bluuebunny/crossref_metadata_2025 huggingface dataset:
401-P: Mortality, Major Adverse Cardiovascular Events (MACDE), and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Testosterone Undecanoate Injections (TU): 11-Year Real-World Data
Authors: HAIDER AHMAD , HAIDER KARIM S. , SAAD FARID
Published: June 2020

Background: Men with hypogonadism are at increased risk of MACE and mortality. Studies in men with T2DM show that testosterone therapy (TTh) reduces both MACE and mortality.

Methods: In a registry of 858 men with hypogonadism, 356 men (41.5%) had T2DM. 178 received testosterone undecanoate injections (TU) 1000 mg/12 weeks (T-group) and 178 opted against treatment (CTRL). MACE, mortality, and diabetic complications were recorded and compared between groups.

Results: Mean baseline age in the T-group and CTRL was 61.8±5.1 and 63.6±4.9 years, respectively. Mean follow-up in T-group vs. CTRL was 7.4 and 8.3 years, respectively. 69 patients (38.8%) in the T-group and 70 (39.3%) in CTRL had a history of cardiovascular disease (myocardial infarction, stroke, or coronary artery disease diagnosis) (p=0.9135). Baseline smoking prevalence was 41.6% (74 men) in the T-group and 38.2% (68 men) in CTRL (p=0.5161). The T-group had significantly worse baseline risk factor profile than CTRL: BMI (36.5±4.5 vs. 33.4±5.3 kg/m²), systolic blood pressure (163.0±13.3 vs. 145.6±14.6 mmHg), LDL (4.7±0.9 vs. 4.1±1.4 mmol/L), HbA1c 9.4±1.4 vs. 7.8±0.7% (p<0.0001 for all). Mortality: during the entire observation period, 13 patients (7.3%) died in the T-group vs. 48 (27.0%) in CTRL (p<0.0001). MACE: in the T-group, there were no cases of myocardial infarction or stroke. In CTRL, there were 55 cases of myocardial infarction (30.9%) and 45 cases of stroke (25.3%). Diabetic complications: in the T-group vs. CTRL, the incidence of retinopathy was 3.4% and 16.9% (p<0.0001), nephropathy 0.6% and 4% (p<0.05), polyneuropathy 6.2% and 54.8% (p<0.0001), diabetic foot syndrome 0% and 9.6% (p<0.0001).

Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM significantly reduces MACE and mortality, as well as diabetic complications compared to untreated controls.

Disclosure

A. Haider: None. K.S. Haider: None. F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG.

Funding

Bayer AG
409-P: Engineered Cardiac Tissues: A Novel In Vitro Model to Investigate the Pathophysiology of Diabetic Cardiomyopathy
Authors: WANG XIANG , ZHENG YANG , KELLER BRADLEY B. , CAI LU
Published: June 2020

Rodent diabetic models have advanced our understanding of the pathophysiology of diabetic cardiomyopathy (DCM), however these models require long timelines to display DCM, and also display confounding influences inherent to in vivo models, but in vitro cardiomyocyte cultures could not reflect the structure-function relationship specific to the heart. Over the past 2 decades, engineered cardiac tissues (ECTs) have emerged as robust 3D in vitro models to investigate cardiac tissue maturation, structure-function relationships, cardiac injury response and repair. Advanced glycation end-products (AGEs), the proteins or lipids that become glycated in response to hyperglycemia, produce diabetes-associated tissue injury via receptor (RAGE) activating reactive oxygen or nitrogen species (ROS/RNS). Therefore, we developed a ECT model to investigate cardiac injury produced by AGEs. We used ECTs composed of neonatal murine cardiac cells and found: (1) AGEs at 150 µg/ml did not cause significant cytotoxicity (necrosis, detected by medium LDH or apoptosis, detected by c-caspase 3), but negatively impacted ECT function by 9-day treatment; (2) AGEs triggered fibrotic (Collagen I-α1, Collagen III-α1, FN1) and hypertrophic (ANP and β-MHC) responses on day 3 - 9 after treatment; (3) AGE also increased ECT’s oxidative stress (3-NT, 4-HNE, HO-1, CAT, SOD2) and inflammation (PAI-1, TNF-α, NF-κB, ICAM); (4) All AGE-induced oxidative stress, inflammation, fibrotic response and hypertrophy and ECT dysfunction were prevented by the RAGE inhibitor FPS-ZM1 or by inhibiting ROS/RNS production via NAC. Thus, AGEs-treated neonatal murine ECTs recapitulate key cellular and molecular pathophysiological features of DCM and can serve as a robust ex vivo model to investigate cell-cell specific pathways relevant to DCM along with cardioprotective strategies. This model even has a great potential to directly investigate the effect of diabetes on human ECTs if human iPSC can be introduced.

Disclosure

X. Wang: None. Y. Zheng: None. B.B. Keller: None. L. Cai: None.
41-LB: Effectiveness of a Two-Year Peer Support Diabetes Education Intervention Implemented in a Semiurban Mayan Community in the Yucatan, Mexico
Authors: CASTILLO-HERNÁNDEZ KAREN G. , LAVIADA HUGO , ESPINOSA-MARRÓN ALAN , MOLINA FERNANDA
Published: June 2020

Type 2 diabetes (T2D) prevalence in adults has increased significantly in Mexico in recent years. In the Mayan population, factors like poverty and language barriers intensify the problems of living with T2D. Peer support is a promising approach to diabetes care as it helps patients to support each other throughout their everyday lives. This program was first evaluated by our group in Komchen, a rural mayan community, where peer support had significant reductions in A1c levels at 4 and 8 months of follow-up. The aim of this study is to assess the effects of a two-year peer support education program for patients with T2D in a semi-urban Mexican Mayan community.

Methods: Patients with previous diagnosis of T2D were recruited from the community clinics (n=156) and randomized to: 1) Participants invited to attend the Education Program (EP)delivered by a certified diabetes educator; or 2) Participants were invited to attend the EP plus peer support meetings (PSM) facilitated by leaders with type 2 diabetes.

Results: Unlike our experience in Komchen, adherence to the EP in Conkal, a more populated and urbanized town, was lower: 80% in Komchen vs. 33% in Conkal, the same fact occurred for PSM. We found a relevant clinical difference in A1c level between groups (Figure 1) although difference was not statistically significant.

Conclusions: It remains a tendency to maintain or decrease A1C levels through time on intervention groups compared to the control.

Disclosure

K.G. Castillo-Hernández: None. H. Laviada: None. A. Espinosa-Marrón: None. F. Molina: None.

Funding

AstraZeneca Mexico (D1843L00017)
414-P: Hand-Grip Strength and Type 2 Diabetes Are Mutually Independent Predictors of Cardiovascular Events and of Mortality in Patients with Established Cardiovascular Disease
Authors: LARCHER BARBARA , VONBANK ALEXANDER , MADER ARTHUR , MAECHLER MAXIMILIAN , SPRENGER LUKAS , LEIHERER ANDREAS , PURIN DANIELA , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2020

Impaired skeletal muscle function is involved in the pathogenesis of type 2 diabetes (T2DM) as well as of cardiovascular disease (CVD). Hand grip strength (HGS) is a simple, inexpensive and non-invasive diagnostic parameter for muscle function. Its association with cardiovascular events and mortality in patients with established CVD is unclear and is addressed in the present study. We prospectively recorded cardiovascular events over a mean follow up time of 8.9±3.2 years in a cohort of 876 patients with established CVD (672 patients with angiographically proven coronary artery disease and 204 patients with sonographically proven peripheral artery disease). From our patients, 274 (31.3%) had T2DM at baseline; HGS did not differ significantly between patients with T2DM and nondiabetic subjects (35.3±11.9 vs. 36.6±11.9 kg; p=0.082). Prospectively, cardiovascular events occurred in 387 patients, and 278 patients died during follow-up. T2DM and low HGS after multivariate adjustment in Cox regression models proved to be mutually independent predictors of cardiovascular events (adjusted HR 1.52 [1.23-1.89]; p<0.001 and standardized adjusted HR 0.85 [0.74-0.99]; p=0.032, respectively) as well as mortality (adjusted HR 1.79 [1.39-2.29]; p<0.001 and standardized adjusted HR 0.69 [0.58-0.83]; p<0.001, respectively). We conclude that low HGS and T2DM are mutually independent predictors of cardiovascular events as well as of mortality in patients with established CVD.

Disclosure

B. Larcher: None. A. Vonbank: None. A. Mader: None. M. Maechler: None. L. Sprenger: None. A. Leiherer: None. D. Purin: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
416-P: Change in Extent of Coronary Artery Disease in People with and without Diabetes Undergoing Coronary Angiography
Authors: KIBURG KATERINA V. , MACISAAC ANDREW I. , SUNDARARAJAN VIJAYA , MACISAAC RICHARD
Published: June 2020

Objective: To assess whether improvements in preventative care for people with diabetes have resulted in a relative decrease in the burden of coronary artery disease (CAD) compared to people without diabetes.

Methods: All patient-level linked coronary angiography and hospital separation data at a large Australian tertiary referral hospital between 2013 and 2019 were obtained. Indication for angiography and extent of CAD were based on original classification by treating cardiologists, classified as no disease, mild, moderate or severe. Propensity scores were estimated to match people with and without diabetes on a 1:1 ratio. Ordinal logistic regression models were fitted to assess trends in CAD severity in people with and without diabetes over time with adjusted odds ratios (adjOR) reported.

Results: For 3,016 people identified in the coronary angiography database and matched using propensity scores, 1508(50%) were diagnosed with diabetes. Angiographic evidence of CAD was detected in 1155(77%) and 1257(83%) people without and with diabetes. For people with diabetes there was an increased risk of more extensive CAD in 2018 compared to 2013 (adjOR: 2.02 95% C.I. 1.36, 2.99). This risk appears to have been attenuated in 2019 with no significant change in CAD burden between 2013 and 2019 (adjOR: 1.33 95% C.I. 0.90, 1.98). In contrast, there was no effect of time on CAD burden in people without diabetes.

Conclusions: The initial increase in severity of disease burden seen in our study for people with diabetes compared to those without diabetes may represent improved CAD screening rather than suboptimal application of preventative therapies. Possibly, greater recent use of newer glucose lowering medications with cardiovascular protective effects accounts for the attenuation of CAD burden in 2019 for people with diabetes. These findings highlight the importance of aggressive risk factor modification for people with diabetes to minimize the development and progression of CAD.

Disclosure

K.V. Kiburg: None. A.I. MacIsaac: None. V. Sundararajan: None. R. MacIsaac: None.
432-P: Creatinine-to-Cystatin C Ratio in Relation to Intima-Media Thickness in Patients with Type 2 Diabetes
Authors: SHIN JANG YEL
Published: June 2020

Skeletal muscle mass (SM) was shown to be inversely related to cardiovascular disease (CVD) and mortality in some studies. However, the causal relationship between SM and CVD is not fully understood. Recently, creatinine-to-cystatin C ratio (Cr/cysC) has been suggested to be a useful surrogate marker for an estimation of SM. In the present study, we investigated whether Cr/cysC was related to intima-media thickness (IMT) in subjects with type 2 diabetes. A total of 459 patients with type 2 diabetes were recruited. Serum Cr and cysC were measured. All subjects were divided into three groups by gender-specific tertiles of Cr/cysC. We assessed carotid IMT using B-mode ultrasound. High IMT was defined as ≥ 75 percentiles of gender-specific maximal IMT. We checked body compositions using dual-energy X-ray absorptiometry. Patients with the highest tertile of Cr/cysC were younger and had higher prevalence of current smoking and regular exercise (RE) compared with those with the lowest. Also, they had higher values of Cr, fasting glucose (FG), HOMA-IR, and appendicular SM (ASM)/BMI, but had lower values of waist circumference (WC), cysC, Cr-based estimated glomerular filtration rate (Cr-eGFR), and IMT than those with the lowest. In the Pearson correlation, Cr/cysC was negatively related to age, BMI, and Cr-eGFR, but showed positive associations with FG and ASM/BMI in both genders. While WC and body fat percent were negatively associated with Cr/cysC in women alone. The odd ratios (ORs) for high IMT after adjusted for age were 0.76 (95% CI, 0.46-1.27) in the middle and 0.45 (95% CI, 0.25-0.79) in the highest, respectively. The OR in the highest was maintained significant after further adjustments for hypertension, current smoking, RE, BMI, WC, blood pressure, HDL, triglyceride, C-reactive protein, FG, HOMA-IR, and Cr-eGFR.

In conclusion, the present study showed that higher Cr/cysC was significantly related to the protection of risk for high IMT independently of multiple metabolic risk factors.

Disclosure

J. Shin: None.
434-P: Possible Mechanisms of Cardioprotective Effects of Metformin in Patients with Type 2 Diabetes and Chronic Heart Failure
Authors: HOŠKOVÁ EVA , KOPECKY JAN , VELEBA JIRI , MALINSKA HANA , VELEBOVA KATERINA , MELENOVSKY VOJTECH , PELIKANOVA TEREZIE
Published: June 2020

Background and Aims: Metformin (MET) treatment in patients with type 2 diabetes (T2D) and chronic heart failure (HF) is associated with better cardiovascular outcomes. Possible mechanism of cardioprotective effect of metformin may be a reduction of dicarbonyl and oxidative stress. In particular, a reduction of methylglyoxal levels (MG). The aim of our study was to evaluate the effect of MET on cardiac structure, cardiac function and exercise capacity in patients with T2D and HF.

Materials and Methods: A randomized, double-blind, placebo-controlled, crossover study in a total time of six months testing the effect of 3- month usage of MET (2 g/day) vs. placebo. A group of 44 treatment naive patients with T2D and HF were included. At the beginning and at the end of each intervention period various metabolic tests were done including echocardiography, spiroergometry, and parameters of dicarbonyl stress like MG, Glutathione (GSH), glutathione disulfide (GSSG), and the activity of Glyoxalase1 (GLO-1).

Results: MET treatment led to a decrease in HbA1c levels (∆ MET vs. placebo: -3.39 ± 5.33mmol/mol, p = 0.00007), and fasting plasma glucose levels (∆MET vs. placebo: -0.381 ± 1.1mmol/l; p = 0.00145). MET had no effect on oxygen consumption at the maximum tolerated load during spiroergometry (VOmax) (∆MET vs. placebo: -0.142 ± 1.18ml/kg/min; p = 0.64). MET did not affect left ventricular ejection fraction (∆MET vs. placebo: -0.789 ± 6.32%; p = 0.53). The levels of MG didn’t change after MET (∆ MET vs. placebo: 0.0306 ± 0.13nmol/ml; p = 0.19). The activity of GLO-1 was not affected too (∆ MET vs. placebo: 0.0073 ± 0.017 mmol/min/mg Hb; p = 0.22).

Conclusion: MET treatment is safe in patients with severe heart failure. Our results do not support the evidence that one of the cardioprotective pathways of metformin is through reducing dicarbonyl stress.

Disclosure

E. Hošková: None. J. Kopecky: None. J. Veleba: None. H. Malinska: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None.

Funding

Institute for Clinical and Experimental Medicine 00023001)
436-P: Characterization of Autoimmunity in the Acceleration of Atherosclerosis in Type 1 Diabetes
Authors: PARK KYOUNGMIN , LI QIAN , PARK HYUNSEOK , ST-LOUIS RONALD , FU JIALIN , RASK-MADSEN CHRISTIAN , MADDALONI ERNESTO , YOKOMIZO HISASHI , KISSLER STEPHAN , LICHTMAN ANDREW H. , KING GEORGE L.
Published: June 2020

Hyperglycemia, hyperlipidemia and hypertension have been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the impact of autoimmunity in T1DM on CVD has not been determined. We have generated several mice models of atherosclerosis including ApoE-/-/NOD, ApoE-/-/NOD (congenic non diabetes and non-autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, nondiabetes) and ApoE-/-/NOD autoimmune diabetic mice. All groups of mice have high plasma lipids but only ApoE-/-/NOD diabetic mice had hyperglycemia. However, ApoE-/-/NOD (insulitis and nondiabetes) and ApoE-/-/NOD (insulitis and diabetes) had high titers of autoantibodies to IA2 compared to control CongApoE-/-/NOD mice or nondiabetic ApoE-/-/NOD mice (P<0.0001). For the the severity of atherosclerosis, the presence of hyperglycemia in ApoE-/-/NOD-DM mice showed greater levels of lipid deposition in the descending aorta (22%) by en face assessment as compared to nondiabetic ApoE-/-/NOD mice (P<0.01). Similarly, we also observed in the macrophage content of the descending aorta, was greater in numbers in the ApoE-/-/NOD mice than in ApoE-/-/CongNOD mice (P<0.05) but less than in ApoE-/-/NOD-DM mice. FACS of the descending aorta showed the elevated CD3+/CD28- T-cells (CD4 and CD8) by 4.5 folds and decreased CD3+/CD28+ Treg cells by 46% at the atherosclerotic plaques of ApoE-/-/NOD mice, compared to those of CongApoE-/-/NOD mice. To further confirm the elevated infiltrate and accumulated CD3+ T-cells in vivo, we will investigate the levels of macrophages and CD3+ T-cells in the arterial wall of the coronary artery from the Medalists group T1D and autoimmunity with positive HLA DR3/4 risk alleles and autoantibodies and lacking monogenic diabetic variants, as compared to the group lacking HLA DR3/4 risk alleles and autoantibodies. These studies suggest that autoimmunity exacerbates atherosclerosis in T1D, independently and synergically hyperglycemia.

Disclosure

K. Park: None. Q. Li: None. H. Park: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: None. E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. H. Yokomizo: None. S. Kissler: None. A.H. Lichtman: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Funding

National Institutes of Health (R01DK053105); Thomas J. Beatson, Jr. Foundation
437-P: Postprandial Hyperglycaemia Is Associated with Coronary Plaque Rupture in Diabetic Patients with Acute Coronary Syndrome
Authors: SU GONG , ZHANG TAO , ZHUANG SHAOWEI
Published: June 2020

Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of postprandial hyperglycemia and short-term glycemic excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD; however, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). A total of 132 diabetic patients with NSTE-ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 38 patients with plaque rupture and 94 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBS), hemoglobin A1c (HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) level was measured and corrected by creatinine clearance. Patients with ruptured plaque had significantly lower serum 1,5-AG levels and a tendency of higher hemoglobin A1c levels than patients without ruptured plaque. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.3; p = 0.006) in diabetic patients with NSTE-ACS, but HbA1c was not. The area under the receiver-operating characteristic curve for 1,5-AG (0.678, p = 0.001) to predict plaque rupture was superior to that for HbA1c (0.618, p = 0.034). Levels of 1,5-AG were significantly correlated with urinary 8-iso-PGF2α (r=-0.224, p = 0.010). Thus, postprandial hyperglycaemia appeared to be superior to long-term average blood glucose levels in predicting plaque rupture in culprit lesions, which may be useful to assess the cardiovascular outcomes in diabetic patients.

Disclosure

G. Su: None. T. Zhang: None. S. Zhuang: None.

Funding

Outstanding Clinical Discipline Project of Shanghai Pudong (PWYGY 2018-05); Beijing Health Special Foundation (JING 15-10)
443-P: Effect of 3-Month Therapy with Liraglutide on Ambulatory Blood Pressure in Patients with Type 2 Diabetes Mellitus
Authors: PAPAZAFIROPOULOU ATHANASIA , MPOUMI LOUIZA , RALLATOU MARIA , PAPANTONIOU STYLIANI S. , KAMARATOS ALEXANDROS , ANTONOPOULOS STAVROS , MELIDONIS ANDREAS
Published: June 2020

Background and Aims: Liraglutide, has been found to reduce systolic (SBP) and to a lesser extent diastolic blood pressure (DBP). The purpose of this study is to evaluate the effect of liraglutide on ambulatory BP in patients with poorly controlled type 2 diabetes (T2D).

Materials and Methods: A total of 42 patients (20 men) with T2D, mean age (± standard deviation) 60.6 ± 9.4 years, HbA1c 8.5 ± 1.1%, body mass index 37.1 ± 5.3 Kg/m2, duration of T2D 10.1 ± 4.3 years, were included. All patients underwent a complete clinical examination, laboratory testing, and ambulatory BP recording both on entry into the study and three months after initiation of treatment with liraglutide (background antidiabetic therapy remained stable during the study period). Ambulatory BP was measured with the oscillometric Mobil-O-Graph NGW 24-hour ambulatory BP and PWA monitor (IEM; Stolberg, Germany).

Results: At baseline, mean daytime SBP and DBP were 128.0 ± 11.2 and 77.2 ± 11.0 mmHg, respectively. After 3-month liraglutide therapy, daytime SBP and DBP were: 124.0 ± 7.8 and 73.5 ± 7.8 mmHg, respectively. Daytime SBP and DBP, mean change from baseline was -4.0 mmHg (P=0.26) and -3.6 mmHg (P=0.05). Nighttime mean SBP and DBP at baseline, were127.5 ± 12.6 and 73.7 ± 14.2 mmHg. After 3-month therapy, the above values were as follows: 118.6 ± 11.1 and 68.1 ± 9.8 mmHg, respectively. Nighttime SBP and DBP, mean change from baseline was -8.9 mmHg (P=0.009) and -5.6 mmHg (P=0.009). In accordance, pulse pressure change was: 53.9 ± 8.6 (baseline) to 50.6 ± 11.2 mmHg (3 months) and for heart rate: 75.9 ± 10.1 (baseline) to 77.8 ± 14.3 bpm (3 months). Pulse pressure and heart rate change from baseline was -3.2 mmHg (P=0.14) and -1.9 bpm (P=0.36), respectively.

Conclusion: In accordance with the existing data, 3-month therapy with liraglutide had a favorable effect of ambulatory BP, in terms of daily DBP and SBP and DBP during the night. In contrast, no significant effect on heart rate was observed despite the existing data.

Disclosure

A. Papazafiropoulou: None. L. Mpoumi: None. M. Rallatou: None. S.S. Papantoniou: None. A. Kamaratos: None. S. Antonopoulos: None. A. Melidonis: None.
457-P: Quantification of Vascular Density by 3D Light Sheet Imaging in a Surgical Ligation of the Left Anterior Descending Artery (LAD) Model in Mouse
Authors: ZOIS NORA E. , ROOSTALU URMAS , THISTED LOUISE , PEDERSEN PHILIP J. , FOSGERAU KELD , JELSING JACOB , VRANG NIELS
Published: June 2020

Introduction: Patients with diabetes have an increased risk of cardiovascular disease including myocardial infarction (MI). A major consequence of MI is left ventricular (LV) remodeling including compensatory hypertrophy without concomitant adaptation of the capillary vasculature. Targeting capillary density is thus a promising therapeutic strategy but methods for unbiased and direct quantification are lacking. In a surgical MI model, we used 3D light sheet imaging to visualize and quantify LV remodeling including capillary density.

Methods: Surgical ligation of the left anterior descending artery (LAD) was performed in male C57BL/6 mice. Infarct localization and LV function were evaluated by echocardiography, and LV remodeling and capillary density quantified by 3D light sheet imaging.

Results: Ejection fraction (EF) as measured by echocardiography was reduced in LAD-ligated mice with anterior wall MI compared to mice without MI (29.1±1.5 vs. 55.2±1.1 %, p<0.001), while internal LV volume (as assessed by 3D imaging) was increased (16.6±0.7 vs. 22.7±1.3 mm3, p<0.01) 10 days after LAD ligation. Furthermore, EF and LV volume correlated (R2: 0.59, p<0.001, slope -0.32). The capillary density in the infarct zone was reduced in MI versus no MI mice (10.5±1.00 vs. 23.5±2.5 % of total tissue volume, p<0.001). In a subsequent treatment study, EF was reduced by 43.2% in MI compared to no MI mice (p<0.001) 7 days after LAD ligation. The effects of 4 weeks of treatment with captopril on LV function, remodeling and capillary density was investigated by echocardiography and 3D light sheet imaging.

Conclusions: The combination of echocardiography and 3D light sheet imaging offers a novel approach to visualize and quantify LV function, remodeling and capillary density in a mouse model of MI. This high-resolution 3D imaging technology thus allows for preclinical efficacy testing of novel therapeutics for heart disease including MI.

Disclosure

N.E. Zois: Employee; Self; Gubra. U. Roostalu: Employee; Self; Gubra. L. Thisted: Employee; Self; Gubra. P.J. Pedersen: Employee; Self; Gubra. K. Fosgerau: None. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra.
464-P: Linagliptin Directly Enhances Cardiac Contractile Recovery through Nitric Oxide Mediated Endothelial–Cardiomyocyte Communication
Authors: YERRA VEERA GANESH , BATCHU SRI NAGARJUN , LIU YOUAN , KLEIN THOMAS , ADVANI ANDREW
Published: June 2020

Despite a similar mechanism of action underlying their glucose-lowering effects, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. This possibility is supported by heterogeneous heart failure outcomes in cardiovascular trials, although few head-to-head comparisons exist. To explore the possibility of DPP-4 inhibitor cardiac heterogeneity, we perfused mouse hearts with different DPP-4 inhibitors at concentrations equivalent to their peak plasma levels achieved in humans with standard dosing (Cmax). We studied male and female mice, young nondiabetic mice and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA-sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Thus, at concentrations achieved with standard dosing in humans, linagliptin has direct effects on the recovery of mouse cardiac contractility after ischemia-reperfusion, most likely through NO-mediated endothelial-cardiomyocyte communication. The complex cardiac actions of NO (that depend on comorbidity, concurrent medications and disease setting, for instance) may contribute to both the discordance in DPP-4 inhibitor outcomes between preclinical and clinical observations and the heterogeneous outcomes observed in clinical trials to date.

Disclosure

V. Yerra: None. S. Batchu: None. Y. Liu: None. T. Klein: Employee; Self; Boehringer Ingelheim International GmbH. A. Advani: Research Support; Self; Boehringer Ingelheim International GmbH.

Funding

Boehringer Ingelheim
47-LB: Impact of Activity Intensity on Glucose Variability among Adolescents with Type 1 Diabetes
Authors: JAGGERS JASON R. , KING KRISTI , MCKAY TIM E. , DYESS RYAN J. , WINTERGERST KUPPER A.
Published: June 2020

Studies have consistently shown improvements in daily glucose and hemoglobin A1c (HbA1c) for both type 1 and type 2 diabetes with increased moderate and/or vigorous physical activity (PA). A limitation with prior investigations is that they only tested this relationship in adult populations and seldom looked at glucose variability (GV). Whether or not similar results would be observed in a pediatric population with type 1 diabetes (T1D) is unknown.

Purpose: The purpose of this investigation was to test the relationship between GV and intensity of PA, and if duration of activity is predictive of changes in GV in a sample of teenagers with T1D. Methods: Data for this investigation were used from an ongoing study at a local pediatric Diabetes Center. Participants who wore a continuous glucose monitor (CGM) and Fitbit consecutively for a period of two weeks or more were included in the data analysis. GV was determined using 2-weeks of CGM data and PA intensity time was retrieved through Fitabase. Pearson’s correlation and a simple linear regression were used for final analysis with a p-value of 0.05 to determine significance.

Results: Minutes of daily moderate intensity activity had a significant inverse relationship (r= -0.59; p = 0.04) with GV, whereas moderate and vigorous PA (MVPA) combined showed a stronger inverse relationship (r= -0.86; p = 0.03). When placed in a simple linear regression only MVPA significantly predicted changes in glucose variability (β= -0.12, p=0.03).

Conclusion: These data show that not only is duration of PA an important factor when it comes to managing diabetes, but that more attention should be paid to the time spent at various intensity levels. Although more research is needed to determine feasibility it could be of great benefit for individuals managing diabetes to incorporate an activity monitor into their daily routine to share with their diabetes care team to better understand how PA levels impact their blood glucose.

Disclosure

J.R. Jaggers: None. K. King: None. T.E. McKay: None. R.J. Dyess: None. K.A. Wintergerst: None.
470-P: SIK2 Protects against Renal Tubular Injury by Inhibiting Endoplasmic Reticulum Stress
Authors: LIAO XIAOYU , LIU BINGYAO , ZHENG HONGTING
Published: June 2020

Background and Aims: Identification of new biomarkers and drug targets for diabetic nephropathy (DN) is required for the development of more effective therapy. In this study, we investigated the role of SIK2 in protecting against renal tubular injury.

Methods: Diabetes was induced in C57BL/6 mice by streptozotocin (STZ) injection. Inhibitor ARN-3236 was administered 4 weeks after STZ injection 6 weeks, and metabolic indices and renal function were assessed. The apoptosis of HK2 cells was detected by flow cytometric analysis. The transcriptome sequencing was performed after SIK2 overexpression.

Results: Salt inducible kinase 2 (SIK2) expression was obviously decreased in the diseased kidneys from humans and mice, especially in the tubules. In vivo, downregulation of SIK2 with specific inhibitor ARN3236 accelerates tubular mitochondrial dysfunction, endoplasmic reticulum (ER) stress and apoptosis in STZ mice. In tubular epithelial cells, SIK2 overexpression attenuates thapsigargin-induced ER stress and apoptosis, whereas SIK2 knockdown aggravates apoptosis. Mechanistically, SIK2 overexpression upregulates HSP70 expression by phosphorylating HSF1, and then inhibits ER stress.

Conclusions: The newly identified SIK2/HSF1/HSP70 axis clarified the molecular mechanism of tubular epithelial cells apoptosis, indicating that SIK2 might be a novel target for therapeutic prevention of renal tubular injury.

Disclosure

X. Liao: None. B. Liu: None. H. Zheng: None.
475-P: Renal Loss of mTORC2 Is Associated with Improved Diabetic Nephropathy in Type 1 Diabetes
Authors: CHANG CHENG , ZHANG ZHAO , XU KEXIN , BHAT MANZOOR , SHI QIAN
Published: June 2020

One of the major pathological features of early stage diabetic nephropathy (DN) is tubulointerstitial fibrosis on renal proximal tubular cells (RPTCs), which eventually progresses to fibrosis without proper renal function. However, little is known about the factors regulating these processes. Here, we show that mTOR complex 1 and 2 specifically regulate metabolic control processes of type-1 diabetes in kidney. Using conditional mouse genetic approaches to disable subunits of mTORC1 (Rictor) and mTORC2 (Raptor), respectively or both in PRTCs (Pax8cre), we showed that mice lacking Rictor or Raptor/Rictor develop improved renal pathologies in STZ induced type-1 diabetic model, including low levels of proteinuria, reduced matrix protein accumulation/matrix expansion and tubulointerstitial inflammation. However, the mice lacking Raptor alone were still largely susceptible to STZ toxicity. Meanwhile, Nox4 and oxidative stress levels were significantly reduced in RictorcKO diabetic animal, but to a lesser extent in RaptorcKO diabetic mice. Transcriptome analysis of kidney cortex identified unique pathways that play roles in mTORC/Nox4 pathway during type-1 diabetic pathogenesis, including autophagy, metabolism of lipids and fatty acid regulation. These pathways were largely unchanged in RictorcKO mice when they were exposed to STZ induction. Functionally, losing mTORC2 complex resulted in reduced cellular death and oxidative stress levels, and a profound perturbation of the endocytic machinery. Finally, we found that the treatment with pp242, the mTORC1/2 dual inhibitor, greatly ameliorated the renal pathology in OVE26 mice, a spontaneous type-1 diabetic model. Collectively, our findings highlight a novel mTOR-dependent regulatory network for maintaining metabolic homeostasis in RPTCs during the pathogenesis of DN, and further validates the relevance of simultaneously targeting Nox4 and mTORC2 as a potential early therapeutic option for treating DN.

Disclosure

C. Chang: None. Z. Zhang: None. K. Xu: None. M. Bhat: None. Q. Shi: None.

Funding

JDRF (1-FAC-2019-858-A-N)
483-P: Key Biochemical and Histopathological Markers of Diabetic Nephropathy Correlate with Hypertension in the Renin-AAV Uninephrectomized db/db Mouse Model
Authors: ØSTERGAARD METTE V. , SØRENSEN IDA R. , PEDERSEN ANNEMARIE A. , SECHER THOMAS , SEMBACH FREDERIKKE E. , MADSEN MARTIN R. , FOSGERAU KELD , FINK LISBETH N. , VRANG NIELS
Published: June 2020

Introduction: Diabetic nephropathy (DN) is a long-term complication that occurs in ∼40% of diabetes patients and is a leading cause of end-stage renal disease. In a newly established mouse model of progressive DN, we investigated the effects of hypertension on kidney injury.

Methods: Female db/db mice were uninephrectomized (UNx) at 8 weeks of age and injected i.v. with a Renin adeno-associated virus (AAV) construct at different doses to induce hypertension, while a LacZAAV construct was used as negative control. Sham-operated db/+ mice served as healthy controls. Blood pressure and glomerular filtration rate (GFR) was measured at 22 weeks of age, while urine albumin to creatinine ratio (ACR) was measured before termination and kidney tissue sampling 24 weeks of age.

Results: GFR measurements indicated hyperfiltration in all AAV-injected UNx db/db mice compared to db/+ mice, while ReninAAV tended to dose-dependently decrease GFR compared to LacZAAV in UNx db/db mice. Urine ACR was worsened by ReninAAV-induced hypertension compared to LacZAAV controls. 3D kidney imaging demonstrated increased glomerular volume in LacZAAV UNx db/db mice compared to db/+ mice with no further effect in ReninAAV groups. Automized AI-based glomerulosclerosis scoring showed ReninAAV dose-dependent increases in glomerulosclerosis compared to LacZAAV controls. RNA sequencing revealed upregulated gene expression markers of kidney fibrogenesis (Col1a1, Col4, Fn1) and tubular injury (Ngal and Kim-1), as well as downregulation of proximal tubular markers (Megalin, Aqp1) in ReninAAV UNx db/db mice compared to LacZAAV controls.

Conclusion: ReninAAV-induced hypertension in female UNx db/db mice aggravates albuminuria and glomerulosclerosis paralleled by increased expression of genes associated with tubular injury renal fibrosis, thus confirming that ReninAAV UNx db/db mice is a reliable model of DN with features of late stage human disease.

Disclosure

M.V. Østergaard: None. I.R. Sørensen: None. A.A. Pedersen: None. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Gubra. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. F.E. Sembach: Employee; Self; Gubra. M.R. Madsen: None. K. Fosgerau: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra.
488-P: Isoliquiritigenin Protects Renal Tubular Epithelial Cells from Inflammatory and Oxidative Injuries via Directly Activating SIRT1 in Type 1 Diabetic Nephropathy
Authors: CHEN XIONG , SHEN FEIXIA
Published: June 2020

Emerging evidence shows that increasing fibrosis and apoptosis have been observed in the tubular epithelia in the progression of type 1 diabetic nephropathy (DN). Excessive inflammatory response and oxidative stress contribute to the pathogenesis of progression. Isoliquiritigenin (ISL), a natural chalcone compound, has been reported to exert anti-inflammatory and anti-oxidative properties. However, little is known about the effects of ISL on diabetic nephropathy and its mechanism. In this study, we investigated the potential protective effects and pharmacological mechanisms of ISL on DN in vivo and in vitro. We test beneficial activities of ISL on streptozotocin (STZ)-induced type 1 diabetes mellitus mice and renal tubular epithelial NRK-52E cells. The study showed that ISL attenuated diabetic nephropathy by decreasing both pro-fibrotic and pro-apoptotic biomarkers. Diabetes or high glucose (HG) induced inflammatory response and oxidative stress were eliminated by ISL administration. The molecular docking using the multiple ligand simultaneous docking (MLSD) software indicated that three molecules of ISL might bound to the binding site of SIRT1 and formation of a stable complex. We also found ISL could neutralize HG-mediated inactivation of SIRT1. Activation of SIRT1 could attenuate HG-induced inflammation, oxidative stress, fibrosis and apoptosis in NRK-52E cells, paralleled with the effects of ISL. While inhibition of SIRT1 could significantly abrogate the protective effects of ISL. Our study implicated that ISL might have great pharmacological actions on attenuating tubular damage of diabetic nephropathy. The beneficial effects of ISL are likely associated with inhibiting excessive inflammatory response and oxidative stress via directly activating SIRT1.

Disclosure

X. Chen: None. F. Shen: None.

Funding

Wenzhou Science and Technology Bureau (Y20190125); First Affiliated Hospital of Wenzhou Medical University (FHY2019015)
494-P: Effects of a Novel Xanthine Oxidase Inhibitor, TMX-049, on Urinary Albumin Excretion in Patients with Type 2 Diabetes and Albuminuria
Authors: BAKRIS GEORGE , MIKAMI HIDETAKA , HIRATA MASAYUKI , CRESSMAN MICHAEL
Published: June 2020

Background: TMX-049 is a novel xanthine oxidase (XO) inhibitor that reduced both liver and kidney XO activity and decreased albuminuria in a type 2 diabetes (T2D) rat model. This 12-week, placebo-controlled, double-blind study (ClinicalTrials.gov: NCT03449199) was designed to assess effects of TMX-049 40 or 200 mg (T40 or T200) compared to placebo (P) on urinary albumin to creatinine ratio (UACR) in participants with T2D and albuminuria despite treatment with an angiotensin inhibitor.

Methods: Eligible participants had T2D, HbA1c ≤ 11%, UACR 200-3000 mg/g, CKD-EPI eGFR ≥ 30 ml/min/1.73 m2 and serum uric acid (sUA) 4-10 mg/dL and were randomized to P (n=42), T40 (n=44) or T200 (n=44). The primary efficacy analysis utilized change from Baseline to Week 12 (or the last observation) in log-transformed UACR in an analysis of covariance (ANCOVA) model.

Results: Reductions in UACR from Baseline to Week 12 were P: 9%, T40: 14%, T200: 41%; the difference in change was statistically significant vs. P in the T200 group (p=0.031) but not in the T40 group (p=0.795). The reduction with T200 relative to P was 35% (95% CI: 4-56%). Mean changes in sUA were T40: -2.4 mg/dL and T200: -3.2 mg/dL (p<0.001 vs. placebo for both comparisons). A correlation between sUA and UACR change was not apparent in either the T40 or the T200 group. Both TMX-049 doses were generally well tolerated but 2 participants in the T200 group had episodes of gout. The proportion with any AE (P: 45%, T40: 43%, T200: 39%) or any serious AE (P: 10%, T40: 9%, T200: 5%) was similar in the P, T40 and T200 groups. No serious treatment related cutaneous, liver or renal adverse events were reported in either TMX-049 dose groups.

Conclusions: Once daily dosing of T40 or T200 was well tolerated in this 12-week study of participants with T2D and albuminuria. Although both doses reduced sUA, albuminuria reduction was only observed with T200. Reduced DKD progression may be achievable with TMX-049, a dual hepatic and renal XO inhibitor.

Disclosure

G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. H. Mikami: Employee; Self; Teijin Pharma Limited. M. Hirata: Employee; Self; Teijin Pharma Limited. M. Cressman: Employee; Self; Covance, LabCorp.

Funding

Teijin America, Inc.
50-OR: Beta Cell GDF15 Contributes to Diabetic Stress-Induced Beta-Cell Loss
Authors: XU GUANLAN , JO SEONGHO , CHEN JUNQIN , GRAYSON TRUMAN , SHALEV ANATH
Published: June 2020

Endoplasmic reticulum (ER) stress has been shown to play an important role in beta cell loss in diabetes. However, the factors involved in this process are still not fully understood. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor beta (TGFβ) family, is a stress response gene and is involved in various diseases. GDF15 is expressed in adult human beta cells; however, its role in beta cells and diabetes had not been elucidated. Interestingly, we now have identified GDF15 as a key factor involved in ER stress-induced beta cell loss. We found that GDF15 mRNA, protein levels and promoter activity were significantly induced by ER stress in INS-1 cells, Akita beta cells, and primary human islets and we identified the transcription factor involved. Moreover, we discovered that overexpression of GDF15 exacerbated, while knockdown of GDF15 inhibited ER stress-induced beta cell apoptosis, at least in part by regulating the pro-apoptotic factor CHOP. Most importantly, we found that GDF15 knockout mice were protected from STZ-induced diabetes, maintained insulin producing beta cells and exhibited improved serum insulin levels. Taken together, our findings suggest that GDF15 plays an important role in ER stress-induced beta cell death and that inhibition of GDF15 may represent a novel strategy to reduce beta cell loss and treat diabetes.

Disclosure

G. Xu: None. S. Jo: None. J. Chen: None. T. Grayson: None. A. Shalev: None.
505-P: Relationship between Plasma CRP and Fibrinogen Measured Using Dried Blood Samples and Vascular Complications in Type 2 Diabetes
Authors: IZUORA KENNETH , BASU ARPITA , ALVER AMALIE , SALAZAR ANTHONY , CAPURRO ANTONINA , GEWELBER CIVON L. , CROSS CHAD L. , WILLIAMS SHELLEY J. , EBERSOLE JEFFREY L.
Published: June 2020

Background: Measurement of biomarkers associated with cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) should improve our understanding of the pathogenesis of CVD and enhance disease prediction. Innovative approaches like the use of dried blood samples in assessing these biomarkers could simplify population-based studies.

Method: In this ongoing cross-sectional study, we enrolled 44 patients with T2DM (41% male, mean age 63.7 years). Following a fingerstick, five drops of blood were collected using a device containing absorbent paper and a desiccant (HemaSpot-HF®). Levels of C-reactive protein (CRP) and fibrinogen were measured using a Luminex assay. The presence of vascular complications (retinopathy, nephropathy, neuropathy, heart disease or stroke) was determined through an interview of each participant and a detailed chart review. Nonparametric M-W tests with exact p-values were used to compare groups using SPSS and R software.

Results: Patients with nephropathy had significantly higher levels of fibrinogen recovered from the devices (147.55 ± 163.27 mg/dl) compared to those without nephropathy (22.64 ± 10.27 mg/dl), (p=0.043). There was no significant relationship between fibrinogen and other vascular complications or CRP with any of the vascular complications associated with T2DM (p>0.05 for all).

Conclusion: Higher plasma fibrinogen was found among patients with T2DM and nephropathy compared to those without nephropathy. This may reflect a higher state of systemic inflammation related to tissue damage. The use of a dried blood sample method for biomarker assays can be applied to larger population studies and towards simplifying translational biologic research.

Disclosure

K. Izuora: None. A. Basu: None. A. Alver: None. A. Salazar: None. A. Capurro: None. C.L. Gewelber: None. C.L. Cross: None. S.J. Williams: None. J.L. Ebersole: None.
507-P: Changes of miR-223-3p May Play an Important Role in Renal Endothelial Cell Injury of Diabetes Kidney Disease (DKD)
Authors: LI RONG , JIE LIN , LUO JINGMEI , YANG ZHONGCE , ZHANG LIHUA
Published: June 2020

In our previously study, we found and verified the significantly decreased expression level of miR-223-3p in the plasma of DKD patients with plasma microarray, which was correlated with the severity of DKD. Some studies have found that Il-6/miR-223/STAT3 positively regulates the expression of pro-inflammatory cytokines and is involved in biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. In this study, in vitro and in vivo methods were used high glucose to stimulate human Glomerular endothelial cells (GEnCs) and kidney tissues of db/db DKD mice, respectively, to observe the changes of miR-223-3p and endothelial function indicators change. The preliminary study found that the expression of miR-223-3p in human GEnCs was significantly decreased under high glucose stimulation, and the mRNA expression of target gene IL6ST was significantly increased, as was the mRNA expression of VEGF. Western Blot showed significant increases in p-JAK2 and p-STAT3.In the kidney tissues of db/db DKD mice; miR-223-3p expression was also significantly decreased, while ll6st and Vegfa mRNA expression were significantly increased. The results indicated that the expression of miR-223-3p in human GEnCs stimulated by high glucose and renal tissues of db/db DKD mice were significantly decreased and the indicators of endothelial fine injury increased. Combined with cell and animal levels, the results suggested that miR-223-3p might be associated with DKD endothelial cell injury and endothelial dysfunction.

Disclosure

R. Li: None. L. Jie: None. J. Luo: None. Z. Yang: None. L. Zhang: None.

Funding

National Natural Science Foundation of China (81560126); Department of Science and Technology of Yunnan Province (2017FE468-042)