bluuebunny/crossref_metadata_2025 huggingface dataset:
421-P: Documentation of Heart Failure in Outpatients with Type 2 Diabetes and Evidence of Volume Overload: A Report from the Diabetes Collaborative Registry (DCR)
Authors: ARNOLD SUZANNE V. , KOSIBOROD MIKHAIL N. , JONES PHILIP , BEASLEY MICHAEL H. , GOYAL ABHINAV , CORDOVA JEANINE M. , FONAROW GREGG C. , SEMAN LEO J.
Published: June 2019

Background: Heart failure (HF) is one of the most common and morbid complications of T2D. Prompt recognition of early signs of HF may avert HF hospitalization and may also impact T2D meds (e.g., TZDs or possibly SGLT2i). We determined the rate and factors associated with HF diagnosis in T2D patients with evidence of volume overload requiring loop diuretics.

Methods: DCR is a U.S. registry of outpatient T2D patients from 3074 cardiology, endocrinology, and primary care providers. Among T2D patients receiving loop diuretics, we examined the rate of documentation of HF. We excluded patients with chronic liver disease, as they may have a non-HF indication for loop diuretics.

Results: Among 931,361 adults with T2D, 215,957 (23%) were on a loop diuretic of whom 110,809 (51%) had documentation of HF. Patients seen by cardiologists and PCPs were more likely have HF documented vs. endocrinologists (52% and 50% vs. 22%; p<0.001). Younger age, male sex, lower BMI, afib, CKD, and CAD were associated with greater odds of HF diagnosis (Figure).

Conclusions: Among U.S. outpatients with T2D, 23% had evidence of volume overload of whom half had a diagnosis of HF. While there may be non-HF indications for loop diuretics, our data suggest that a substantial proportion of T2D patients may have unrecognized HF and therefore could be missing therapies that could alter the clinical course of HF.

Disclosure

S.V. Arnold: None. M.N. Kosiborod: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eisai Co., Ltd., GlaxoSmithKline plc., Glytec, LLC, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P. Jones: None. M.H. Beasley: None. A. Goyal: None. J.M. Cordova: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. G.C. Fonarow: Consultant; Self; Abbott, Amgen Inc., Bayer US, Janssen Pharmaceuticals, Inc., Medtronic, Novartis Pharmaceuticals Corporation. L.J. Seman: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc.
43-OR: Post-transcriptional Regulation of Slc16a1 mRNA Is Essential for Maintaining Normal ß-Cell Function
Authors: MOSTAFA DINA , TAKAHASHI AKINORI , YAMAMOTO TADASHI
Published: June 2019

Slc16a1 gene belongs to a family of genes that are selectively silenced in mature β-cells as compared to other mammalian cell types and thereby named “β-cell disallowed genes.” Forced expression of Slc16a1 in β-cells interfered with insulin secretion and normal β-cell function. Slc16a1 is previously shown to be regulated by promoter methylation transcriptionally and miRNA post-transcriptionally. Here, we show deadenylation by CCR4-NOT complex is involved in silencing of Slc16a1 and maintaining normal β-cell function. We have previously shown that β-cell specific knockout of CNOT3 (CNOT3βKO), a CCR4-NOT complex and a positive modulator of its function causes upregulation of β-cell disallowed genes among them is Slc16a1 alongside with the decreased expression of β-cell specific genes and loss of normal β-cell function. In this study, we demonstrate the molecular mechanism by which CCR4-NOT complex is involved in silencing Slc16a1. Slc16a1 mRNA is stabilized in CNOT3βKO islets compared to wild type islets as assessed by calculating the relative amounts of introns and exons for Slc16a1 using total RNAseq data. RNA immunoprecipitation revealed Slc16a1 mRNA binds to CCR4-NOT complex. Expression of luciferase constructs bearing the 3′-untranslated regions (3’UTR) of Slc16a1 mRNA in wild type or CNOT3 knockdown HEK293T cells demonstrated that Slc16a1 mRNA is a direct target of CNOT3. CCR4-NOT complex binds to its target genes through interaction with RNA binding proteins that bind to special motifs in 3’UTR. We identified Roquin, an mRNA binding protein that binds to stem-loop structure in Slc16a1 3’UTR. Thus, CCR4-NOT complex -Roquin axis inhibits Slc16a1 expression in β-cells maintaining normal β-cell function.

Disclosure

D. Mostafa: None. A. Takahashi: None. T. Yamamoto: None.
431-P: Diabetic Retinopathy and Risk of Lower-Extremity Artery Disease in Type 2 Diabetes
Authors: FOUSSARD NINON , SAULNIER PIERRE , BERTRAND CAPUCINE , GAND ELISE , RAGOT STEPHANIE , POTIER LOUIS , VELHO GILBERTO , MARRE MICHEL , ROUSSEL RONAN , RIGALLEAU VINCENT , MOHAMMEDI KAMEL , HADJADJ SAMY
Published: June 2019

Diabetic retinopathy (DR) has been linked to lower-extremity artery disease (LEAD), but there remains some uncertainty as whether this association is mediated by other conditions. We assessed the association between DR and LEAD risk; and the influence of diabetes duration and control, systolic (SBP) or diastolic (DBP) blood pressure, smoking, diabetic kidney disease (DKD), or cardiovascular disease (CVD) in such association in the French prospective SURDIAGENE (SURVIe, DIAbete de type 2 et GENEtique) type 2 diabetes cohort. Baseline DR was staged as absent, non-proliferative, or proliferative. Major LEAD was defined as lower-limb amputation or peripheral revascularization requirement. Cox regression model was fitted to compute hazard ratio (HR) and 95% CI for major LEAD during follow-up by baseline DR stages. The prognostic value of DR in LEAD discrimination was tested using C-statistics. Among 1412 participants at baseline (men 58%, age 64.7±10.6 years, non-proliferative 37% and proliferative DR 7%), 112 (7.9%) developed a major LEAD during 6 years of follow-up. The incidence of LEAD increased with worsening DR: 4.1% (absent), 12.6% (non-proliferative), and 14.1% (proliferative)(p<0.0001). This association remained significant after adjustment for confounding variables (non-proliferative versus absent DR 2.29 [1.44-3.63], p<0.0001; proliferative versus absent DR 3.03 [1.54-5.96], p=0.001). No heterogeneity was observed across subgroups by diabetes duration, HbA1c, SBP, DBP, smoking, DKD, and CVD (all p-interaction>0.05). In addition to usual risk factors, DR improved LEAD discrimination (C-statistics change +0.023 [0.004-0.038], p=0.01). LEAD risk increases proportionally with DR severity, independently of diabetic, blood pressure, renal or cardiovascular conditions. DR has a significant prognostic value in LEAD prediction in people with type 2 diabetes.

Disclosure

N. Foussard: None. P. Saulnier: None. C. Bertrand: None. E. Gand: None. S. Ragot: None. L. Potier: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Sanofi. G. Velho: None. M. Marre: Advisory Panel; Self; Servier. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. R. Roussel: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Physiogenex. Research Support; Self; Janssen Pharmaceuticals, Inc. V. Rigalleau: None. K. Mohammedi: None. S. Hadjadj: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Servier. Research Support; Self; Bayer AG, Janssen Research & Development. Speaker's Bureau; Self; Abbott, Valbiotis.
438-P: Comparative Cardiovascular Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists vs. Other Glucose-Lowering Agents in Patients with Type 2 Diabetes—A Nationwide Cohort Study Using Prevalent New-User Design
Authors: YANG CHUN-TING , YANG CHENYI , KUO SHIHCHEN , OU HUANG-TZ
Published: June 2019

Introduction: Clinical trials have shown cardiovascular disease (CVD) benefits associated with glucagon-like peptide 1 receptor agonists (GLP-1ra) vs. placebo in patients with type 2 diabetes (T2DM). However, only few rigorous clinical trials and real-world studies exist for head-to-head comparison of GLP-1ra with other glucose-lowering agents (GLA). We aimed to investigate CV outcomes of GLP-1ra vs. dipeptidyl peptidase 4 inhibitors (DPP-4i), sulfonylureas (SU), and insulin.

Method: A nationwide cohort study was conducted using Taiwan’s National Health Insurance Research Database. Study cohort consisted of patients older than 18 years old and diagnosed with T2DM during 2004-2014, and followed until death or the end of 2015. Prevalent new-user design was adapted where all users who initiated GLP-1ra stably were retained for analyses and the comparability between GLP-1ra and other GLA users was matched by various confounders in patient characteristics. Study outcomes included composite CVD and 3-point major adverse CV event (MACE). Cox models were employed to assess the association between drug exposure and study outcomes.

Result: After 1:1 propensity score matching, 1,893, 1,573, and 1,367 GLP-1ra users were compared to DPP-4i, SU, and insulin users, respectively. Using GLP-1ra was associated with significantly lower risks of composite CVD (GLP-1ra vs. DPP-4i, SU, and insulin: hazard ratio, 0.73 [95% confidence interval, 0.57-0.96]; 0.71 [0.54-0.95]; 0.64 [0.49-0.83]) and 3-point MACE (GLP-1ra vs. DPP-4i, SU, and insulin: 0.55 [0.35-0.86]; 0.71 [0.44-1.15]; 0.46 [0.28-0.76]). In patients without CVD history, using GLP-1ra yielded a greater risk reduction in both CVD outcomes.

Conclusion: In real-world clinical practice, using GLP-1ra vs. other 3 major classes of GLA in Taiwanese T2DM patients showed CVD benefits, especially in those without CVD history.

Disclosure

C. Yang: None. C. Yang: None. S. Kuo: None. H. Ou: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092926)
445-P: Modified LDL-Immune Complexes (IC) and the Risk of CVD in Type 1 Diabetes
Authors: LOPES-VIRELLA MARIA F. , BEBU IONUT , HUNT KELLY J. , VIRELLA GABRIEL , BAKER NATHANIEL L. , BRAFFETT BARBARA , LACHIN JOHN ,   DCCT/EDIC RESEARCH GROUP
Published: June 2019

We have previously shown that high levels of oxidized LDL and AGE-LDL in circulating IC are strong predictors of atherosclerosis progression in 518 subjects with type 1 diabetes from the DCCT/EDIC cohort. In this study we investigated whether oxLDL, MDA-LDL and AGE-LDL in circulating IC measured in the same subjects at DCCT baseline were associated with acute CVD events. Three overlapping CVD outcomes were considered: any CVD events, major adverse cardiac and cerebrovascular events (MACE) and myocardial infarction (MI). Cox proportional hazards models assessed the association between IC biomarker values and the subsequent risk of CVD, using inverse probability weighting to obtain results representative of the full DCCT/EDIC cohort.

Results: Levels of AGE-LDL, oxLDL and MDA-LDL in circulating IC, measured at baseline (Table) were significantly associated with the 3 CVD outcomes in unadjusted models and were minimally attenuated after adjustment for age and mean HbA1c. After adjustments for conventional CVD risk factors, including LDL-Chol, high levels of oxLDL-IC and MDA-LDL-IC remained independently associated with increased subsequent risk of any CVD, and higher oxLDL-IC with increased risk of MACE and MI events.

Conclusions: High levels of oxLDL-IC measured more than one decade prior to the occurrence of CVD events identified patients at high risk, even after adjustment by LDL-C and conventional CVD risk factors.

Disclosure

M.F. Lopes-Virella: None. I. Bebu: None. K.J. Hunt: None. G. Virella: None. N.L. Baker: None. B. Braffett: None. J. Lachin: Board Member; Self; Tolerion, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
446-P: Associations of Blood Pressure (BP) with Incidence of Coronary Artery Disease (CAD)/Cerebrovascular Disease (CVD) According to Glucose Tolerance Status (GTS)
Authors: HARADA MAYUKO , FUJIHARA KAZUYA , YAMAMOTO MASAHIKO , KANEKO MASANORI , KITAZAWA MASARU , SUZUKI HIROSHI , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , YAMANAKA NAUTA , SEIDA HIROYASU , OGAWA WATARU , SONE HIROHITO
Published: June 2019

Although the 2017 ACC/AHA guidelines indicated a generalized BP goal of less than 130/80 mm Hg, the impact of BP separately on CAD or CVD in people with different GTSs has yet to be clarified. To clarify this, data from a nationwide claims database involving 293,396 participants without prior CAD or CVD during 2008-16 were analyzed. Multivariate Cox regression model was used to identify risks of a CAD and/or CVD event. Hazard ratios (HRs) were compared among 4 groups of participants divided according to stratified levels of BP [i.e., <130/90 mmHg, systolic BP (SBP) =130-139 and/or diastolic BP (DBP) =80-89 mmHg, SBP≥140 or DBP>90 mmHg, ≥140/90 mmHg] according to GTS [i.e., normal glucose tolerance (NGT), prediabetes (pre-DM), diabetes mellitus (DM)]. During the study period, 1099 CAD and 1990 CVD events occurred. Despite that a significant trend between BP and incident CAD was observed regardless of GTS, risk for CVD was dependent on BP only in the NGT and pre-DM groups. Moreover, there were no significant differences in CVD risks between categories of BP<130/90 mmHg and SBP=130-139 and/or DBP=80-89 mmHg among patients with DM. These results implied the necessity of setting specific BP goals according to GTS for prevention of CAD/CVD.

Disclosure

M. Harada: None. K. Fujihara: None. M. Yamamoto: None. M. Kaneko: None. M. Kitazawa: None. H. Suzuki: None. Y. Matsubayashi: None. T. Yamada: None. N. Yamanaka: None. H. Seida: None. W. Ogawa: Consultant; Self; Abbott. Research Support; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Lilly Diabetes, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.
449-P: Pulsed Electromagnetic Field Attenuates Cardiomyocyte Damages Induced by Ischemia in Hyperglycemic H9c2 Cells
Authors: TERRUZZI ILEANA , SENESI PAMELA , VACANTE FERNANDA , LUZI LIVIO
Published: June 2019

Cardiovascular complications are known as the main cause of mortality in subjects with diabetes mellitus (DM). In particular, ischemic heart disease is more common in patients with DM than in nondiabetics and promising therapeutically strategies to repair heart damages, including progenitor cell therapy or reprogramming non-cardiac cells, are inadequate in patients with DM. Emerging evidence indicates that hyperglycemia and oxidative stress are the primary causes of cardiac regenerative therapies’ failure in DM. Thus, it is essential to develop new therapeutic approaches aimed at contrasting the cardiac hyperglycemic microenvironment. Several researchers have proposed pulsed electromagnetic field (PEMF), an innovative medical device, to regenerate bone tissue, but very few works have studied PEMF possible use in other pathological condition and, in particularly, in cardiac damages. For the first time, we investigated the effects of PEMF preconditioning treatment on ischemic damages in H9c2 rat cardiomyocytes grown in hyperglycemic condition (25 mmol/L glucose). H9c2 cardiomyocytes were directly exposed to PEMF for 30 minutes (PEMF were generated by a commercially device having these features: 1,33 ms pulses at 75 Hz-1,5 mT) before ischemic injury. Ischemia was simulated by treating H9c2 cells with 5μM rotenone for 3 hours. Control cells were not pretreated with PEMF. Protein kinase B (Akt) and extracellular signal-regulated kinases (ERKs) activation were increased by PEMF stimuli: these kinases are closely related to attenuated cell apoptosis and oxidative stress. Indeed, our results indicated that PEMF treatment could significantly reduce reactive oxygen species (ROS) levels in hyperglycemic H9c2. Taken together, our preliminary study indicated that PEMF could be a potential strategy to improve the efficacy of cardiac regenerative therapies in diabetic patients.

Disclosure

I. Terruzzi: None. P. Senesi: None. F. Vacante: None. L. Luzi: Consultant; Self; McKinsey & Company. Research Support; Self; Allergan, Gelesis, SunStar Inc. Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Menarini Group, Novartis AG, Novo Nordisk Inc., Sunstar Foundation.
45-LB: Results of a Pilot Evaluation of a Novel Autologous Homologous Skin Construct Treatment of Diabetic Foot Wounds Refractory to Conventional Treatments
Authors: ZELEN CHARLES , ARMSTRONG DAVID G.
Published: June 2019

Background: An autologous homologous skin construct (AHSC) has been developed to treat complex cutaneous wounds (burns, chronic defects, and acute trauma) and was evaluated for treating diabetic foot ulcers (DFUs).

Methods: AHSC was manufactured from 1.5cm2 healthy full-thickness skin harvest. All of the tissue is utilized and the endogenous regenerative populations are activated during processing. It is spread evenly across the wound bed and dressed similar to an autologous skin graft. Eleven Wagner 1 and Wagner 2 DFUs refractory to conventional therapies including advanced wound care products were treated with a single application of AHSC.

Results: All harvests and deployments were performed in the outpatient setting. Wounds were dressed with silicone, compression bolster, and off-loading for the first 3 weeks followed by standard of care until closure. All harvest sites were primarily closed with no complications. All 11 wounds demonstrated complete graft take with one application. One patient with prior lower extremity hardware developed an infection separate from the AHSC-treated wound requiring extensive debridement including the treated wound. The remaining 10/11 wounds were closed by 10 weeks with a median of 5.8 weeks. Wounds remained closed at 2-week post-closure follow-up. There were no adverse events related to the AHSC treatments.

Conclusions: AHSC was able to close DFUs refractory to standard of care with one treatment utilizing normal clinic work flow and requiring only one application. Further evaluation with randomized controlled trials are warranted.

Disclosure

C. Zelen: Research Support; Self; Musculoskelatal Transplant Foundation, Polarity TE. D.G. Armstrong: None.
454-P: Weight Loss and Type 2 Diabetes Are Mutually Independent Predictors of Mortality in Patients with Established Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN-PURIN DANIELA , LARCHER BARBARA , MADER ARTHUR , SAID ABDURAHMAN , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2019

Obesity is a major risk factor for type 2 diabetes (T2DM), coronary artery disease (CAD) and premature mortality. This, however, does not necessarily imply that weight loss in patients who already have established CAD is associated with an improved outcome. In this study, we prospectively investigated the association of weight loss with mortality in a consecutive series of 483 patients with angiographically proven CAD. Weight was measured at baseline and after 4 years, and deaths were recorded over a mean follow-up period of 11.5±3.9 years. At baseline, weight was significantly higher in patients with T2DM (n=137) than in nondiabetic subjects (83±14 vs. 78±14 kg, p=0.003, amounting to BMI scores of 28.9±3.9 vs. 27.4±3.8 kg/m2; p<0.001). Prospectively, 56 (42.4%) of the patients with T2DM and 104 (31.2%) of the nondiabetic patients died (p=0.022); weight loss occurred in 76.6% of the patients with T2DM and in 73.4% of the patients who did not have diabetes (p=0.464). The amount of weight loss significantly predicted cardiovascular mortality univariately (standardized HR 1.14 [1.03-1.27]; p=0.013), as well as after multivariate adjustment including T2DM status (standardized adjusted HR 1.18 [1.05-1.33]; p=0.005). Conversely, T2DM remained a significant predictor of mortality after multivariate adjustment including weight loss (HR 1.67 [1.19-2.33]; p=0.003). We conclude that weight loss and T2DM are mutually independent predictors of mortality in patients with established CAD.

Disclosure

C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin-Purin: None. B. Larcher: None. A. Mader: None. A. Said: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
457-P: One-Year Administration of Anti-PCSK9 Antibody Is Enough to Stabilize Vulnerable Coronary Plaques in Diabetic Patients, which Are Resistant to Intensive Statin Therapy
Authors: HIRAI AIZAN , FUJIMURA KOJI , HIRAI KEIJI , KONDO SEIYA , SHIRAKAMI ATSUSHI , SAKAI TAKENORI , MURATA KAZUYA , TANIAI HISANORI , OKUZAKI KAZUTOSHI , KAGEYAMA TAKAHIRO
Published: June 2019

Purpose: Coronary plaque progression despite very low levels of LDL-C has been reported in the patients with coronary artery disease (CAD) who received intensive statin therapy (IST). Coronary CT Angiography (CCTA) has been applied to evaluate vulnerable coronary plaques having low attenuation of CT value. The major function of PCSK9 is the binding to hepatic LDL receptors, leading to their degradation. PCSK9 is produced also in vascular smooth muscle cells constituting the atherosclerotic lesion in addition to hepatocytes. PCSK9 promotes foam cell formation by suppressing the excretion of cholesterol from macrophages. Statin is demonstrated to promote PCSK9 production. PCSK9 has been proposed to play a crucial role in the pathogenesis of IST resistance. The present study was performed to establish a novel therapeutic approach to IST resistant vulnerable plaque of coronary artery in diabetic patients.

Methods: The present study included 142 T2DM patients with non-FHC asymptomatic CAD who developed vulnerable coronary plaques despite IST over 2 years. CCTA by use of 320-slice CT was applied to evaluate vulnerable coronary plaques. During the administration of anti-PCSK9 antibody, changes in serum lipids and CT value of vulnerable coronary plaques were determined.

Results: During 1 year administration of anti-PCSK9 antibody, 74% decrease in serum LDL-C was observed. Also, improvement of vulnerable coronary plaque, e.g., rise in the CT value of plaque (from 43.2 ±12.0 HU to 128.5 ± 52.3 HU, p<0.0001) was observed. Of the 142 patients, 95 patients finished the administration of the drug.

Conclusion: One year administration of anti-PCSK9 antibody produced a significant stabilization of vulnerable coronary plaques in the patients with asymptomatic CAD who are resistant to IST. An analysis of the plaque quality by CCTA is useful method for the evaluation of the effect of the drug on vulnerable coronary plaques.

Disclosure

A. Hirai: None. K. Fujimura: None. K. Hirai: None. S. Kondo: None. A. Shirakami: None. T. Sakai: None. K. Murata: None. H. Taniai: None. K. Okuzaki: None. T. Kageyama: None.
460-P: Treatment with Dipeptidyl Peptidase Inhibitors (DPP-4_Rx) Is Associated with Significant Reduction in Macrovascular Events Independent of Glucose Control
Authors: GARCIA-TOUZA MARIANA
Published: June 2019

We have observed renal protective effects with DPP-4 inhibitor therapy in a prior study done at the VA. Effects of DPP-4_Rx on cardiovascular morbidity and macrovascular events are disputed. Data from a large cohort of veterans diagnosed with type 2 diabetes mellitus (T2DM) were used to identify patients on DPP-4_Rx and without (control). Groups were matched for age (years), sex, BMI, initial renal function, follow-up time (FU, minimum 365 days). Propensity score matching (PSM) was used to adjust groups with a best odds ratio about 1:1. Groups were compared to determine the effect of DPP-4_Rx on the emergence of new macrovascular events identified by ICD-9 and all-cause mortality. Data were extracted using the Veterans Administration Informatics and Computing Infrastructure (VINCI), and analyzed using SAS. Results were compared using t-tests, frequency tables, Kaplan Meier survival curves, hazard ratios (HR) and p values.

Results show that subject with DPP-4 (N=24,763) had baseline variables similar to control. DM control improved with DPP-4_Rx but remained worse than control. A significant reduction in new macrovascular events was seen in DPP-4 group (Table). Mortality from all causes was reduced by 78.1%, but time to death was not changed.

We conclude that DPP-4_Rx associates with a significant reduction in frequency of all-cause mortality and macrovascular events independent of glucose control. The reduction of macrovascular events explains in part the improved survival and improvements in renal outcomes we have seen before.

Disclosure

M. Garcia-Touza: None.
466-P: Effect of Metformin on Cardiovascular Function in Type 1 Diabetes
Authors: ABOLARIN JOSHUA , SCHAUER IRENE E.
Published: June 2019

Cardiovascular (CV) disease remains the leading cause of mortality in type 1 diabetes (T1D) despite advances in glycemic control and to a greater extent than predicted by traditional CV risk factors. Metformin is generally thought to have vascular benefit in T2D and other insulin resistant states, though conclusive data for CV outcomes is lacking. In T1D metformin has been studied for glycemic control, but little attention has been paid to CV effects. We hypothesized that metformin would improve insulin sensitivity (IS), vascular function and compliance, and mitochondrial function in T1D. T1D participants (n=23) underwent a placebo-controlled, double-blind, random order, cross-over design intervention with 6 weeks of metformin vs. placebo. Glycemic control (CGM), cardiac function (echocardiography), vascular stiffness (Sphygmacor and Dynapulse), autonomic function, IS (hyperinsulinemic euglycemic clamp), and mitochondrial function in vivo (31P MRS) and ex vivo (muscle biopsy with high resolution respirometry) were measured after each phase. Glucose control and IS by clamp were not improved with metformin. Oxidative phosphorylation was increased in vivo, but ex vivo mitochondrial function was not improved. Cardiac contractility and output, arterial stiffness, systemic vascular resistance, and possibly autonomic function, were improved with metformin. These results suggest that metformin may provide CV benefit in T1D.

Disclosure

J. Abolarin: None. I.E. Schauer: Other Relationship; Spouse/Partner; Kestrel Labs.

Funding

National Institutes of Health
47-OR: Regulation of SIRT1 as a Target of Prevention of Diabetic Retinopathy in db/db Mice
Authors: VIEIRA CRISTIANO P. , LONGHINI ANA LEDA , CALZI SERGIO LI , DESIREE` DUPONT MARIANA , BUSIK JULIA V. , GRANT MARIA B.
Published: June 2019

SIRT1 is critical to vascular health and regulates glucose and lipid metabolism through its deacetylase activity. Type 2 diabetes-associated decreases in SIRT1 levels result in increased levels of acetylated LXR leading to reduced expression of reverse cholesterol transport genes and increased expression of NFκB-controlled pro-inflammatory genes. Diabetic circulating angiogenic cells (CAC) which are critical in vascular repair also demonstrate reduced SIRT1 and increasing its levels corrects CAC dysfunction (1). db/db mice were given SRT-1720 hydrochloride (100 mg/kg body weigh/day for 2 or 6 mo.) in their chow or fed normal chow beginning at diabetes onset. Retinal tissue, blood and bone marrow (BM) were collected. Electroretinograms (ERG) were performed at 2 and 6 mo. The BM supernatant was analyzed for cytokines. BM hematopoietic stem cells and CACs were assessed by flow cytometry. Retinal lipids were assessed by Mass Spectroscopy. At 2 mo, the retina of SRT1720-treated db/db mice demonstrated an increase in the ratio of total cholesterol/demosterol/lanosterol (197±85) compared to db/db (65±12. p<0.05). The percent of CAC was increased in db/db mice treated with SRT1720 (2.1±0.6 vs. 0.2±0.1 db/db. p<0.01). Most interestingly, SRT1720-treated db/db mice showed a decrease in the percentage of proinflammatory granulocyte-macrophage progenitors (1.7±0.3 vs. 2.8±0.6 db/db, p<0.008) and BM IL-1 beta (5±0.5 SIRT vs. 10±2.4 control db/db, p<0.01) levels. db/db mice with 6 months of diabetes showed a significant reduction in the ERG scotopic response and SRT-1720 treatment corrected this dysfunction (165±60 in SRT1720 db/db vs. 76±20µV, p<0.03), compared to controls (194±60µV). These findings support that activation of SIRT1 has multiple LXR-mediated beneficial effects. Namely, it improved the visual response in T2D model by regulating retinal cholesterol metabolism, increased vascular protective CACs and decreased pro-inflammatory progenitor cells and cytokines in the BM.

Disclosure

C.P. Vieira: None. A. Longhini: None. S. Li Calzi: None. M.D. DuPont: None. J.V. Busik: None. M.B. Grant: None.

Funding

National Institutes of Health (EY025383)
479-P: Combination of Trans-resveratrol and Hesperetin Corrects Unscheduled Increased Glucose Metabolism Driving Dysfunction of Human Periodontal Ligament Fibroblasts in Hyperglycemia In Vitro
Authors: RABBANI NAILA , ASHOUR AMAL A. , XUE MINGZHAN , THORNALLEY PAUL
Published: June 2019

Dysfunction of human periodontal ligament fibroblasts (PDLFs) contributes to increased prevalence and severity of periodontitis in diabetes. Hyperglycemia induces multiple pathways of metabolic dysfunction: mitochondrial dysfunction, hexosamine and protein kinase C pathway activation and increased formation of methylglyoxal (MG) in human periodontal ligament fibroblasts in vitro. We recently showed that increased glucose metabolism driving metabolic dysfunction in hyperglycemia is produced by glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis, increasing HK2 activity. In this study we investigated correction of this by combination of resveratrol and hesperetin (tRES-HESP) which induces expression of glyoxalase 1 (Glo1) and protects against increased MG. Human PDLFs were incubated in primary culture with 8 mM or 25 mM glucose for 3 days with and without 10 µM tRES-HESP. Glucose consumption and flux of MG formation was measured by enzymatic assay. Activity of glyoxalase 1 (Glo1) was measured by spectrophotometric assay. HK2 protein was determined by Western blotting. The flux of glucose consumption in high glucose concentration cultures of PDLFs was increased, compared to low glucose concentration control (10,658 ± 1,141 vs. 5,923 ± 706 nmol/106 cells/day, n = 3; +80%, P<0.01). Flux of formation of MG was increased similarly: 9.74 ± 0.42 v 6.79 ± 0.47 nmol/106 cells/day, n = 3; +44%, P<0.001). Glo1 activity was decreased in high glucose culture: 485 ± 78 vs. 946 ± 99 mU/mg protein (-49%, P<0.001). HK2 protein was increased: +32% at day 3 (P<0.05). tRES-HESP corrected increased glucose consumption and MG formation, and decreased Glo1 activity in high glucose concentration cultures. tRES-HESP offers a new therapy to prevent diabetic periodontitis.

Disclosure

N. Rabbani: None. A.A. Ashour: None. M. Xue: None. P. Thornalley: None.
485-P: Combination of Trans-resveratrol and Hesperetin Corrects Unscheduled Increased Glucose Metabolism Driving Endothelial Cell Dysfunction in Hyperglycemia In Vitro
Authors: THORNALLEY PAUL , ASHOUR AMAL A. , XUE MINGZHAN , RABBANI NAILA
Published: June 2019

Endothelial dysfunction contributes to the development of vascular complications of diabetes. Hyperglycemia induces multiple pathways of metabolic dysfunction: mitochondrial dysfunction, hexosamine and protein kinase C pathway activation and increased formation of methylglyoxal (MG). We recently showed that increased glucose metabolism driving this is produced by glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis, increasing HK2 activity. In this study we investigated correction of this by combination of resveratrol and hesperetin (tRES-HESP) which induces expression of glyoxalase 1 (Glo1) and protects against increased MG. Human aortal endothelial cells (HAECs) were incubated in primary culture with 5 mM or 20 mM glucose for 6 days with and without 10 µM tRES-HESP. Glucose consumption and flux of MG formation was measured by enzymatic assay. Activity of glyoxalase 1 (Glo1) was measured by spectrophotometric assay. HK2 protein was determined by Western blotting. The flux of glucose consumption in high glucose concentration cultures of HAECs was increased, compared to low glucose concentration control (1647 ± 242 vs. 748 ± 150 nmol/106 cells/day, n = 8; +120%, P<0.01). Flux of formation of MG was increased similarly: 1.13 ± 0.10 v 0.62 ± 0.07 nmol/106 cells/day, n = 8; +81%, P<0.01). Glo1 activity was decreased in high glucose culture: 1822 ± 143 vs. 1370 ± 160 mU/mg protein (-25%, P<0.01). HK2 protein was increased: +94% at day 3 and + 58% at day 6 (P<0.001). tRES-HESP corrected increased glucose consumption and MG formation, and decreased Glo1 activity in high glucose concentration cultures. This was achieved by inducing expression of glucose-6-phosphate dehydrogenase (G6PD), decreasing HK2 expression by decreasing the glucose-6-phosphate (G6P) and related carbohydrate response element transactivation by G6P/Mondo A/Mlx. tRES-HESP offers a new effective therapy of endothelial dysfunction.

Disclosure

P. Thornalley: None. A.A. Ashour: None. M. Xue: None. N. Rabbani: None.
49-OR: Association of Gene Polymorphisms and Plasma MiRNAs with Diabetic Retinopathy
Authors: POLINA EVELISE REGINA , SBRUZZI RENAN C. , DE OLIVEIRA FERNANDO MARQUES , CRISPIM DAISY , ENOIA MARIA ENOIA D. , CANANI LUIS H. , SANTOS KATIA G.
Published: June 2019

Circulating microRNAs (miRNAs/miRs) have emerged as potential disease biomarkers; however, their expression in diabetic retinopathy (DR) has been evaluated only recently in humans. Whilst it is recognized that sequence variants in miRNA genes (miRSNPs) can alter the miRNA-mediated regulation of gene expression, there are almost no studies on the association of miRSNPs with DR. In this case-control study, we investigated whether the functional polymorphisms rs531564 G>C (MIR124-1), rs4636297 A>G (MIR126) and 2910164 C>G (MIR146A) are associated with DR in 1,025 Brazilians with type 2 diabetes. We also evaluated whether the plasma levels of miR-124, miR-126 and miR-146a are associated with DR and with miRSNPs in 182 patients. Blood donors were included to determine the prevalence of miRSNPs (n = 104) and miRNA expression (n = 20) in the general population. Genotyping was done by real-time PCR and plasma levels were quantified by RT-qPCR. Genotype and allele frequencies in diabetic subjects did not significantly differ from those of blood donors, and the minor allele frequencies were similar to those reported in other populations. The MIR126 heterozygous genotype was more frequent in patients without DR than in those with DR (52% versus 44%, respectively, p = 0.040), and remained associated with this complication after controlling for clinical covariates. MiR-126 was markedly downregulated in diabetic subjects as compared to blood donors and even more reduced among those with DR (mean log2 fold-change of -0.7 ± 1.7, -1.1 ± 2.0 and -1.7 ± 1.6 for subjects without DR, with nonproliferative DR or with proliferative DR, p = 0.002). Patients carrying the A allele of the rs4636297 polymorphism had almost twice higher levels of miR-126 than patients with GG genotype. MiR-126 and miR-146a were strongly correlated and the levels of miR-146a were also lower in diabetic subjects than in blood donors. Overall, our findings reinforce that gene variants and expression of miRNAs are associated with DR in type 2 diabetes.

Disclosure

E.R. Polina: None. R.C. Sbruzzi: None. F.M. de Oliveira: None. D. Crispim: None. M.D. Enoia: None. L.H. Canani: Research Support; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. K.G. Santos: None.

Funding

Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (1994-2551/13-4); Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (14-0645)
492-P: A Novel Renoprotective Target of SGLT2 Inhibitor: HIF-1α Inhibition and AMPK Activation in Renal Proximal Tubular Epithelial Cells
Authors: BESSHO RYOICHI , TAKIYAMA YUMI , TAKIYAMA TAKAO , OTA TSUGUHITO
Published: June 2019

The renoprotective mechanism of SGLT2 inhibitors has not been fully elucidated. Tubular hypoxia is major driving force for proximal tubulopathy in diabetic kidney. In addition, diabetes causes dysregulation of AMP-activated protein kinase (AMPK) in kidney cortex. In this study, we assessed the effects of luseogliflozin, an SGLT2 inhibitor, on hypoxia inducible factor-1α (HIF-1α) expression and AMPK phosphorylation in cultured human renal proximal tubular epithelial cells (HRPTECs) and on tubulointerstitial pathological changes in diabetic mice. Luseogliflozin inhibited hypoxia (1%O2, 24h)-induced HIF-1α protein expression in HRPTECs in a dose-dependent manner (1-100µM). In addition, luseogliflozin increased AMPKα protein phosphorylation (Th172) in normoxic and hypoxic condition. Intriguingly, luseogliflozin suppressed oxygen consumption rate (OCR) measured by oxygen quenching phosphorescent probe by 69% in HRPTECs from normoxic condition. Hypoxia decreased OCR by 52% and luseogliflozin further decreased OCR by 33% from hypoxic condition. Moreover, luseogliflozin rescued hypoxic state in HRPTECs even under hypoxic conditions assessed by a hypoxia-sensitive dye, pimonidazole. These data indicate luseogliflozin inhibits HIF-1α expression through suppression of mitochondrial OCR, which leads to restore intracellular hypoxia. We next treated db/db mice with 15 mg/kg/day luseogliflozin for 8 weeks. Luseogliflozin ameliorated tubular injury compared to non-treated db/db mice. Furthermore, immunostaining of HIF-1α and fibronectin in cortical tubules revealed that luseogliflozin decreased HIF-1α and fibronectin expression in db/db mice.

In conclusion, luseogliflozin decreases mitochondrial OCR and ameliorates tubular fibrosis at least partly by suppressing HIF-1α expression and activating AMPK in renal proximal tubules of diabetic mice. These results may provide a novel renoprotective target of SGLT2 inhibitor.

Disclosure

R. Bessho: None. Y. Takiyama: None. T. Takiyama: None. T. Ota: None.
496-P: A New Method to Image Sweet Taste Receptors in the Pathogenesis of Diabetic Nephropathy: Detection of 18F Lactisole with PET/CT
Authors: ZHOU LUPING , HUANG WEI , LIU NAN , MA XIU M. , GUO MAN , CHEN QING , GAO CHENLIN , XU YONG
Published: June 2019

Previous studies showed that the expression of sweet taste receptors (STRs) was obviously downregulated in the pathogenesis of diabetic nephropathy (DN), suggesting that STRs may act as new therapeutic targets of DN. However, STRs are weakly expressed in kidneys, it is necessary to find a non-invasive method for detection of STRs distribution in the whole body and kidney. Lactisole, a broad-acting sweet antagonist, is commercially available and may be useful to assess the function and physiological role of the STRs. Whether the detection of isotope 18F labeled lactisole (18F-lactisole) with PET/CT can be used as a probe for imaging STRs expression differences is unclear. In this study, DN mouse model was induced by streptozotocin (STZ) in vivo, mouse glomerular mesangial cells (GMCs) and human proximal tubular cells (HK-2) were stimulated by high glucose in vitro, exogenous lactisole was used as an intervention reagent, 18F-lactisole was used as probe agent to evaluate the expression and distribution of STRs in the pathogenesis of DN. Our results showed that both the expression and distribution of STRs in mice were clearly imaged by PET/CT via intravenous injection of 18F-lactisole, 18F-lactisole signal in renal tissue was attenuated under the condition of diabetes, this trend persisted 2 hours after furosemide injection. Furthermore, exogenous lactisole significantly mitigated the effect of high glucose on STRs in vitro and vivo, which were detected by PET/CT or radioactive dosimeter via 18F-lactisole. These combined results support the hypothesis that detection of 18F-lactisole with PET/CT can be used as a new probe to image STRs and distinguish its expression level, suggesting a new method for non-invasive diagnosis of DN.

Disclosure

L. Zhou: None. W. Huang: None. N. Liu: None. X.M. Ma: None. M. Guo: None. Q. Chen: None. C. Gao: None. Y. Xu: None.
50-LB: Impact of Diabetes Self-Management Education (DSME) on A1C in High-Risk and Low-Income Chinese Immigrant Populations Residing in Urban Communities
Authors: SITU ESTHER , WOO JOSEPH , ZHANG XINYU
Published: June 2019

Background: Asian American Medical Group serves predominately monolingual senior or low income Chinese immigrants in the San Francisco Bay Area. This clinical study evaluated the difference of A1c improvement between T2DM patients who received DSME along with standard care vs. standard care alone. DSME has been widely underutilized by physicians in the independent practice setting.

Method: In this study, treatment was applied to 36 patients from a sample of 130 with T2DM with A1c >=8% and the average age were 70 years old for both cohorts per electronic medical record from 2017-2018. Before treatment, the treatment group’s average A1c was 9.83% vs. the control group was 8.96%. A dietitian with CDE was assigned to provide 1:1 counseling to patients/patient’s caregiver(s) on diabetes management, implement patient goals, and provide individualized care. RD actively communicated with PCPs for changes in care as needed. This program was provided to patients based on their demands and needs; ranging from 1-5 visits within a year.

Results: A total of 84% of patients receiving DSME reduced their A1c levels; 68% reducing A1c by >= 0.88%, 41% reducing A1c by >=1.76%. Comparatively, 48% of patients who didn’t receive DSME reduced their A1c levels, 37% reducing A1c by >= 0.88% and 25% reducing A1c by >=1.76%. A comparison between the cohorts that experienced an A1c reduction of >=0.88% revealed statistical significance at 95% confidence level (p = 0.0474). The data shows that there is a 31% difference between these two cohorts. Overall, patients receiving treatment experienced a mean reduction in A1c of 1.54% compared to an increase of 0.08% for the control group. Furthermore, 50% from the treatment side did lower A1c <8% whereas only 26% from the control.

Conclusion: The study demonstrated that DSME program improves A1c and points to the value of DSME. Thus, DSME should be promoted and widely utilized as a standard care regiment in the out-patient setting.

Disclosure

E. Situ: None. J. Woo: None. X. Zhang: None.
513-P: Adenosine Signal Plays an Important Role in Renoprotective Effects of SGLT2 Inhibitor in Proteinuric Diabetic Mice
Authors: SHIMADA KEIJI , TAKAGAKI YUTA , KANASAKI KEIZO , KOYA DAISUKE
Published: June 2019

Background: SGLT2 inhibitor (SGLT2i) displayed remarkable and early renal protection in overt nephropathy cases in clinical trials. However, detailed molecular mechanisms by which SGLT2i ameliorated renal damage in proteinuric diabetic patients were not elucidated yet. Here, we investigated that SGLT2i exerted renal protective effects via adenosine signal in diabetic mice with overt proteinuria.

Methods: STZ (200mg/kgBW) was injected intraperitoneally to induce diabetes in 8-week-old CD-1 mice. Four weeks later, mice were treated with intraperitoneal injection of bovine serum albumin (BSA: 0.3g/30gBW) with or without oral administration of SGLT2i TA-1887 (30mg/kg).

Result: In the STZ+BSA, pronounced renal tubular damages and interstitial fibrosis were observed; TA-1887 significantly ameliorated. The mRNA microarray analysis of kidney samples revealed that gene expressions related to TGF-β signaling pathway and epithelial-mesenchymal-transition program were increased in the STZ+BSA compared to the Control+BSA; TA-1887 suppressed them. Furthermore, the expression of ecto 5'-nucleotidase (5'-NT), which is essential for production of adenosine from AMP, was suppressed in STZ+BSA compared to Control+BSA; TA-1887 restored 5’-NT levels. In the immunohistological analysis, 5'-NT was expressed in glomeruli including mesangial cells and renal tubules of cortex/medulla in control kidney. However, 5’-NT was suppressed in all areas of STZ+BSA kidney; TA-1887 reversed the 5'-NT expression and distribution. Glomerular filtration rate (GFR) evaluated by inulin clearance was significantly greater in the STZ+BSA group and suppressed by TA-1887; the administration of the adenosine type 1 receptor inhibitor, DPCPX, cancelled the effects of TA-1887 on GFR and renal tubule damage.

Conclusion: The adenosine signal plays an important role in the renal protective effects of SGLT2i in diabetic mice with proteinuria.

Disclosure

K. Shimada: None. Y. Takagaki: None. K. Kanasaki: Other Relationship; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Toyama Pharmaceutical. D. Koya: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co., Ltd.

Funding

Japan Society for the Promotion of Science
516-P: Preventive Effect of Sulforaphane on Type 2 Diabetes-Induced Diabetic Nephropathy via AMPK-Mediated Activation of Glucose/Lipid Metabolism and Nrf2 Antioxidative Function
Authors: LI ZHUO , CAI LU , SUN YIKE
Published: June 2019

AMP-activated protein kinase (AMPK), particularly AMPK-α2 isoform, can attenuate the nephropathic pathogenesis by improving lipid metabolism. The objective of the present study was to define if sulforaphane (SFN) can protect type 2 diabetes (T2D)-induced nephropathy (DN) by activating AMPKα2 and Nrf2-mediated anti-oxidative pathways. AMPKα2 knockout (AMPKα2-KO) mice and their wild type (WT, C57BL/6J) mice were fed high-fat diet (HFD) for 3 months to induce insulin resistance, followed by an i.p. injection of streptozotocin (STZ) to induce hyperglycemia, i.e.:T2D. Control mice were fed normal diet without STZ. T2D and control mice were treated with or without SFN for 3 months and then stop SNF treatment, remained feeding either ND or HFD. These mice were collected 24-hour urine and then sacrificed at 3 and 6 months after diabetes onset to collect kidney’s tissue for pathological examination and molecular assays. Proteinuria was significantly increased in T2D mice at 3 and 6 months, but not in SFN-treated T2D mice. The destruction of kidney structure induced by T2D, including renal fibrosis, lipotoxicity, inflammation, oxidative stress/damage along with significant suppression of AMPK signaling pathways was prevented by SFN in WT diabetic mice. Specifically, T2D-induced, time-dependent from 3 to 6 months, increased accumulation of FN and COL-1, increased expression of TGF-β PAI-1, TNF-α and decreased phosphorylation of AMPKα and its downstream markers (ACC, CPT1-A, Sirt-1, PGC1α, PPARα, and Nrf2). All these pathogenic changes were prevented by SFN in WT diabetic mice, which was more at 6 months compared to 3 months. However, in AMPKα2-KO mice, suggesting that all these are AMPK-dependent. Therefore, the present study suggests that SFN protects against T2D-induced DN via AMPKα2-mediated improvement of lipid metabolisms and up-regulation of Nrf2-mediated anti-oxidative defense system.

Disclosure

Z. Li: None. L. Cai: None. Y. Sun: None.