bluuebunny/crossref_metadata_2025_split huggingface dataset:
396-P: Real-Life Evaluation of Sodium–Glucose Cotransporter 2 Inhibition in Type 1 Diabetes
Authors: STOUGAARD ELISABETH BUUR , KRISTENSEN PETER L. , KIELGAST URD , ANDERSEN SR., HENRIK U. , HAMID YASMIN H. , GÆDE PETER , SØNDERGAARD ESBEN , DØRFLINGER GRY , FJELDBORG KAREN K. , HANSEN KLAVS W. , THOMSEN HENRIK H. , AL-IMARI THURAYA , RØDER MICHAEL , ROSSING PETER , PERSSON FREDERIK 
Published: May 2022

Background: The indication for treatment of type 1 diabetes (T1D) with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been withdrawn from the European market likely because of concern for diabetic ketoacidosis (DKA) . We aimed to calculate the incidence of DKA in people with T1D treated with SGLT2i in Denmark.
Methods: The study is based on clinical data from adults with T1D in Denmark, diagnosed according to the treating specialist and carefully selected for treatment with SGLT2i. Data were collected from nine outpatient clinics. Our National electronic health record system makes it is possible to search for a specific diagnosis both in an outpatient setting and during hospitalization, which makes the search for DKA accurate.
Results: From a population of 10.500 adults with T1D followed at the nine sites, we observed 134 people treated with SGLT2i over a total period of 222 patient years. Of them 72% were female, mean age (SD) was 51.4 (13.6) years and median duration of treatment (median, IQR) with an SGLT2i were 12.0 (6.0-29.0) months. The incidence of DKA was 0%.
Conclusion: In this retrospective observational study based on reported data from nine participating centers in Denmark in 134 people with T1D treated with SGLT2i we found that none of the participants developed DKA during the treatment.

Disclosure
E.Buur stougaard: Other Relationship; Novo Nordisk. K.W.Hansen: Advisory Panel; Abbott Diagnostics. H.H.Thomsen: Other Relationship; Boehringer Ingelheim International GmbH. T.Al-imari: None. M.Røder: None. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. F.Persson: Advisory Panel; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. P.L.Kristensen: Speaker's Bureau; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. U.Kielgast: Advisory Panel; Abbott, Eli Lilly and Company, Mundipharma, Novo Nordisk, Sanofi, Consultant; Boehringer Ingelheim International GmbH, Other Relationship; Boehringer Ingelheim International GmbH, Novo Nordisk, Novo Nordisk. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. Y.H.Hamid: n/a. P.Gæde: Advisory Panel; AstraZeneca, Research Support; Novo Nordisk. E.Søndergaard: None. G.Dørflinger: None. K.K.Fjeldborg: Other Relationship; AstraZeneca.
398-P: KIM-1 and TNFR 1 and Associations with Early Diabetic Nephropathy Histology
Authors: TIAN FRANCES , PRINCE DAVID , DORIA ALESSANDRO , MAUER MICHAEL , KESTENBAUM BRYAN 
Published: May 2022

Aim: GFR and urine albumin excretion (UAE) are prevailing measures used to detect and monitor diabetic nephropathy (DN) . We tested whether serum kidney injury molecule-1 (KIM-1) and tumor necrosis factor receptor-1 (TNFR1) , markers of DN progression, are associated with DN renal structural parameters in persons with TIDM.
Methods: We measured KIM-1 and TFNR1 in 285 participants from the Renin Angiotensin System Study (RASS) . Participants had T1DM for 2-20 yrs and were free of any clinical DN. Baseline iGFR and kidney biopsies were obtained. We used linear regression to estimate cross-sectional associations of markers with renal structural measures.
Results: Mean age was 30 ± yrs; mean iGFR was 125 ± 18 ml/min/1.73 m2; median UAE was 5 (IQR 4- 7) . Higher KIM-1 was associated with significantly greater mesangial fraction volume [Vv (Mes/glom) ] and the tubular atrophy (table 1) . Higher TNFR1 was associated with significantly higher Vv (Mes/glom) and glomerular basement membrane (GBM) width. Neither iGFR nor UAE were significantly associated with lesions.
Conclusion: Serum KIM-1 and TNFR1 were associated with higher values for Vv (Mes/glom) , GBM, and tubular atrophy in persons with T1DM and normal kidney function, suggesting relevance as markers of early DN structural changes prior to UAE elevation or GFR decline. KIM-1 is specific to the tubules, highlighting the importance of characterizing the natural history of tubular functions in DN.

Disclosure
F.Tian: None. D.Prince: None. A.Doria: Research Support; Novo Nordisk Foundation. M.Mauer: None. B.Kestenbaum: Consultant; Reata Pharmaceuticals, Inc.

Funding
T32
402-P: Machine Learning Approach to Evaluate the Prospective Kidney Failure Risk of the Complement Proteome in T1D
Authors: DOM ZAIPUL MD , MOON SALINA , PICKETT SARA , DILLON SIMON , NIEWCZAS MONIKA 
Published: May 2022

We tested the Complement proteome’s prognostic accuracy for kidney outcomes in T1D using a machine learning (ML) approach.
Methods: This prospective cohort study comprised 193 Joslin Kidney Study subjects with T1D and an overt diabetic kidney disease at baseline followed for years. We performed urinary measurements of the Complement proteins (n=82) using aptamer proteomics. The outcomes of interest included developing end-stage kidney disease (ESKD) in or 3 years and a kidney slope. We tested biostatistical logistic regression (LR) and 7 ML models (principal component (PCA) ; decision tree: random forest (RF) and generalized boosting (GB) ; penalized regression: elastic net (EN) , lasso (LS) and ridge (RD) ; and neural network (NN)) .
Results: The LR model with the top protein had decent model accuracy (c=0.80-0.86) across the kidney outcomes, which was further improved in the ML model with proteins (PCA) . The performance of the 7 ML was comparable or higher with the best ML model being EN (AUC=0.80-0.90) . Accuracy was better for the shorter follow-up period or slope-based outcomes (Figure 1) . Models fed with 82 proteins did not much improve performance.
Conclusions: Multiple Complement proteins are strongly associated with short-to-long term kidney outcomes in T1D and offer attractive prognostic accuracy in ML models to complement biostatistical tools.

Disclosure
Z.Md dom: None. S.Moon: None. S.Pickett: None. S.Dillon: None. M.Niewczas: None.

Funding
National Institutes of Health (RO1 DK123459) Beatson FoundationHearst Foundation
404-P: Relationships among Triglyceride (TG) Concentrations across Lipoprotein Subclasses, Intraglomerular Hemodynamics, and Kidney Oxygen Availability in Adolescents with Type 1 Diabetes (T1D)
Authors: PAULEY MEGHAN E. , TOMMERDAHL KALIE L. , VINOVSKIS CARISSA , PYLE LAURA , WADWA R. PAUL , NELSON ROBERT G. , NADEAU KRISTEN J. , BJORNSTAD PETTER 
Published: May 2022

TG concentrations across lipoprotein subclasses associate with diabetic kidney disease (DKD) in adults with T1D, but little is known about this relationship in youth with T1D. We evaluated cross-sectional relationships among TG concentrations across lipoprotein subclasses, intraglomerular hemodynamics, and renal oxygen availability (RO2) in youth with T1D. Glomerular filtration rate (GFR) , RO2, renal plasma flow (RPF) , afferent arteriolar resistance (RA) , efferent arteriolar resistance (RE) , intraglomerular pressure (PGLO) , and urine albumin-to-creatinine ratio (UACR) were assessed. Concentrations of lipid constituents from lipoprotein subclasses were quantified via targeted nuclear magnetic resonance spectroscopy (Nightingale Health Ltd., Helsinki, Finland) . Particle sizes for VLDL, LDL, intermediate-density lipoprotein, and HDL were measured. Fifty youth with T1D (age 16.0 ± 3.0 years, 50% female, HbA1c 8.7 ± 1.3%, T1D duration 5.7 ± 2.6 years) and 20 without T1D were included. VLDL-TG concentrations and small LDL-TG correlated with intraglomerular hemodynamic function parameters and RO2. To conclude, strong relationships were found among renal function markers and TG concentrations across lipoprotein subclasses in adolescents with T1D.

Disclosure
M.E.Pauley: None. K.L.Tommerdahl: None. C.Vinovskis: None. L.Pyle: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.

Funding
MEP supported by NIH (T32DK063687) ; KLT supported by NIH (K23 HL159292) , Children’s Hospital Colorado Research Institute Research Scholar Award, University of Colorado Diabetes Research Center (P30 DK116073) , Ludeman Family Center for Women’s Health Research at the University of Colorado, and Dept of Pediatrics, Section of Endocrinology at University of Colorado School of Medicine; PB supported by NIDDK (RDK129211, R21 DK129720, K23 DK116720, UC DK114886, and P30 DK116073) , JDRF (2-SRA-2019-845-S-B, 3-SRA-2017-424-M-B, 3-SRA-2022-1097-M-B) , Boettcher Foundation, American Heart Association (20IPA35260142) , Ludeman Family Center for Women’s Health Research at the University of Colorado, Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine
408-P: Fibrosis 4 Index Related to Microalbuminuria in Tibetan Patients with T2D and NAFLD
Authors: ZHANG CHENGHUI 
Published: May 2022

Aim: The co-existence of type 2 diabetes (T2D) with nonalcoholic fatty liver disease (NAFLD) significantly increases the prevalence of advanced fibrosis and end-stage liver disease, as well as cardiovascular disease risk and mortality. Fibrosis 4 (FIB-4) index has been described as a non-invasive marker to detect liver fibrosis, based on several laboratory texts (AST/ALT/Platelets) . This study aimed to explore the relationship between FIB-4 index and macroalbuminuria in patients with T2D and NAFLD.
Methods: This cross-sectional utilized data in Tibetan patients with T2D and NAFLD from 2020-2021. Patients were divided into two groups based on FIB-4 index (group 1: FIB-4&lt;1.45; group 2: FIB-4≥1.45) . Reduced eGFR was defined as eGFR &lt;60 ml/min per 1.73 m2 and macroalbuminuria was defined as urinary albumin/creatine ≥ 300 mg/g.
Results: A total of 362 patients were recruited. Clinical characteristics of subjects were showed in Table 1. In Multiple logistic regression analysis, compared to patients with FIB-4 &lt;1.45, those with FIB-4 ≥ 1.45 were at a 2.26-fold (95% CI:1.08-4.73) for macroalbuminuria, after adjusted for age, gender, duration of T2D, BMI, LDL-C, HbA1c and hypertension. However, FIB-4 index was not associated with reduced eGFR (OR: 2.34, 95% CI: 0.89-6.18) .
Conclusions: Our finding showed that an increase in FIB-4 index was independently associated with macroalbuminuria in T2D patients with NAFLD.

Disclosure
C.Zhang: None.
418-P: Certain Patient Subgroups with Type 2 Diabetes May Benefit from Intensive Glycemic and Blood Pressure Control from Reductions in Major Adverse Cardiovascular Events (MACE) : A Machine Learning–Based Post Hoc Analysis of ACCORD Trial Data
Authors: KIANMEHR HAMED , ZHANG PING , OSPINA NAYKKY SINGH , SHI LIZHENG , FONSECA VIVIAN , GUO JINGCHUAN , SHAO HUI 
Published: May 2022

Negative or neutral treatment effects reported in many clinical trials reflect average treatment effects in the trial population and may mask heterogeneous treatment effects across patient subgroups. Machine learning (ML) methods are valuable tools to study these treatment heterogeneities. Using ML methods and data collected in the ACCORD trial, we identified patient subgroups that might benefit from intensive glycemic and blood pressure intervention. The ACCORD found that intensive glucose (A1c &lt;6.0% vs. A1c 7.0% to 7.9%) and SBP (&lt;120 mmHg vs. &lt;140 mmHg) control did not significantly reduce CVD risks. We reanalyzed data from 10,251 participants from the glucose trial and 4,733 from the SBP sub-trial separately. We used Major Adverse Cardiovascular Events (MACE) as our CVD outcome. We applied causal forest (CF) and causal tree (CT) models to identify participant characteristics that modulate the effectiveness of intensive glycemic and SBP intervention from a list of 48 candidate variables (demographics, disease histories, medications, and biomarkers) at the study baseline. Compared to controls, intensive SBP intervention reduced MACE in those with normal HDL (women &gt;55 mg/dL, men &gt;45 mg/dL; relative risk [RR] 0.51, 95% CI: 0.34-0.74%) and those with LDL &gt;100 mg/dL (RR: 0.74, 95% CI: 0.59-0.94) , but had no significant effects in other patient groups. Intensive glycemic control reduced MACE in those with baseline A1c &lt;8.5% (RR: 0.79, 95% CI: 0.67-0.93) and those with glomerular filtration rate &gt;1mL/min/1.73m2 (i.e., highest quartile; RR: 0.74, 95% CI: 0.55-0.99) ; reductions were not significant in other patient groups. Our findings may assist clinicians in developing a more precise approach to managing persons with type 2 diabetes at high risk of CVD events. Future clinical trials may be needed to confirm these findings.

Disclosure
H.Kianmehr: None. P.Zhang: None. N.Singh ospina: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
42-LB: Distress in Living with Diabetes Links to Age, Sex, Weight, and Good Glycaemic Control
Authors: HEALD ADRIAN H. , WAHEED UNAIZA , STEDMAN MICHAEL , PAISLEY ANGELA N. , SOLOMON EMMA 
Published: May 2022

Diabetes impacts on mental health. We investigated patient characteristics of those most at risk and consequences for glycaemic control.
Depression (PHQ-9) , Diabetes Distress Screening Scale (DDSS) and Quality of Life (EQ5D) on-line questionnaires were completed by people with diabetes and linked to data extracted data from responders’ clinical records. Sources of distress were also considered through evaluating sub-scales Emotional, Physician, Regimen and Interpersonal DDSS scores.
130 responses with 34% T1DM, 56% women, median age 59 (IQR47-67) years were recorded. The median scores were EQ5D=0.74 (IQR 0.64 - 0.85) UK median 0.83; DDSS=1.9 (IQR1.3-2.7) (≥2 indicates moderate distress) and PHQ9=5 (IQR2-11) (≥5 indicates depression) .
Higher DDSS/lower EQ5D5L/higher PHQ-9 within the response group were linked to female sex (DDSS 0.5/25% above median) , younger age (&lt;50years DDSS 0.7/35% above median) , fewer years after diagnosis (&lt;10years DDSS 0.8/40% above median) , and obesity (BMI&gt;35 DDSS 0.6/30% above median) .
33 people with good (HbA1c≤48mmol/mol) or improving glycaemic control (HbA1c reduced by 2mmol/mol since previous reading) had higher DDSS = 2.4 versus the others = 1.9.
The link between individual DDSS and PHQ-9 scores was significant r2=0.4, while the association to EQ5D was less r2=0.11. For 30 people with history of anti-depressant medication use, DDSS was 0.9/45% above median, showing medical diagnosis confirmed self-reported distress.
DDSS scores did not significantly link to diabetes type or insulin use.
Physician related DDSS higher scores came from women, younger age, overweight, early years after diagnosis, plus history of antidepressant use. This is potentially remediable.
Level of distress is associated/maybe required in achieving and maintaining lower HbA1c. The impact on mental health of younger women/people with shorter diabetes duration should be noted when considering psychosocial intervention/behaviour change messaging.

Disclosure
A. H. Heald: None. U. Waheed: None. M. Stedman: None. A. N. Paisley: None. E. Solomon: None.
44-LB: Evaluating the Effectiveness of a Novel Form of Online Cognitive Behavioural Therapy for Patients with Type 2 Diabetes and Comorbid Anxiety or Depression
Authors: HAYES ANN G. , CATARINO ANA , MEHEW SHAUN , BLACKWELL ANDREW 
Published: May 2022

Mental health disorders like depression and anxiety are highly prevalent in people with diabetes and are associated with poorer outcomes. The current study investigated the effect of a novel online cognitive behavioural therapy (CBT) based intervention derived from Acceptance and Commitment Therapy (ACT) for people with type 2 diabetes. A total of 102 patients with type 2 diabetes and a concomitant mental health disorder completed a course of the novel CBT-based intervention, delivered one-to-one over the internet, using text, by therapists who were specially trained in diabetes. Patients showed pre-treatment scores indicative of moderate to severe depression and anxiety and clinically significant diabetes distress. The treatment paradigm caused statistically significant and clinically meaningful decreases in depression, anxiety and diabetes distress scores. Changes in patient activation further illustrated the degree of improvement seen, with the proportion of patients at the lowest level of activation decreasing from 44.1% to 23.5%, pre- to post-treatment, and half of patients increasing by at least one level of activation. Comparisons between the study group and different synthetic control groups, derived from real-world data obtained using the same online platform as used for the trial, underlined the marked improvements achieved - recovery rates of 76% in the study group compared to 56% and 68% in the synthetic control arms. This study demonstrates that this novel CBT-based treatment, delivered by therapists who have specialism in the disease, provides an integrated therapy which can deliver substantial clinical benefit to patients with diabetes and comorbid mental health problems. Moreover, because it is delivered online, it can be given at a time and place that is convenient to both patients and therapists.

Disclosure
A. G. Hayes: Consultant; Ieso Digital Health Ltd. A. Catarino: Employee; ieso. S. Mehew: None. A. Blackwell: Employee; IESO.

Funding
Roche Diabetes Care Limited
442-P: Sorbs2 Deficiency–Mediated Vascular BK Channel Dysfunction in Type 2 Diabetes
Authors: LU TONG 
Published: May 2022

Vascular BK channels, composed of the pore-forming α-subunits (BK-α) and the regulatory β1 subunits (BK-β1) , is a key determinant of vasoreactivity, and its function is impaired in diabetes. However, our understanding of the mechanisms causing BK channel dysfunction in diabetic vessels is incomplete. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is abundantly expressed in vascular smooth muscle cells (SMCs) . We hypothesize that Sorbs2 is critical for vascular BK channel physiology. In this study, we compared vascular BK channel function between Sorbs2 KO and WT mice at 4 months of age. There was no difference in body weight and blood glucose between WT and Sorbs2 KO mice (body weight: 25.9±1.3 g of WT vs. 23.3±1.5 g of KO, n=14, p=N.S.; blood glucose: 166.4±7.7 mg/dL of WT vs. 152.2±12.2 mg/dL of KO, n=14, p=N.S.) . However, Sorbs2 KO mice have markedly reduced cell surface and cytoplasmic expression of BK-α and BK-β1, as well as BK channel-mediated vasodilation in carotid arteries with a maximal dilatation of 64.70±1.92% for WT mice (n=4) and 20.74±4.66% for KO mice (n=5, p&lt;0.05) . Patch clamp experiments revealed that BK channel sensitivity to Ca2+ activation was impaired in the coronary SMCs of Sorbs2 KO mice (EC50: 2.87±0.68 µM, n=13, p&lt;0.05) with decreased Hill coefficient (nH: 1.26) , compared to those of WT mice (EC50: 0.48±0.µM, nH: 2.70, n=13) . In vivo studies showed that Sorbs2 interacted with BK-α and BK-β1 protein in vascular SMCs. Silencing of Sorbs2 by shRNA decreased BK-α and BK-β1 expression, while adenoviral expression of Sorbs2 increased BK-α and BK-β1 expression in vascular SMCs. Most importantly, Sorbs2 expression was significantly reduced in the arteries of db/db type 2 diabetic mice and high fat diet-induced diabetic mice. Our results indicate that Sorbs2 plays an important role in regulating BK channel function and expression in vascular SMCs. Sorbs2 deficiency is a risk factor of BK channelopathy and vasculopathy in diabetes, independent of obesity and glucotoxicity.

Disclosure
T.Lu: None.
447-P: C/EBPß-Lin28a Positive Feedback Loop Mediated by C/EBPß Hypomethylation Promotes the Proliferation and Migration of Vascular Smooth Muscle Cells in Restenosis
Authors: JIANG SHAN , ZHOU XIAOJUN , ZHANG QIAN , GUO SIYI , SHENG QIQI , LI XIANZHI , ZHANG RUI , XU CHUNMEI , GONG PIYUN , LIAO LIN , DONG JIANJUN 
Published: May 2022

Background: The main reason for restenosis (RS) after percutaneous transluminal angioplasty is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs) . C/EBPβ plays an important role in the process of vascular remodeling. However, the role of C/EBPβ in RS has not been clarified.
Methods: The type 2 diabetes rat models of RS and atherosclerosis (AS) were established to detect the difference in DNA methylation and expression levels of C/EBPβ. Simultaneously, the effect of C/EBPβ on the proliferation and migration of VSMCs was clarified by regulating C/EBPβ and Lin28a in vitro. The effect of decitabine, a demethylating agent, on the expression of C/EBPβ and Lin28a, and the further regulation of VSMCs proliferation and migration was confirmed.
Results: C/EBPβ was highly expressed and had a lower methylation level in RS compared with AS. In vitro C/EBPβ overexpression facilitated the proliferation and migration of VSMCs with increased expression of Lin28a. Conversely, C/EBPβ knockdown resulted in opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to the promoter of Lin28a. Furthermore, increased expression of C/EBPβ and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. And mechanical stretch promoted the expression of C/EBPβ and Lin28a. Additionally, C/EBPβ expression increased following the overexpression of Lin28a. The reversed result was found in the Lin28a knockdown cells.
Conclusion: Our results have demonstrated that C/EBPβ expression is regulated partly by DNA methylation. Meanwhile, as a transcription factor, C/EBPβ promotes the transcription of Lin28a and enhances the proliferation and migration of VSMCs through a positive feedback loop between the two. Our study suggests C/EBPβ-Lin28a axis is a driver of the RS progression, providing a promising therapeutic strategy for RS.

Disclosure
S.Jiang: n/a. L.Liao: None. J.Dong: None. X.Zhou: n/a. Q.Zhang: None. S.Guo: None. Q.Sheng: None. X.Li: None. R.Zhang: None. C.Xu: None. P.Gong: None.

Funding
National Natural Science Foundation of China Grants (81800732,81670757,82170824) , Shandong Provincial Medicine and Health Science and Technology Development Program (No.202103060766) and Shandong Provincial Hospital Research incubation Fund (No.2021FY059)