bluuebunny/crossref_metadata_2025_split huggingface dataset:
440-P: The Effects of DPP-4 Inhibitors on Plasma Catecholamines and Their Metabolites in Patients with Type 2 Diabetes
Authors: PARK IE BYUNG , LEE DAEHO , LEE KIYOUNG 
Published: June 2019

Previous preclinical and clinical studies have raised a concern that dipeptidyl peptidase 4 inhibitors (DPP-4i) increased sympathetic activity, which may be related with increased risk of heart failure in DPP-4i-treated type 2 diabetics. In this study, we aimed to evaluate the relationship between DPP-4 activity and catecholamine secretion in patients with type 2 diabetes. Patients with type 2 diabetes (n=119) and normal healthy control subjects (n=25) participated in this cross-sectional study which included the measurement of serum DPP-4 activity and plasma levels of epinephrine (Epi), norepinephrine (NE), metanephrine (MET) and normetanephrine (NMET), other blood and urine biochemical tests, and the collection of demographic and clinical data. The median ages of patients with type 2 diabetes and healthy control subjects were 61 and 56 years, respectively. Compared with the control group, patients with type 2 diabetes were associated with lower plasma levels of catecholamines and their metabolites. In DPP-4i-treated diabetic patients (n=86) had lower plasma NMET level compared with other antidiabetic treatment group (n=36) [0.31 (IQR: 0.21, 0.43)] nmol/L vs. 0.41 (0.29, 0.46) nmol/L, p&lt;0.05], while the plasma concentrations of the two catecholamines and MET were comparable. The difference in plasma NMET level between the two treatment groups was not affected by beta-blocker and angiotensin II receptor blocker therapy, respectively. Additionally, in DPP-4i-treated type 2 diabetics, DPP-4 activity showed inverse correlations with plasma levels of NE (r=-0.312, p&lt;0.01) and NMET (r=-0.275, p&lt;0.05). However, those inverse correlations were not observed in the healthy control group and type 2 diabetics treated with non-DPP-4i antidiabetic agents. Our results suggest that DPP-4i treatment in type 2 diabetics affects NE release from sympathetic nerve in a DPP-4 inhibitory action-dependent manner.

Disclosure
I. Park: None. D. Lee: None. K. Lee: None.
450-P: Impact of Prior Coronary Artery Disease (CAD)/Cerebrovascular Disease (CVD) and Diabetes Mellitus (DM) on Incident CAD/CVD in Japanese
Authors: FUJIHARA KAZUYA , MATSUBAYASHI YASUHIRO , HARADA MAYUKO , OSAWA TAEKO , YAMAMOTO MASAHIKO , KITAZAWA MASARU , KANEKO MASANORI , SEIDA HIROYASU , YAMANAKA NAUTA , KODAMA SATORU , SONE HIROHITO 
Published: June 2019

Although DM and prior CAD/CVD are established risk factors for subsequent CAD and CVD, which has the higher impact on future events is unclear. Moreover, few studies have evaluated combined risks of a history of CAD/CVD on subsequent events in the same cohort. Thus, we analyzed a nationwide claims-based database of 292477 people in 2008-17. Participants had either non-DM or DM based on blood tests and prescriptions (non-DM 274860, DM 17617). They were also classified as with or without prior CAD/CVD based on ICD-10 codes and questionnaire. Cox regression model showed that compared with DM(-)CAD(-), DM(+)CAD(-), DM(+)CAD(-), and DM(+)CAD(+) had 5.2(4.1-6.6), 2.6(2.3-3.0), and 8.9(6.7-11.8) times increased risk of CAD, respectively. Compared with DM(-)CVD(-), DM(-)CVD(+), DM(+)CVD(-), and DM(+)CVD(+) had 5.8(4.6-7.4), 1.4(1.2-1.6), and 5.8(4.0-8.6) times increased risk of CVD, respectively. A stratified analysis of 8 groups of combinations of DM status and prior CAD/CVD showed that those with prior CVD had a significantly increased risk of future CVD and those with prior CAD and DM(+) had a high risk of subsequent CAD (Table). This shows that prior CAD/CVD confers a far higher risk than DM status alone for future CAD/CVD. Prior CAD and DM additively increased the risk of future CAD, while prior CVD alone increased the risk of future CVD without additional effects by diabetes.

Disclosure
K. Fujihara: None. Y. Matsubayashi: None. M. Harada: None. T. Osawa: None. M. Yamamoto: None. M. Kitazawa: None. M. Kaneko: None. H. Seida: None. N. Yamanaka: None. S. Kodama: None. 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.
464-P: Visceral Adiposity Index Identifies Both Type 2 Diabetes Mellitus and Prediabetes Better than Established Indices of Visceral Obesity in a Pad Cohort
Authors: ZIERFUSS BERNHARD , HOEBAUS CLEMENS , HERZ CARSTEN T. , KOPPENSTEINER RENATE , SCHERNTHANER GERIT-HOLGER 
Published: June 2019

T2DM is a major risk factor for cardiovascular morbidity and mortality in PAD. Clinical assessment of patients at risk for the development of T2DM remains challenging. Visceral obesity is a known risk factor of T2DM, but there is no consensus for a clinically applicable measurement. This study aimed to investigate the potential association of a novel visceral obesity parameter, visceral adiposity index (VAI), with dysglycemia (prediabetes and T2DM) in comparison to established indices in a PAD cohort. 366 patients with diagnosed PAD (defined by an ABI&lt;0.9 and Fonaine stage) were enrolled into this cross-sectionally designed study. All patients without known T2DM underwent screening with an OGTT. T2DM and prediabetes (PRE - IFG and IGT) were defined according to the ADA criteria. VAI was calculated according to the Amato formula. The cohort consisted of 43 patients with normal glucose tolerance (NGT), 159 patients with PRE and 164 patients with manifest T2DM. VAI was significantly higher in T2DM and PRE against NGT (median 2.33, IQR 1.35-3.44; 1.95, 1.26-2.86; 1.41, 1.18-2.41; p=0.006). In a multivariable binary logistic regression model adjusted for age, gender, LDL-C, serum creatinine, systolic blood pressure, smoking status and CRP the odds ratio for the highest VAI tertile for dysglycemia was 3.34 (95% confidence interval 1.38-8.06), 1.9 (1.07-3.38) for T2DM and 2.65 (1.05-6.68) for PRE alone. The same model for dysglycemia was significant, but weaker, for BMI above 25 kg/m2(2.27, 1.11-4.66) and waist circumference (WC) &gt;80cm in female and &gt;94cm in male patients (2.38, 1.01-5.62), but not significant for waist-hip ratio (WHR) &gt;0.85 in female and &gt;0.9 in male patients (2.24, 0.91-5.52). BMI, WC and WHR models neither predicted T2DM nor PRE (data not shown). Higher VAI values are associated with different states of dysglycemia alone and combined in a PAD cohort. In these patients VAI is superior to more common parameters of obesity.

Disclosure
B. Zierfuss: None. C. Hoebaus: None. C.T. Herz: None. R. Koppensteiner: None. G. Schernthaner: None.
47-LB: Readmission and Comprehension of Diabetes (DM) Education at Discharge
Authors: PINKHASOVA DIANA , SWAMI JANYA , PATEL NEETI , DONIHI AMY , SIMINERIO LINDA M. , FRENCH ESRA KARSLIOGLU , DELISI KRISTIN , HLASNIK DEBORAH S. , RUBIN DANIEL J. , KORYTKOWSKI MARY T. 
Published: June 2019

Hospitalized patients with DM are at high risk for early readmission. Improving inpatient education and discharge (DC) processes are proposed interventions for reducing this risk.
We examined the contribution of blood glucose (BG) 48 hr prior to DC (nadir, peak, STD, CV) and patient comprehension (PC) of instructions for home DM management following DC to risk for 30d readmission.
Insulin treated non-critically ill patients with DM (N=202) were recruited. Diabetes Early Readmission Risk Indicators (DERRI) were calculated for each participant, who were contacted within 48 hr of DC to complete a PC Questionnaire (PCQ).
Of 126 participants [age mean (STD) 61(12) years, BMI 32.9 (9.6) kg/m2, A1c 8.0 (2.2%), 45% women, 22% black, 85% type 2DM] who completed the PCQ, 42 (33%) required clarification of misunderstood DC instructions. PC scores were negatively correlated with BG STD (-0.17, 95% CI:-0.32,-0.02) and CV (-0.38, -0.7, -0.05).
There was no difference in median (25ile, 75ile) PC scores between patients with and without 30d readmission (79 (67, 93%) vs.83 (71,100%), p=0.19); however, there were more readmissions in those with PC scores &lt;100% compared to scores of 100% (n = 34) (29% vs. 15%, OR=2.4, 95% CI: 0.83, 6.88).
Among all 202 participants, median DERRI scores were higher in the 25% with 30d readmission (27 (24, 30)) than those without (19 (20, 24), p = 0.002).
In summary, these results demonstrate deficiencies in the hospital DC process as demonstrated by the need for clarification of information in &gt;30% of patients following DC. It is possible that this corrected information may have served as an intervention to reduce readmission risk. PC scores were negatively associated with glycemic variability preceding DC and scores &lt;100% were associated with a higher risk for readmission. DERRI scores were strongly associated with risk for 30d readmissions, representing the first prospective external validation of this tool. These results support proposals to improve the DC process and post-DC follow-up of patients with DM.

Disclosure
D. Pinkhasova: None. J. Swami: None. N. Patel: None. A. Donihi: None. L.M. Siminerio: None. E. Karslioglu French: None. K. Delisi: None. D.S. Hlasnik: None. D.J. Rubin: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. M.T. Korytkowski: None.

Funding
National Institutes of Health (UL1-TR-001857)
473-P: Identification of Novel Genes Participating in Diabetic Macrovascular Complications by DNA Methylation Modulation
Authors: LIAO YUNFEI , CHEN LULU , ZENG TIANSHU 
Published: June 2019

Diabetic vascular complications contribute to the increased morbidity and mortality of diabetic patients. However, the mechanism of diabetic macrovascular complication remains unclear.
Objective: We intend to unleash the role of DNA methylation modification in the pathological process of diabetic macrovascular complication and identify the potential biomarkers that could be beneficial for early intervention.
Methods: We screened for differentially methylated genes by methylated DNA immunoprecipitation chip (MeDIP-chip) in diabetic patients. The validation of MeDIP-chip was performed by methylation-specific PCR (MSP). Furthermore, we investigated the expressions of the aberrantly methylated genes and their functions in the model of diabetic mice.
Results: Serval aberrantly methylated genes have been explored, including phospholipase C beta 1 (PLCB1), cam kinase I delta (CAMK1D), and dopamine receptor D5 (DRD5) which participated in calcium signaling pathway. Meanwhile, vascular endothelial growth factor B (VEGFB), placental growth factor (PLGF), fatty acid transport protein 3 (FATP3), coagulation factor II thrombin receptor (F2R), and fatty acid transport protein 4 (FATP4) which participated in vascular endothelial growth factor receptor (VEGFR) signaling pathway, were also been found. After MSP and gene expression validation in peripheral blood of patients, PLCB1, PLGF, FATP4, and VEGFB were corroborated. Combining with the detection of fatty acid uptake by radionuclide tracing, DNA methylation regulated VEGFR signaling pathway was demonstrated to mediate the lipid deposition in aortas of diabetic mice.
Conclusions: Our study identifies novel biomarkers and therapeutic targets in diabetic macrovascular complications. DNA methylation in VEGFR signaling pathway might play an important role in diabetic macrovascular complications.

Disclosure
Y. Liao: None. L. Chen: None. T. Zeng: None.

Funding
National Natural Science Foundation of China
482-P: Linagliptin Induces M2 Macrophage Polarization and Suppresses Progression of Atherosclerosis in High-Fat-Fed ApoE-Deficient Mice
Authors: NISHIDA SHUHEI , MATSUMURA TAKESHI , SENOKUCHI TAKAFUMI , ISHII NORIO , MURAKAMI-NISHIDA SAIKO , YAMADA SARIE , MORITA YUTARO , WADA TOSHIAKI , MOTOSHIMA HIROYUKI , KONDO TATSUYA , ARAKI EIICHI 
Published: June 2019

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppressed the progression of atherosclerosis in atherosclerotic mouse models. However, exact mechanism has been unclear. In this study, we investigated whether linagliptin suppressed progression of atherosclerosis in high fat diet (HFD)-fed apolipoprotein-E-deficient (ApoE KO) mice via anti-inflammatory effects on macrophages.
Methods: HFD-fed ApoE KO mice were treated orally with linagliptin (10 mg/kg/day). After 8 weeks of treatment, whole aorta and aortic sinus were stained with Oil red O, or anti-4-Hydroxynonenal (4-HNE) and anti-F4/80 antibodies. Mouse bone marrow-derived macrophages were used in vitro study. Intracellular ROS generation was evaluated by H2DCF-DA assay. Expression of iNOS, MCP-1, TNF-α, arginase-1, Mgl2 and Ym1 mRNA, and macrophage polarization were evaluated by real-time RT-PCR and FACS scan, respectively.
Results: There were no significant differences on food intake, body weight, blood glucose levels between each group, but cholesterol concentrations in VLDL and LDL particle were lower in linagliptin group. Oil-Red-O staining demonstrated that size of atherosclerotic lesions was decreased in linagliptin group. The 4-HNE-positive area and number of macrophages in plaques were decreased, and mRNA expression of arginase-1, Mgl2 and Ym1 in the aorta were higher in linagliptin groups than those in control groups. Linagliptin suppressed ROS generation, increased mRNA expression of arginase-1, Mgl2 and Ym1, and ameliorated LPS+IFNγ-induced reduction of M2 macrophages.
Conclusion: This study suggests that linagliptin suppresses the progression of atherosclerosis in HFD-fed apoE KO mice. Moreover, linagliptin suppresses ROS generation and increases the polarization of M2 macrophages. These findings may indicate the beneficial effects of linagliptin for the prevention of diabetic macrovascular complications.

Disclosure
S. Nishida: None. T. Matsumura: None. T. Senokuchi: None. N. Ishii: None. S. Murakami-Nishida: None. S. Yamada: None. Y. Morita: None. T. Wada: None. H. Motoshima: None. T. Kondo: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi.
486-P: Hyperglycemia Promotes Epigenetic Priming of RELA/p65 Gene in Cord Blood-Derived CD34+ Stem Cells and Their Differentiation into Proinflammatory CD16 Myeloid Cell Population
Authors: VINCI MARIA CRISTINA , VIGORELLI VERA , GENOVESE STEFANO , POMPILIO GIULIO 
Published: June 2019

Background: Diabetic patients are characterized by a systemic pro-inflammatory state and an increased propensity to develop atherosclerosis. Since epigenetic mechanisms are known to be involved in the regulation of inflammatory genes of vascular cells under diabetic conditions, we hypothesized that uncontrolled hyperglycemia may epigenetically skew circulating CD34+ progenitors towards an inflammatory phenotype.
Results: We investigated the impact of hyperglycemia on the epigenetic makeup of NFkB gene, a gate-keeper of the inflammatory control of CD34+ cells, and on the differentiation into myeloid progenitors. CD34+ cells exposed to high glucose (HG) showed a significant reduction of the repressive epigenetic modification H3K9me3 on RELA/p65 gene encoding for nuclear factor NF-kappa-B p65 subunit. This epigenetic alteration coincided with an increased recruitment of RNA polymerase II at level of p65 promoter and with a significant transcription up-regulation. Interestingly, the KAT2B/PCAF gene, an histone acetyltransferase implicated in NFkB-p65 acetylation and nuclear stabilization, was also overexpressed. Consistently, HG-CD34+ cells showed higher acetylation of NFkB in the lysine-310 and increased expression and secretion of the NFkB-p65 target cytokines, TNFα and IL6. Moreover, in vitro differentiation of HG-CD34+ cells into myeloid lineage generated higher level of pro-inflammatory CD16+ and CD14+ CD16+ monocyte subsets when compared to the normoglycemic counterpart.
Conclusions: These results suggest that elevated glucose exposure might epigenetically prime CD34+ cells for a pro-inflammatory response as well as skew CD34+ cell differentiation into inflammatory cell lineages.

Disclosure
M. Vinci: None. V. Vigorelli: None. S. Genovese: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Hikma Pharmaceuticals. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. G. Pompilio: None.

Funding
Ricerca Finalizzata, Ministero della Salute (PE-2011-02348537)
5-LB: Improving Diabetes Prevention with Benefit-Based Tailored Treatment: Disseminating Individualized Risk Estimates
Authors: CIEMINS ELIZABETH L. , POWELSON JILL E. , NELSON JASON P. , COLANGELO FRANCIS R. , CUDDEBACK JOHN K. , KENT DAVID M. 
Published: June 2019

Objective: Implement in an electronic health record (EHR) a predictive model for people with prediabetes that provides individualized benefit estimates for taking metformin or participating in the Diabetes Prevention Program (DPP). This model stratifies people with prediabetes by the potential to reduce their risk of progression to diabetes based on regression models developed directly on the DPP trial and recalibrated to Optum data. With 1/3 of adults having prediabetes, health systems need a way to prioritize.
Study Design: Pre/post implementation study including provider and patient surveys and data on use of the predictive model. The model estimates risk of progression to diabetes with usual care, the DPP, or metformin, based on 11 demographic, biometric and diagnosis variables available in the EHR.
Population Studied: Patients with prediabetes at 10 pilot primary care clinics, where providers access the model via an EHR click and the data elements are automatically populated from the EHR.
Principal Findings: The predictive model was used on 68% (n=2,304) of patients with prediabetes between 5/1/18 and 1/31/19. A total of 43% of patients were classified as high-risk, 54% as moderate-risk, and 4% as low-risk. Treatment - either referrals to the DPP or prescriptions for metformin - was provided for 63% of high-risk, 15% of moderate-risk, and 4% of low-risk patients. DPP referrals and metformin prescriptions for these high-risk patients increased substantially after implementation of the calculator (DPP: 0% to 44%; Metformin: 2% to 19%).
Conclusions: A predictive model, embedded in the EHR, that predicts individual patient risk for developing diabetes at the point of care improved treatment for patients with prediabetes. Use of individualized risk estimates resulted in the prioritization of treatment for patients at greatest risk of developing type 2 diabetes.

Disclosure
E.L. Ciemins: None. J.E. Powelson: None. J.P. Nelson: None. F.R. Colangelo: None. J.K. Cuddeback: None. D.M. Kent: None.

Funding
Patient-Centered Outcomes Research Institute
501-P: ROCK2 Activation Accelerates Podocyte Injury in Diabetic Kidney Disease
Authors: MATOBA KEIICHIRO , KAWANAMI DAIJI , TAKEDA YUSUKE , NAGAI YOSUKE , UTSUNOMIYA KAZUNORI 
Published: June 2019

Podocyte apoptosis is a key pathological finding in the progression of diabetic kidney disease. Here we demonstrate that Rho-kinase (ROCK) mediates transforming growth factor β (TGF-β)-induced podocyte apoptosis. Mechanistically, ROCK regulates Notch ligand induction via the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) but not Smad pathways. Consistently, the ROCK inhibitor fasudil suppressed albuminuria and the urinary excretion of nephrin in type 2 diabetic db/db mice and attenuated podocyte apoptosis. The expression of Notch ligand and apoptosis markers such as Bax and cyclin-dependent kinase inhibitor 1A (CDKN1A) was decreased in podocytes derived from fasudil-treated db/db mice. In order to elucidate the isoform-specific roles of ROCK, we knocked down ROCK1 and ROCK2 separately using siRNA duplexes. Importantly, Notch ligand expression was specifically regulated by ROCK2 but not ROCK1. In renal tissue, ROCK2 was expressed mainly in nucleus of glomerular cells, tubules, and vascular walls in wild type mice. Podocyte colocalization was revealed by immunofluorescence of ROCK2 and nephrin, indicating the involvement of ROCK2 in diabetic podocytopathy. The present study provides evidence that ROCK plays a key role in podocyte apoptosis. ROCK2 may be an attractive therapeutic target for diabetic kidney disease.

Disclosure
K. Matoba: Research Support; Self; Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Sanofi, Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited. D. Kawanami: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Y. Takeda: None. Y. Nagai: None. K. Utsunomiya: None.

Funding
Japan Society for the Promotion of Science; Uehara Memorial Foundation; Japan Diabetes Society; Ichiro Kanehara Foundation; MSD Life Science Foundation; Yokoyama Foundation
510-P: Protection of Kidney and Pancreas in Diabetes via Rescuing Disruption of STRA6-Retinol Cascade by SGLT2 Inhibitor, not Sulfonylurea
Authors: SHIN SHYI-JANG 
Published: June 2019

Sodium glucose co-transporter 2 (SGLT2) inhibitors have been proved to be beneficial for cardiovascular and renal outcome in diabetic patients. Our study demonstrated that disruption of intracellular retinol signaling is associated with diabetic nephropathy. Retinoid homeostasis, regulated by RBP4/STRA6/CRBP1/LRAT/RARs pathway, is also very crucial in cell biological function of pancreas and islets. This study aimed to demonstrate whether SGLT2 inhibitor or sulfonylurea could protect pancreas and kidney from diabetes-related injury. Diabetic db/db mice were treated with empagliflozin or glibenclamide for 4 weeks at their age of 8 weeks. This study analyzed RBP4/STRA6/CRBP1/LRAT/RARs signals and p-JNK, caspase in both pancreas and kidney, and functional markers of pancreatic β-cells (insulin, MafA, Pdx1, and NKX6.1) in pancreas of wild type, db/db, glibenclamide-treated db/db and empagliflozin-treated db/db mice. Significant reduction of insulin, MafA, Pdx1 and NKX6.1 protein and mRNA in pancreas of db/db mice were found and could be rescued in empagliflozin-treated db/db mice, but not in glibenclamide-treated db/db mice. STRA6, CRBP1, LRAT and RARβ protein and mRNA levels were reduced, while p-JNK and caspase expression increased in pancreas and kidneys of db/db mice. These changes were recovered in empagliflozin-treated db/db mice, but not in glibenclamide-treated db/db mice. The concentration of retinol, and retinoic acid, measured by HPLC, were also conserved in pancreas of empagliflozin-treated db/db mice, not in glibenclamide-treated db/db mice.
In conclusion, this study indicates that empagliflozin, but not glibenclamide, exerts protective effects on pancreas and kidneys from diabetes through retrieving the disruption of STRA6-retinol signals in db/db mice.

Disclosure
S. Shin: None.

Funding
Taiwan Ministry of Science and Technology