated with increased risk of heart failure. Hypothesis: There is limited knowledge on genes regulating cardiac TnT levels. We conducted a genome wide association study (GWAS) for circulating cardiac TnT levels among individuals with type 1 diabetes (T1D). Methods: The study included 849 T1D individuals recruited from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Serum high sensitive TnT (hsTnT) levels were measured and log transformed for normalization after check for outliers (mean ± 4 SD). Genotyping on 538,448 single nucleotide variants (SNVs) was done using Illumina Human Core Exome Chip. After quality control filters: hardy weinberg equilibrium (p &gt;10 -6 ), European ancestry, genotype call rates &gt;95%, common variants were examined in 740 individuals with hs TnT data. We ran linear regression based additive genetic models adjusting for age, sex, diabetes duration and population sub structure using Plink and R statistical programs. P &lt;5 x 10 -8 was genome wide significant (GWS) while 5 x 10 -8 &lt; p &lt; 1 x 10 -6 was considered suggestive. Results: Participants had a mean (SD) age of 43.7 (11.1) years, 57.4% were men, with diabetes duration of 28.0 (9.5) years, HbA1c 8.9 (1.3) % and 50.5% with diabetic nephropathy. Median (IQR) hsTnT levels were 64.7 (29.2-175.6) pg/ml. We identified a GWS missense common variant in the CISD3 gene locus on chromosome 17 (p=1.7 x 10 -8 ) for cardiac hsTnT levels. This gene codes CDGSH Iron Sulfur Domain 3 protein also called Mitochondrial Inner NEET Protein. Two suggestive loci were PTPRD (Protein Tyrosine Phosphatase Receptor Type D; p=4.9 x 10 -7 ) and DCC (DCC Netrin 1 Receptor; 6.6 x 10 -7 ) on chromosomes 9 and 18. PTPRD is a known GWS locus for hsTnT that we reconfirm among T1D individuals. Conclusions: We identify a novel gene locus for circulating cardiac hsTnT levels among T1D individuals of European ancestry. CISD3 is expressed in heart tissue regulating mitochondrial functions. Further validation is suggested.

The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial

We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c. The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25kg/m2, 30-70years of age, and prediabetes (HbA1c 39-47mmol/mol [5.7-6.4%]) were randomised 1:1:1:1 to dapagliflozin (10mg once daily), metformin (1700mg daily), interval-based exercise (5days/week, 30min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26weeks after randomisation. The primary outcome was the 13week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). One hundred and twelve participants attended the examination at 13weeks and 111 attended the follow-up visit at 26weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI -1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI -16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI -1.1, 29.1; p = 0.065) lower in the exercise group after 13weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI -14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain. ClinicalTrials.gov NCT02695810 FUNDING: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS Graphical abstract.

Quality assessment of a screening algorithm for diabetic retinopathy: prolongation of screening intervals with minimal effect of HbA1c and arterial hypertension on the length of intervals.

At Steno Diabetes Center Copenhagen (SDCC), diabetic retinopathy (DR) screening intervals are based on quantification of retinal lesions. Screening intervals are, for the milder forms of DR, prolonged to 2-3years. The purpose of the present study was to evaluate the effect of the prolongation on developing unexpected events and to evaluate the effect of HbA1c and arterial hypertension. We assessed 18972 screening intervals from 6000 patients from 1/1-2003 to 1/5-2017 for occurrence of unexpected events, defined as: (1) DR progression requiring treatment, at the following screening date, and (2) DR-related hospital contact within the planned interval. We modelled the effect of several risk factors for developing unexpected events in a Cox regression. Furthermore, we assessed the risk of unexpected events in a logistic regression analysis using cubic splines to model the effect of HbA1c , stratified by arterial hypertension status. 16283 (86%) intervals followed the planned interval and among those, only 86 (0.5%) experienced unexpected events. Intervals of dysregulated patients (86% of all intervals) did not experience more unexpected events, compared with well-regulated patient intervals (Hazard Ratio: 1.12, 95% CI: 0.55-2.27). We found a nonlinear effect of HbA1c on the risk of unexpected events which peaked around HbA1c levels of 80mmol/mol. Having arterial hypertension slightly increased the risk of unexpected events. The present study supports the validity of the current algorithm. We found no increased risk of unexpected events among dysregulated intervals but a nonlinear effect of HbA1c . Age, diabetes duration and diabetes type were significantly associated with unexpected events.

Sex differences in the association between myocardial function and prognosis in type 1 diabetes without known heart disease: the Thousand & 1 Study.

In type 1 diabetes mellitus (T1DM), recent findings suggest that women have a greater excess risk of cardiovascular diseases (CVDs) compared to men. Impaired diastolic function is a common feature in T1DM. We investigated the association between myocardial function by echocardiography and outcomes in T1DM males and females without known heart disease. A prospective cohort of individuals with T1DM without known heart disease from the outpatient clinic of Steno Diabetes Center Copenhagen. Follow-up was performed through Danish national registers. Outcomes, major adverse cardiovascular events (MACE) and all-cause mortality, were investigated. A total of 1079 participants (mean age: 49.6 ± 14.5 years, 52.6% male, mean duration of diabetes 25.8 ± 14.6 years) were included in the study. During follow-up (median 6.3 years, interquartile range 5.7-6.9), 142 (13.2%) experienced MACE and 63 (5.8%) died. Gender modified the relationship between E/e' and both MACE and all-cause mortality (P = 0.016 and 0.007, respectively). In females, after multivariable adjustment, both E/e' and global longitudinal strain (GLS) were significantly associated with MACE [E/e': hazard ratio (HR) 1.15 confidence interval (CI) 95%: 1.07-1.24, per 1unit increase; and GLS: HR 1.19 CI 95%: 1.04-1.35, per 1% decrease] and with all-cause mortality (E/e': HR 1.26 CI 95%: 1.11-1.44; and GLS: HR 1.27 CI 95%: 1.03-1.56). In males, the association between E/e' and GLS and outcomes did not reach statistical significance. In female individuals with T1DM both E/e' and GLS provided independent prognostic information, whereas the associations were not significant in males. These results suggest that T1DM affects myocardial function differently in males and females, which may be related to the observed sex difference in CVD risk in T1DM.

2153-PUB: Deep Learning and Laterality of Retinal Images

Background: Retinal fundus images, obtained from routine eye screenings, contain important information, not only concerning microvascular lesions of the retina, but potentially also of the progression and manifestation of various other diabetes complications. Recent advances in the field of machine learning, so-called deep learning neural networks (DNN), make it possible to automatically detect retinal lesions from fundus photos. Our overall aim is to develop a DNN to detect retinal vascular lesions. In this abstract, we describe a pre-processing step consisting of application of a DNN. Methods: For each eye, 5 retinal images of parts of the eye are taken, and collected into a joint mosaic image, used for image grading. There is no automated labelling of the images to identify left or right eyes. To distinguish left- from right eye images, we used a set of 1,916 unique, high-definition retina mosaic fundus images from diabetes patients followed at Steno Diabetes Center Copenhagen (SDCC) between 2003-2017. We trained and validated a DNN, using 964 left-eye (training set: 713, validation: 251) and 952 right-eye images (training set: 706, validation: 246). A DNN is a method that finds the optimal algorithm for relating a large set of input (mosaic fundus images) to output (left or right eye). The DNN used was based on the InceptionV3 architecture and run for 100 epochs with 100 gradient descent steps pr. epoch. Results: The DNN classification obtained a validation AUC-ROC of 0.92 and a validation accuracy of 0.86. Conclusions: The DNN successfully distinguished left-eye from right-eye images. We plan to use the DNN to identify right- and left-eye images in the SDCC image database comprising ∼ 80,000 left-eye and right-eye images. We will subsequently develop a DNN for automated detection of referable diabetic retinopathy of retinal fundus images, for use in the clinic. Disclosure L. Díaz: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. M. Valerius: None. J.N. Hajari: None. H. Lund-Andersen: None. S. Byberg: None.