bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&lt;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&gt;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)
510-P: Serum Mac-2 Binding Protein Is Associated with Diabetic Micro- and Macroangiopathy in People with Type 2 Diabetes
Authors: HASHIMOTO YOSHITAKA , HAMAGUCHI MASAHIDE , FUKUI MICHIAKI 
Published: June 2020

A close relationship between type 2 diabetes and nonalcoholic fatty liver disease, including liver fibrosis, has been reported. Mac-2 binding protein glycosylation isomer (M2BPGi) is reported as a non-invasive new serological glyco-biomarker for liver fibrosis. The purpose of this cross-sectional study was to investigate the association between serum M2BPGi levels and diabetic complications in people with type 2 diabetes. Serum M2BPGi levels were measured in terms of cut-off index (C.O.I.) units. Urinary albumin excretion (UAE) was calculated and nephropathy was graded as normo-, micro-, or macroalbuminuria. Retinopathy was divided into three groups: no- (NDR), simple- (SDR), or proliferative diabetic retinopathy (PDR). Mean age for 363 people (212 males) was 66.4 (10.6) years, the median M2BPGi level was 0.77 (0.57-1.04) C.O.I., and the median UAE was 22 (9-82.1) mg/g Cr. Serum M2BPGi level was increased with levels of diabetic microangiopathy. Furthermore, the M2BPGi levels in people with a history of cardiovascular diseases were higher than that in people without (0.82 [0.65-1.22] vs. 0.76 [0.55-1.03] C.O.I., p = 0.019). The logarithm of M2BPGi was associated with the logarithm of UAE after adjusting for covariates (β = 0.107, p = 0.031). This study reveals a close association between serum M2BPGi levels and diabetic micro- and macroangiopathy in people with type 2 diabetes.

Disclosure
Y. Hashimoto: None. M. Hamaguchi: None. M. Fukui: None.
515-P: Nonalbuminuric Diabetic Kidney Disease in Type 1 Diabetes: Incidence of Major Vascular Outcomes over a 10-Year Follow-Up
Authors: GAROFOLO MONIA , GUALDANI ELISA , CAMPI FABRIZIO , ARAGONA MICHELE , LUCCHESI DANIELA , BIANCHI CRISTINA , MICCOLI ROBERTO , FRANCESCONI PAOLO , PENNO GIUSEPPE , PRATO STEFANO DEL 
Published: June 2020

Non-albuminuric diabetic kidney disease (Alb-DKD) has been associated with a raised risk of CV outcomes and all-cause mortality in T1D. We report about the association between DKD phenotypes and CV outcomes in a single-centre, prospective, 10.4±2.9 years observation of 774 T1D. Rates of outcomes and vital status were censored on December 2017. Out of 774 T1D, 692 (89.4%) had no-DKD, 53 DKD 1-2 (6.8%), 17 (2.2%) Alb-DKD and 12 (1.6%) Alb+DKD. Incidences of CV outcomes, coronary events and ESRD were available for 736 subjects (95.1%). A CV event occurred in 49 T1D (6.7%; 6.42 events x 1000 PYs), rising from no-DKD (4.2%) to DKD 1-2 (28.6%) and Alb-DKD (35.3%). In Alb+DKD, due to competition with all-cause death, only 1 event occurred. Compared to no-DKD, the adjusted HRs were 4.43 (95%CI 2.27-8.61, p&lt;0.0001) in DKD 1-2 and 3.44 (1.34-8.81, p=0.010) in Alb-DKD. After further adjustment for prior CVD, the HR was fully preserved for DKD 1-2 (p&lt;0.0001), but attenuated for Alb-DKD (p=0.064). A coronary event occurred in 35 T1D (4.8%; 4.54 events x1000 PYs), rising from 3.0% in no-DKD to 18.4% in DKD 1-2 and 29.4% in Alb-DKD. Compared to no-DKD, the adjusted HRs were 3.85 (1.72-8.65, p=0.001) in DKD 1-2 and 4.75 (1.66-13.56, p=0.004) in Alb-DKD. After adjustment for prior CVD, the HRs were preserved for both DKD 1-2 (p&lt;0.0001) and Alb-DKD (p=0.016). Only 11 subjects developed ESRD (1.5%): 0.9% in no-DKD, 2.0% in DKD 1-2, 17.6% in Alb-DKD and 10.0% in Alb+DKD. Compared to no-DKD, the risk of ESRD raised only in Alb-DKD (HR 6.59, 95%CI 1.31-33.20, p=0.022). After adjustment for prior CVD, this HR was 5.26 (p=0.058). Compared to no-DKD, the risk of death was increased to the same extent of about four-five fold in Alb-DKD and Alb+DKD (p&lt;0.0001). In T1D, Alb-DKD was independently associated to a raised rate of CV, mainly coronary, morbidity. Though preliminary, our data do not to confirm Alb-DKD does not increase risk of ESRD. This DKD phenotype deserves intensive prevention strategies.

Disclosure
M. Garofolo: None. E. Gualdani: None. F. Campi: None. M. Aragona: None. D. Lucchesi: None. C. Bianchi: None. R. Miccoli: None. P. Francesconi: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited.
516-P: Urine Metabolite Biomarkers Predict Progression of Diabetic Nephropathy in 2,531 Individuals with Type 1 Diabetes
Authors: MUTTER STEFAN , VALO ERKKA A. , AITTOMÄKI VILJAMI , FORSBLOM CAROL , GROOP PER-HENRIK , WURTZ PETER ,   FINNISH DIABETIC NEPHROPATHY STUDY GROUP
Published: June 2020

People living with type 1 diabetes have increased risk to develop diabetic nephropathy. No targeted cure exists, but the progression can be slowed down if detected early. We tested whether metabolic biomarkers measured in urine could predict progression of diabetic nephropathy (DN) in the Finnish nationwide FinnDiane Study.
At baseline, 18 urine metabolites were measured with nuclear magnetic resonance metabolomics and scaled relative to urine creatinine. Individuals were followed for DN status for 9.0 years (± 5.1 years) until they progressed to their most severe DN status (334 events) or the latest known DN status for non-progressors. A Bonferroni-corrected P&lt;0.003 was considered significant.
Five out of 18 urine metabolites were robustly associated with risk for DN progression in Cox regression models adjusted for sex, year of diabetes diagnosis as well as baseline age, DN status, BMI and eGFR. Individuals with elevated urinary levels of alanine (Hazard Ratio (HR) = 1.49 [1.26, 1.77] per 1-SD creatinine-scaled metabolite concentration, , P=3×10-6), valine (HR = 1.34 [1.22, 1.48], P=4×10-9), 2–hydroxyisobutyrate (HR = 1.48 [1.30, 1.67], P=1×10-9), cis-Aconitate (HR = 1.17 [1.06, 1.28], P=9×10-4) and pseudouridine (HR = 1.45 [1.24, 1.69], P=4×10-6) showed higher DN progression rate.
We conclude that urinary biomarkers are indicative of kidney disease progression in type 1 diabetes, independently of baseline microalbuminuria and eGFR. The urinary biomarkers span multiple metabolic pathways, including microbial metabolism, citric acid cycle, and amino acids reflecting adiposity and dietary quality.

Disclosure
S. Mutter: None. E.A. Valo: None. V. Aittomäki: Employee; Self; Nightingale Health Ltd. Other Relationship; Self; Nightingale Health Ltd. C. Forsblom: None. P. Groop: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi, Sanofi. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medscape, Merck Sharp & Dohme Corp., Mundipharma International. P. Wurtz: Employee; Self; Nightingale Health Ltd. Stock/Shareholder; Self; Nightingale Health Ltd.

Funding
Folkhälsan Finland; Novo Nordisk Foundation; Academy of Finland
518-P: Association between Plasma Metabolites in the Urea Cycle and Diabetic Kidney Disease (DKD) in a Japanese Population
Authors: YAMAMOTO MASAHIKO , HARADA SEI , OKAMURA TOMONORI , FUJIHARA KAZUYA , YAGUCHI YUTA , KOMATSU TAKESHI , SATO TAKAAKI , KITAZAWA MASARU , YAMADA MAYUKO H. , KANEKO MASANORI , OSAWA TAEKO , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , KODAMA SATORU , SONE HIROHITO , TAKEBAYASHI TORU 
Published: June 2020

Some plasma metabolites in the urea cycle were reportedly associated with DKD, although results were inconsistent among studies. Also, few studies examined the association between urea cycle metabolites and DKD in community dwellers. To address this, we used the metabolite database from the Tsuruoka Metabolomics Cohort Study, which had global metabolomics in Japan, using capillary electrophoresis-mass spectrometry. Among 10,933 participants, cross-sectionally analyzed were 1,005 who had diabetes mellitus (DM) defined by HbA1c ≥6.5%, and/or fasting blood glucose ≥126 mg/dl and/or antidiabetic drug use. Of these 231 had DKD, which was defined by eGFR &lt;60 ml/min and/or test-strip positive proteinuria. Individuals with DKD (163 men, 68 women, mean age 66 y, mean HbA1c 6.8±1.2%, mean BMI 25.4±4.0) were significantly older than those without (508 men, 266 women, mean age 64 y, mean HbA1c 6.8±0.9%, mean BMI 25.0±3.7). Univariate and multivariate logistic regression models were used to identify the association between plasma metabolites (aspartic acid [Asp], citrulline, symmetric dimethylarginine [SDMA] and ornithine) and DKD in DM patients. We found that urea cycle metabolites were associated with DKD even after adjustment for possible confounders: age, sex, BMI, alcohol intake, smoking habit, energy intake and history of hypertension or dyslipidemia. Odds ratios (ORs) per 1 SD increase in Asp, citrulline, SDMA and ornithine for DKD were 1.24 (95% confidence interval [CI], 1.01-1.53), 1.80 (1.53-2.13), 1.52 (1.30-1.79) and 1.09 (0.95-1.25) as continuous variables, respectively. For sensitivity analyses, participants were divided into quartile groups for each metabolite. Multivariate logistic regression analyses between each metabolite quartile group and DKD showed similar results as above. These results may enable early detection of DKD or clarify the pathophysiology of DKD although a prospective study remains necessary.

Disclosure
M. Yamamoto: None. S. Harada: None. T. Okamura: None. K. Fujihara: None. Y. Yaguchi: None. T. Komatsu: None. T. Sato: None. M. Kitazawa: None. M.H. Yamada: None. M. Kaneko: None. T. Osawa: None. Y. Matsubayashi: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. T. Takebayashi: None.
52-LB: Provider Communication in Black Patients with T2DM Is Associated with Glycemic Control
Authors: REID HADLEY , LIN OLIVIA , FABBRO REBECCA L. , OLSEN MAREN , CHUNG SANGYUN T. , JOHNSON KIMBERLY S. , BATCH BRYAN 
Published: June 2020

Non-Hispanic Blacks (NHB) have a higher burden of T2DM and experience worse outcomes than Non-Hispanic Whites (NHW). Patient and system factors do not fully explain these disparities. We conducted a cross-sectional study of NHB and NHW with T2DM receiving care in 34 primary care practices. We examined the association between HbA1c (glycemic control), patient race, and the Interpersonal Processes of Care survey (IPC) which is divided into 7 subdomains describing the patient-provider relationship. These include hurried communication, elicited concerns and responded, explained results and medications, patient-centered decision making, compassionate and respectful, discriminated, and disrespectful office staff. We used adjusted linear regression to examine association between IPC subdomains, HbA1c and race. Due to large ceiling and floor effects we dichotomized IPC subdomains to the strongest endorsement and at least one answer that was not the strongest endorsement.
A total of 106 NHW and 115 NHB completed the study. The mean age of participants was 64.4 and 55% were female. The average HbA1c of the sample was 7.3%; 7.4% for NHB and 7.3% for NHW. There were no significant main effects of the IPC subscales; however, we found statistically significant race interactions for two of the IPC subscales. The HbA1c was on average 0.45% lower [-1, 0.1] among NHB who reported no hurried communication versus NHB who reported some hurried communication (p=0.48). Similarly, HbA1c was on average 0.64% lower [-1.19, -0.08] among NHB who fully endorsed that their providers explained results and medications compared to those who did not (p=0.01). The relationship between these subdomains and improved glycemic control was not observed in NHW.
These findings indicate that hurried communication and lack of explanation may contribute to worse glycemic control in NHB. Interventions aimed at improving these aspects of the patient-provider relationship may reduce racial disparities in glycemic control.

Disclosure
H. Reid: None. O. Lin: None. R.L. Fabbro: None. M. Olsen: None. S.T. Chung: None. K.S. Johnson: None. B. Batch: None.

Funding
National Center for Advancing Translational Sciences (TL1TR002555)
52-OR: Mitophagy Forms a Protective Response to Inflammatory Damage in Pancreatic ß-Cells
Authors: SIDARALA VAIBHAV , SOLEIMANPOUR SCOTT 
Published: June 2020

Inflammatory damage contributes to beta cell failure in all forms of diabetes, yet few protective responses to inflammation have been described. Mitochondria are a frequent target of inflammatory β-cell damage, thus impairing bioenergetics and initiating the pro-apoptotic machinery. Thus, we hypothesized that clearance of damaged mitochondria by mitophagy is a necessary protective response for inflammatory β-cell damage. Utilizing live-cell imaging, biochemical assays, and in vivo mitophagy biosensors, we observed that pro-inflammatory cytokines promote trafficking of damaged mitochondria through the mitophagy pathway in mouse and human islets. Cytokine treatment dissipated mitochondrial membrane potential, decreased cellular respiration, induced recruitment of the mitophagy initiator Parkin, activated turnover of mitochondrial proteins, and ultimately, targeted damaged mitochondria to lysosomes for clearance. To determine if mitophagy acts as a protective response, we assessed the role of pro-inflammatory agents in mice deficient for T1D gene and mitophagy regulator Clec16a in β-cells. Indeed, Clec16a-deficient β-cells had increased cytokine-mediated apoptosis and worsening hyperglycemia after streptozotocin treatment in vivo as well as an accumulation of fragmented, damaged mitochondria. To explore mechanisms by which mitophagy contributes to cytokine-mediated toxicity, we found that reactive O2 species and nitric oxide (NO) activate mitophagy and that mitophagy-deficient mouse and human islets treated with anti-oxidants or NO inhibitors ameliorated β-cell death. Finally, we observed that adenoviral overexpression of Clec16a rescued cytokine-induced apoptosis in human islets. Together, our studies position mitophagy as a crucial protective response to inflammatory β-cell demise activated by both oxidative and nitrosative stress, which could be targeted to prevent β-cell death in diabetes.

Disclosure
V. Sidarala: None. S. Soleimanpour: None.