bluuebunny/crossref_metadata_2025_split huggingface dataset:
354-P: Interstitial Fluid Glucose as a Measure of Hypoglycemia Burden in Elderly Subjects with Type 2 Diabetes Mellitus
Authors: TIAN KRISTY , ANG LI C. , BEE YONG MONG , GOH SU-YEN , TEH MING M. 
Published: June 2021

Background: Elderly patients with type 2 diabetes mellitus (T2DM) are at high risk of severe hypoglycemia, but evidence addressing this problem is lacking.
Aims: To assess and compare the burden of exposure to low interstitial fluid glucose (IFG) in elderly subjects with tightly controlled T2DM on sulphonylurea (SU) or insulin therapy.
Methods: Outpatient T2DM subjects ≥65 years of age with HbA1c ≤7.5% were recruited to wear a Freestyle Libre-Pro sensor for 2 weeks. Collected data was analyzed for low IFG burden.
Results: A total of 65 subjects (35 male, 30 female), 72.0 ± 5.0 years old with diabetes duration of 21.4 ± 11.1 years and HbA1c of 6.8 ± 0.5% were recruited; 27 were insulin treated and 38 were SU treated. Patients on insulin had longer diabetes duration (25.4 ± 10.9 vs. 18.0 ± 10.4 years, p&lt;0.05) and poorer kidney function (eGFR 58.6 ± 24.7 vs. 87.3 ± 48.0, p&lt;0.05). Greater proportion of the insulin group performed regular capillary blood glucose (CBG) monitoring (74.1% vs. 29.7%). This group also had more monthly self reported hypoglycemic events (0.85 ± 1.70 vs. 0.14 ± 0.35, p&lt;0.05) and a lower GOLD score (2.42 ± 1.72 vs. 3.73 ± 1.75, p&lt;0.05). While there was no difference in mean number of low IFG events with glucose &lt;72.0mg/dL between the 2 groups (0.92 ± 0.79 vs. 0.59 ± 0.48 events, p value &gt;0.05), very low IFG events with glucose &lt;50.0mg/dL occurred in higher proportions (52% vs. 23%, p&lt;0.05), higher frequency (0.48 ± 0.70 vs. 0.16 ± 0.19 events/person, p &lt;0.05) and for longer durations (1.56 ± 2.94 vs. 0.27 ± 0.43 hours/day, p&lt;0.05) in the insulin group. 62.2% of the SU group and 63.0% of insulin group had at least 1 episode of very low IFG, but none of the SU group and only 2 in the insulin group reported hypoglycemic symptoms.
Conclusion: Low IFG was common among the studied population, with a greater burden in insulin treated patients. Majority were unable to detect events despite regular CBG monitoring suggesting the potential use of IFG in evaluating hypoglycemia burden.

Disclosure
K. Tian: None. L. C. Ang: None. Y. Bee: None. S. Goh: None. M. M. Teh: None.
357-P: Advanced Glycation End Products Associate with Vascular Stiffness in Diabetic, Prediabetic, and Normoglycemic Individuals
Authors: BIRUKOV ANNA , CUADRAT RAFAEL , POLEMITI ELLI , EICHELMANN FABIAN , SCHULZE MATTHIAS B. 
Published: June 2021

Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We hypothesized that advanced glycation end-products associate with vascular stiffness independent of glycemic status. Advanced glycation end-products were measured as skin autofluorescence, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index in 3,535 participants from the European Prospective Investigation into Cancer and Nutrition Potsdam cohort (median age 67 years, 60% women). A subset of 1,348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and -0.04 (-0.05; -0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (-0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Our findings indicate that advanced glycation end-products are involved in vascular stiffening independent of glycemic status, age and other cardiometabolic risk factors.

Disclosure
A. Birukov: None. R. Cuadrat: None. E. Polemiti: None. F. Eichelmann: None. M. B. Schulze: None.

Funding
German Ministry of Education and Research; State of Brandenburg (82DZD00302)
367-P: Cardiovascular Risk Categories in Patients with Diabetes According to 2019 ESC/EASD Guidelines in Clinical Practice: Use of a Dedicated App (AWARE)
Authors: BERRA CESARE C. , MANFRINI ROBERTO , GHELARDI RENATA , BOLLATI PAOLA M. , BUCCIARELLI LOREDANA , MIRANI MARCO , MURATORI MILENA , FOLLI FRANCO ,   AWARE STUDY GROUP
Published: June 2021

The 2019 ESC-EASD guidelines provide recommendations for CV risk assessment and medical treatment in diabetic patients. Three CV risk categories were originally defined: 1) very high risk, 2) high risk and 3) moderate risk according to the presence of CVD, other target organ damage (proteinuria, renal impairment defined as eGFR ≥ 30 mL/min/1.73 m2, left ventricular hypertrophy, retinopathy), duration of disease, age, risk factors (hypertension, dyslipidemia, smoking, obesity). In very high risk CV category SGLT2-I and GLP1-RA were identify as treatment of choice. Based on these criteria, we developed the web APP “AWARE”, an application software which runs on a web server and is accessed via internet browser. From November 10th 2020 to January 10th 2021 we employed AWARE as a tool to assess CV risk of 650 type 2 diabetes patients in clinical practice. The APP was implemented with additional features such as HbA1c and therapy. Of the 650 subjects examined, 430 were very high risk (66%), 73 (11,2%) high risk, 5 (0,8%) at moderate risk while 145 patients (22%) didn’t match with any of these categories. We allocated these patients into an additional “undetermined risk” category. Median HbA1c in all subjects was 7.2±1.14 (7,3±1.15% in very high risk category, 7.2±1.15% in high risk category, 6,2±0.41% in moderate risk and 6.9±1.12% in “undetermined” risk). In the very high risk category CVD was present in 166 subject (38%), duration of disease&gt;10 aa in 238 subjects (55%), proteinuria in 53 subjects (12%) (p=0.000 vs. all other categories). Either SGLT2-I or GLP1-RA were prescribed in 30% of patients in the very high risk category. The APP “AWARE” in useful to identify CV risk in diabetic. The classification according to the criteria of 2019 ESC/EASD guidelines does not includes 22% of patients in clinical practice. Around 70% of patients in the very high CV risk category are not treated with the optimal drug therapy suggested by the 2019 ESC/EASD guidelines.

Disclosure
C. C. Berra: None. R. Manfrini: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk, Sanofi. R. Ghelardi: None. P. M. Bollati: None. L. Bucciarelli: None. M. Mirani: None. M. Muratori: None. F. Folli: None. Aware study group: n/a.
373-P: Type 2 Diabetes, Chronic Kidney Disease, and Major Cardiovascular Events in Patients with Established Coronary Artery Disease
Authors: SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2021

Both type 2 diabetes (T2DM) and chronic kidney disease (CKD) confer a high risk of cardiovascular disease (CVD), and these conditions frequently coincide. The aim of this study was to investigate the single and joint effects of T2DM and CKD on major cardiovascular events (MACE) in a high-risk population of patients with established coronary artery disease (CAD).
We prospectively investigated 1460 patients with angiographically proven CAD over 10.4±4.8 years, of whom 454 (30.8%) had T2DM and 251 (17.1%) had CKD.
MACE occurred more frequently in T2DM patients than in nondiabetic subjects (40.4% vs. 28.7%, p&lt;0.001) and in patients with CKD (eGFR &lt; 60ml/min/1.73m2) than in those with an eGRF ≥60ml/min/1.73m2 (51.6% vs. 28.3%, p&lt;0.001). When both, T2DM and CKD were considered, 863 subjects had neither T2DM nor CKD, 346 had T2DM but not CKD, 148 did not have diabetes but had CKD, and 103 had both T2DM and CKD. When compared with the incidence of MACE among patients with neither T2DM nor CKD (25.3%), MACE occurred more frequently in patients with T2DM who did not have CKD (35.8%; p&lt;0.001) as well as in nondiabetic patients with CKD (47.6%; p&lt;0.001) and occurred most frequently in patients with both, T2DM and CKD (57.4%; p&lt;0.001), in whom the incidence of MACE was higher than in those with T2DM but not CKD (p&lt;0.001) or those without T2DM but with CKD (p=0.025); the incidence of MACE was higher in nondiabetic CKD patients than in T2DM patients who did not have CKD (p=0.041). In Cox regression analysis, T2DM (HR=1.46 [1.20-1.78]; p&lt;0.001) and CKD (HR=1.81 [1.45-2.27]; p&lt;0.001) were mutually independent predictors of MACE after multivariate adjustment.
We conclude that T2DM and CKD are mutually independent risk factors for MACE in patients with established CAD. CAD patients with both CKD and T2DM are an extremely high risk for MACE.

Disclosure
L. Sprenger: None. C. H. Saely: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
376-P: REWIND Data on Obesity and Cardiovascular (CV) Health: Waist-to-Hip Ratio (WHR) Independently Predicted CV Outcomes
Authors: FRANEK EDWARD , PAIS PREM , BASILE JAN N. , RAHA SOHINI , AHMAD NADIA , KAN HONG , KONIG MANIGE 
Published: June 2021

Obesity is a major risk factor (RF) for health outcomes such as major adverse cardiovascular events (MACE) and cardiovascular disease (CVD)-related mortality. WHR is a validated measure of central adiposity and has been shown to predict CVD events. The aim of this post hoc analysis was to evaluate if WHR, adjusted for age and sex, was an independent RF for developing MACE-3 (non-fatal myocardial infarction (MI), non-fatal stroke, or CV death) and CVD-related mortality. Data from the REWIND trial placebo group (N=4952) were analyzed. All participants had type 2 diabetes, were aged 50 or older, and had either a previous CV event or CV RFs. During the median follow-up of 5.4 years, there were 663 patients with MACE-3 and 346 CVD-related deaths. A Cox proportional hazard model was used to investigate if WHR, adjusted for age and sex, was a significant RF for MACE-3 and CVD-related mortality, followed by testing additional baseline RFs (demographic, CVD history, and biochemical characteristics) using a stepwise variable selection method where WHR, age, and sex were forced into the model. BMI was tested similarly to WHR. WHR, but not BMI, was an independent risk factor for MACE-3 and CVD-related mortality. As expected, age and sex were significant RFs for both endpoints and were therefore adjusted in the model. Urinary albumin:creatinine ratio (UACR), non-HDL-C, and race (white) were significant RFs for MACE-3. UACR, LDL-C, history of MI, and race (American Indian/Alaska Native) were significant RFs for CVD-related mortality. In the resulting adjusted model, for every unit increase in WHR, there was an estimated 3.50-fold increase in MACE-3 risk (p=0.013) and 5.51-fold increase in CVD-related mortality risk (p=0.005). WHR was an independent predictor of MACE-3 and CVD-related mortality, indicating that central adiposity should be assessed and addressed in patients with or who have a high risk of CVD.

Disclosure
E. Franek: Advisory Panel; Self; Boehringer Ingelheim, Novo Nordisk, Speaker’s Bureau; Self; Boehringer Ingelheim. P. Pais: None. J. N. Basile: Other Relationship; Self; Medtronic, Research Support; Self; Eli Lilly and Company, ReCor. S. Raha: Employee; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company. H. Kan: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Bristol-Myers Squibb Company, GlaxoSmithKline plc. M. Konig: Employee; Self; Eli Lilly and Company.
381-P: Type 2 Diabetes Significantly Modulates the Power of Lipoprotein(a) to Predict Cardiovascular Events and Mortality in Young Coronary Artery Disease Patients
Authors: MADER ARTHUR , MAECHLER MAXIMILIAN , LARCHER BARBARA , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , VONBANK ALEXANDER , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2021

Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor especially in young individuals. The power of Lp(a) to predict cardiovascular events in young coronary artery disease (CAD) patients with type 2 diabetes (T2DM) however is unclear and is addressed in the present study. Lp(a) was measured in a cohort of 731 patients with angiographically proven CAD who were aged &lt;65 years. Vascular events were recorded over a mean follow-up of 6.6±3.2 years. At baseline, 216 patients had T2DM, and 515 did not have diabetes. During follow-up, 30.2% of our patients suffered cardiovascular events. Lp(a) proved to be a strong and independent predictor of vascular events in the total study cohort (standardized adjusted HR=1.30 [1.07-1.56]; p=0.007). In subgroup analyses by diabetes status, Lp(a) significantly predicted vascular events in nondiabetic patients (standardized adjusted HR= 1.39 [1.12-1.74]; p=0.003) but not in diabetic patients (standardized adjusted HR=0.93 [0.63-1.38]; p=0.731). An interaction term Lp(a)xT2DM was significant (p=0.002), indicating that T2DM significantly modulated the power of Lp(a) to predict cardiovascular events. We conclude that Lp(a) significantly modulates the power of Lp(a) to predict cardiovascular events in CAD patients &lt;65 years.

Disclosure
A. Mader: None. C. H. Saely: None. M. Maechler: None. B. Larcher: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. A. Vonbank: None. H. Drexel: None.
388-P: GLP-1 Receptor Agonists Attenuates Secretion of Extracellular Matrix via Inhibiting HMGB1 Signaling in Rat Mesangial Cells
Authors: GU WENSHA , SHI MIN , ZHANG HONG 
Published: June 2021

Background: GLP-1R agonists can exhibit a direct renoprotective effect in patients with diabetic nephropathy (DN) beyond the hypoglycemic effect, but the underlying mechanisms remain unknown. Recent studies have suggested that high mobility group box 1 (HMGB1) contributes to the development and progression of DN. In this study, we assessed whether GLP-1R agonists acts through HMGB1 and explored its downstream signaling pathways in DN.
Methods: Rat glomerular mesangial cells (GMCs) were divided into four groups: normal control (NG), normal control with 10 nmol/L exendin-4 treatment (GLP-1 analog) (NGE), high glucose (HG), and high glucose with 10 nmol/L exendin-4 treatment (HGE) groups. GMCs were transfected with GLP-1R-siRNA using Lipofectamine TM2000 and divided as HG, HGE, HGE + GLP-1R-siRNA, or HGE + scrambled siRNA. FN and type IV collagen (COL-IV) were evaluated by enzyme-linked immunosorbent assay (ELISA). GLP-1R, HMGB1, TGF-β1, phosphorylated and total extracellular signal-regulated kinases (ERK), c-Jun NH2-terminal kinases (JNK), p38 mitogen-activated protein kinases (p38MAPK), and NF-κB p65 were measured by western blot analysis.
Results: FN and COL-IV were higher in the HG group than NG group (P&lt;0.05). Compared with NG group, the level of GLP-1R was decreased, HMGB1 and TGF-β1 were increased in the HG group (P&lt;0.05). Additionally, NF-κB p65, the phosphorylation levels of ERK, JNK, and p38MAPK were all significantly elevated in the HG group (P&lt;0.05). However, all these effects were reversed by Exendin-4 treatment (P&lt;0.05), except phosphorylated p38MAPK (P&gt;0.05). Moreover, the protective effects of Exendin-4 were abolished by GLP-1R knockdown (P&lt;0.05).
Conclusion: These results suggest that GLP-1 receptor agonists attenuates the ECM secretion of GMCs induced by high glucose. The potential mechanism involves it binding to and activating GLP-1R, which prevents ECM production by inhibiting HMGB1 and its signaling pathways.

Disclosure
W. Gu: None. M. Shi: None. H. Zhang: None.

Funding
National Natural Science Foundation of China (81200595, 81400807, 81700723)
391-P: The Nrf2 Activator Increases TFAM and Suppresses STING in Human Renal Proximal Tubular Cells
Authors: BESSHO RYOICHI , TAKIYAMA TAKAO , PROMSUWAN SURATSAWADEE , KITSUNAI HIROYA , SAWAMOTO KAZUKI , TAKEDA YASUTAKA , TAKIYAMA YUMI 
Published: June 2021

Recent study has demonstrated the Nrf2 (NF-E2-related factor 2) activator bardoxolone methyl improved renal function in diabetic kidney disease (DKD). On the other hand, mitochondrial transcription factor A (TFAM) activation inhibits mitochondrial DNA (mtDNA) release into the cytoplasm and suppresses stimulator of interferon genes (STING)-mediated inflammation in renal proximal tubular cells. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is recognized as activators of Nrf2. In this study, we investigated the effects of SFN on TFAM and STING expression and its mitochondrial protective and anti-inflammatory effects. Because mitochondrial damage caused by fatty acids bound to albumin is involved in pathogenesis of DKD due to increased albumin reabsorption, we treated human renal proximal tubular cells (Lonza) with palmitic acid (PA, 200µM). Total RNA, DNA and protein were extracted and analyzed by qRT-PCR and western blotting. To quantify the mitochondrial DNA released into the cytoplasm, DNA was extracted from cytoplasmic and nuclear fractions. SFN (10µM) induced Nrf2 downstream target gene, NAD(P)H:quinone oxidoreductase 1 (NQO-1) mRNA expression to 359% (p&lt;0.05). SFN alone increased TFAM mRNA expression to 132% (p&lt;0.05) and suppressed STING mRNA expression by 26% (p&lt;0.05). Whereas, PA had no effect on TFAM mRNA expression but increased STING mRNA expression to 135% (p&lt;0.05). SFN suppressed PA-induced STING mRNA expression by 34% (p&lt;0.05) and STING protein expression by 48%. PA increased cytoplasmic mtDNA to 237% and SFN decreased PA-induced cytoplasmic mtDNA release by 41%. PA increased IL-6 mRNA expression to 139% (p&lt;0.05) and MCP-1 mRNA expression to 138% (p&lt;0.05). SFN suppressed PA-induced IL-6 mRNA expression by 33% (p&lt;0.05) and MCP-1 mRNA expression by 47% (p&lt;0.05). Together, the Nrf2 activators may have renoprotective effects through mitochondrial protection and anti-inflammatory effect by activating TFAM and inhibiting STING.

Disclosure
R. Bessho: None. T. Takiyama: None. S. Promsuwan: None. H. Kitsunai: None. K. Sawamoto: Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Roche Diagnostics K. K., Taisho Pharmaceutical Co., Ltd. Y. Takeda: None. Y. Takiyama: Other Relationship; Self; Gilead Sciences, Inc., Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Mochida Pharmaceutical Co., Ltd., Roche Diabetes Care, Taisho Pharmaceutical Co., Ltd.
392-P: ROCK2-Mediated Podocyte Dysfunction in Diabetic Nephropathy
Authors: MATOBA KEIICHIRO , TAKEDA YUSUKE , AKAMINE TOMOYO , NAGAI YOSUKE , UKICHI RIKAKO , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI 
Published: June 2021

The small GTPase RhoA and its downstream effector, Rho-kinase (ROCK), are implicated in a variety of cellular functions (e.g., cell adhesion, migration) via effect on cytoskeletal reorganization. We and others have illuminated ROCK as an important pathogenic regulator of diabetic kidney disease. Renal ROCK activity is elevated in both type 1 and type 2 diabetic murine models, as well as in diabetic patients. ROCK has two isoforms, ROCK1 and ROCK2. ROCK1 has been shown to regulate mitochondrial fission and epithelial-to-mesenchymal transition in the setting of diabetic kidney disease: however, the role of renal ROCK2 remain unclear. In the present study, we have demonstrated the upregulation of ROCK2 in glomerular podocytes obtained from 3 established models of diabetic kidney disease, (i.e., streptozotocin injection, db/db, and high-fat diet treatment), and diabetic patients. In an attempt to elucidate the roles of podocyte ROCK2, we generated podocyte-specific ROCK2 knockout mice (PR2KO) by breeding ROCK2 flox mice with Podocin-Cre mice. We found that podocyte-restricted ROCK2 deletion did not lead to any defects in the kidney development and functions. Of note, PR2KO were protected against albuminuria and glomerular sclerosis in streptozotocin-induced diabetic mice. In addition, renoprotective actions of podocyte ROCK2 deletion were also observed in type 2 diabetic db/db mice and high-fat diet-fed animals. Mechanistically, RNA-Seq analysis in ROCK2-null podocytes revealed the recovery of fatty acid utilization. When considered alongside our previous observations, the current work highlights the importance of ROCK2 in diabetic podocytopathy.

Disclosure
K. Matoba: Research Support; Self; Eli Lilly Japan K. K. Y. Takeda: None. T. Akamine: None. Y. Nagai: None. R. Ukichi: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker’s Bureau; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Medtronic, MSD Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding
Japan Society for the Promotion of Science (20K08645, 18K15985); Suzuken Memorial Foundation; Takeda Science Foundation; Yokoyama Foundation for Clinical Pharmacology; MSD Life Science Foundation; Ichiro Kanehara Foundation; Japan Diabetes Foundation; Ueh