bluuebunny/crossref_metadata_2025 huggingface dataset:
472-P: The Profiles of MicroRNAs from Urinary Extracellular Vesicles (EVS) Prepared by Various Isolation Methods and Their Correlation with Serum EV MicroRNAs in Patients with Type 2 Diabetes and Diabetic Nephropathy
Authors: KIM YOOMI , LEE DAEHO , LEE KIYOUNG
Published: June 2020

MicroRNAs that circulate in biological fluids are frequently enclosed in extracellular vesicles. However, urinary EVs and their cargo miRNAs have not been systematically studied according to their EV isolation methods. In type 2 diabetics with nephropathy (n=4), we compared miRNA species in urine EVs prepared by various isolation methods, including ultracentrifugation, qEV original size exclusion column, ExoQuick-TC Plus (ExoQuick), and simple ultrafiltration using Amicon Ultra centrifugal filter devices (Amicons) 10K and 100K. EV miRNAs were profiled by next-generation sequencing . We evaluated the correlations of EV miRNA expression between the urine and serum samples isolated by UC. From each of 100 ml of urine, the UC method yielded the highest number of EV miRNA species (233 ± 37.3), with the ExoQuick yielded the lowest (103 ± 17.4). Urine EV miRNA profiles were highly correlated between UC, qEV, ExoQuick and Amicon 10K methods. EV miRNA profiles between the urine and serum samples showed variable correlations between the patients (paired sample number=3, r =0.39-0.72). we examined EV miRNAs from urine isolated using two pore sizes with 10 kDa and 100 kDa filters. The expression level patterns of EV miRNAs isolated from urine were strongly correlated between Amicon 10K and the other three validated methods (UC, qEV, and ExoQuick). Pearson correlation coefficients between Amicon 100K and the three methods varied from 0.19 to 0.33. UC, qEV, ExoQuick, and Amicon 10K are suitable for urinary EV isolation to profile miRNAs. Urine- and serum-derived EV miRNA profiles have positive and variable correlations depending on specific patients. Further studies are required to identify a factor that influences these correlations and to determine the sample type that better describes the clinical and pathophysiological status of diabetic patients with diabetic kidney disease.

Disclosure

Y. Kim: None. D. Lee: None. K. Lee: None.
478-P: Nox5 Aggravates Renal Injury Independent of Nox4 Expression in Diabetes
Authors: JHA JAY C. , URNER SOFIA , DAI AOZHI , COOPER MARK E. , RODEN MICHAEL , KENNEDY CHRIS , JANDELEIT-DAHM KARIN
Published: June 2020

Background: Oxidative stress plays an important role in the pathogenesis of diabetic kidney disease (DKD). Evidences suggest roles for pro-oxidant enzymes Nox4 and Nox5 in animal models of DKD. Nox5 is present in mans but not in mice/rats. It appears that Nox5 could be a main culprit in human DKD. Therefore, we aimed to examine the roles of Nox5 vs. Nox4 and their relative contribution to renal pathology in DKD.

Methods: We examined the expression and interaction of Nox5 and Nox4 and ROS formation in human kidney biopsies. In vitro, certain human renal cells being knockdown for Nox4 and Nox5 were exposed to high glucose. In vivo, we examined the effect of Nox5 expression in the absence of Nox4 in STZ- diabetic mice. We developed rabbit models of DKD and Nox5KO rabbits.

Results: Increased Nox5 expression and enhanced ROS level was seen in human diabetic kidney biopsies compared to nondiabetic kidney. Nox5 shows the highest upregulation in human renal cells exposed to high glucose in comparison to other Nox isoforms. Nox5 silencing attenuated high glucose induced increased expression of markers of fibrosis, inflammation and putative elements via reduction in ROS formation. Nox5 appears to be upstream of Nox4 and that Nox5 inhibition downregulates Nox4, but not vice versa. In vivo, cell specific expression of Nox5 in both Nox4 KO and GKT137831 (a renal Nox4 inhibitor) treated diabetic mice demonstrated a 30-40% increase in albuminuria, mesangial expansion, renal fibrosis and inflammation as well as enhanced ROS production in comparison to diabetic mice not expressing Nox5. In addition, both high fat feeding and alloxan induced diabetic rabbits showed increased renal Nox5 expression in association with increased renal injury along with upregulation of CTGF, fibronectin and MCP-1 as well as enhanced renal ROS production.

Conclusions: These findings provide evidence that Nox5 plays a superior pathogenic role in DKD in comparison to Nox4. Therefore, targeting Nox5 may represent a better approach to treat and prevent DKD in human.

Disclosure

J.C. Jha: None. S. Urner: None. A. Dai: None. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis AG, Sanofi-Aventis, Servier. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. C. Kennedy: None. K. Jandeleit-Dahm: None.
481-P: Renal Distribution and Expression Analysis of ROCK Isoforms in Diabetic Kidney Disease
Authors: MATOBA KEIICHIRO , TAKEDA YUSUKE , NAGAI YOSUKE , AKAMINE TOMOYO , KANAZAWA YASUSHI , KAWANAMI DAIJI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI
Published: June 2020

The small GTPase Rho and its effector, Rho-kinase (ROCK), are implicated in the fundamental cellular processes (e.g., cell adhesion, migration). Studies over the past decade have illuminated ROCK as an important regulator of diabetic kidney disease. We previously demonstrated elevated renal ROCK activity in both type 1 and type 2 diabetic murine models. In an attempt to elucidate the roles of the activated ROCK, we provided evidence that ROCK inhibition attenuates an increase of urinary albumin excretion, glomerular sclerosis, and podocyte loss in rodents. Mechanistically, ROCK regulates inflammatory events as well as hypoxia-induced fibrotic reactions. However, specific roles of ROCK isoforms, ROCK1 and ROCK2, in diabetic kidneys remain unclear. In the present study, we first investigated the renal distribution of ROCK1 and ROCK2 using wild type mice and human kidneys obtained at necropsy. The immunohistochemical analysis detected both isoforms in glomeruli, tubules, and vessel walls. Whereas ROCK1 was mainly expressed in the cytoplasm, ROCK2 was accumulated in the nucleus of these cells. Double staining with anti-nephrin antibody showed co-localization of ROCK2 with nephrin, indicating distinctive roles of ROCK2 in the glomerular podocyte. In order to elucidate the role of podocyte ROCK2, we next evaluated gene expression levels of ROCK2 in high-fat diet-fed mice and patients with diabetic kidney disease. In both mice and patients, ROCK2 was increased in the setting of diabetes compared to healthy subjects. Of note, glomerular ROCK2 mRNA levels were positively correlated with the increase of urinary albumin excretion in mice. When considered alongside our previous observations, the current work highlights the importance of ROCK2 in diabetic podocytopathy.

Disclosure

K. Matoba: Research Support; Self; Sanofi K.K., Takeda Pharmaceutical Company Limited. Y. Takeda: None. Y. Nagai: None. T. Akamine: None. Y. Kanazawa: None. D. Kawanami: None. K. Utsunomiya: None. R. Nishimura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited.

Funding

Japan Society for the Promotion of Science (18K15985)
492-P: Associations between Novel Biomarkers of Inflammation and Estimated Glomerular Filtration Rate in Adults with Recent-Onset Type 1 and Type 2 Diabetes
Authors: MAALMI HAIFA , HERDER CHRISTIAN , STRASSBURGER KLAUS , URNER SOFIA , JANDELEIT-DAHM KARIN , ZAHARIA OANA P. , KARUSHEVA YANISLAVA , BODIS KALMAN , RATHMANN WOLFGANG , MARKGRAF DANIEL F. , BURKART VOLKER , SZENDROEDI JULIA , RODEN MICHAEL
Published: June 2020

Background: The development of anti-inflammatory therapies for renal function loss in patients with diabetes requires identification of specific biomarkers which might differ by diabetes type. This study aimed to investigate associations between a novel panel of biomarkers of inflammation and estimated glomerular filtration rate (eGFR) in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D).

Methods: This study was based on 145 participants with T1D (mean age 33.8 years, 60.7% males) and 250 participants with T2D (mean age 55.3 years, 66.4% males) from the observational prospective German Diabetes Study (GDS), which includes adults with a diabetes duration <1 year. A panel of 74 biomarkers of inflammation was measured in serum of fasted participants using the proximity extension assay technology. eGFR was calculated from serum creatinine and cystatin C using the CKD-EPI equation. Associations between each biomarker and eGFR were assessed using multiple linear regression adjusting for age, sex, BMI, HbA1c, diabetes duration, lipids, hypertension and use of NSAIDs and glucose-lowering drugs.

Results: Baseline eGFR was higher in T1D compared to T2D (mean (SD) 101.8 (15.3) vs. 89.3 (15.6) mL/min/1.73 m2; P<0.0001). After correction for multiple testing, 6 and 24 biomarkers were inversely associated with eGFR in T1D and T2D, respectively (all P<0.05). TNFB was T1D-specific, while ADA, CD40, CD244, CCL3, CCL20, CCL25, CX3CL1, CXCL9, CSF1, CST5, FGF23, FGF5, IL-15RA, IL12B, MMP10, NT3, SCF, TGFα and uPA were T2D-specific. CCL23, CD5, IL10RB, PDL1 and TNFRSF9 were associated with eGFR in both diabetes types.

Conclusion: We identified novel inflammatory biomarkers, independently associated with eGFR in adults with recently diagnosed T1D and T2D. As a next step, these biomarkers shall be evaluated as potential predictors of incident and progressive diabetic nephropathy.

Disclosure

H. Maalmi: None. C. Herder: Research Support; Self; Sanofi-Aventis. K. Strassburger: None. S. Urner: None. K. Jandeleit-Dahm: None. O.P. Zaharia: None. Y. Karusheva: None. K. Bodis: None. W. Rathmann: Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. D.F. Markgraf: None. V. Burkart: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S.
493-P: Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Uremic Serum and Restored by Empagliflozin
Authors: JUNI RIO , AL-SHAMA RUSHD , KUSTER DIEDERIK , DER VELDEN JOLANDA VAN , VERVLOET MARC , PAULUS WALTER , ERINGA ETTO C. , KOOLWIJK PIETER , VAN HINSBERGH VICTOR W.
Published: June 2020

Background: It has been proposed that diabetes and chronic kidney disease cause heart failure with preserved ejection fraction (HFpEF) through low-grade inflammation and microvascular endothelial dysfunction. We have previously shown that endothelial enhancement of cardiomyocyte contraction and relaxation is mediated by NO, impaired by cytokines, and restored upon treatment with the SGLT2 inhibitor Empagliflozin. Chronic kidney disease (CKD) is linked to diabetes and HFpEF and causes systemic endothelial dysfunction.

Objective: To test the hypothesis that uremic serum from patients with CKD impairs endothelial control of cardiomyocyte contraction and relaxation, and that Empagliflozin protects against this effect.

Methods and Results: Co-culture of rat cardiomyocytes (CM) with human cardiac microvascular endothelial cells (CMECs) enhanced their contraction and relaxation. Pre-treatment with serum from patients with CKD abrogated these effects of CMEC, and treatment of CMECs with Empagliflozin restored the effects of CMECs on CM function. Exposure of CMECs to the uremic serum reduced endothelial NO bioavailability and increased intracellular reactive oxygen species ROS by increasing ROS generation by mitochondria. Uremic serum also increased 3-nitrotyrosine (3-NT) level, indicating scavenging of NO by ROS. Empagliflozin attenuated uremic serum-induced mitochondrial and intracellular ROS, leading to restoration of endothelial NO bioavailability.

Conclusions: Exposure of CMECs to serum from CKD patients impairs CMEC-mediated enhancement of CM contraction and relaxation. Empagliflozin restores the beneficial effect of CMECs on CM function by reducing mitochondrial oxidative damage, leading to a decrease in intracellular ROS accumulation and increased endothelial NO bioavailability.

Disclosure

R. Juni: None. R. Al-Shama: None. D. Kuster: None. J. van der Velden: None. M. Vervloet: None. W. Paulus: None. E.C. Eringa: None. P. Koolwijk: None. V.W. van Hinsbergh: None.

Funding

Netherlands Heart Foundation
5-LB: Consuming High-Fructose Corn Syrup or Sucrose-Sweetened Beverages Increases Hepatic Lipid Content and Decreases Insulin Sensitivity in Young Adults
Authors: SIGALA DESIREE , HIERONIMUS BETTINA , PRICE CANDICE , LEE VIVIEN , NUNEZ MARINELLE , MEDICI VALENTINA , CHAUDHARI ABHIJIT J. , MCGAHAN JOHN P. , ABDELHAFEZ YASSER , KEIM NANCY L. , GORAN MICHAEL I. , PACINI GIOVANNI , TURA ANDREA , HAVEL PETER J. , STANHOPE KIMBER L.
Published: June 2020

Rodent studies demonstrate that compared with diets sweetened with sucrose, high fructose corn syrup (HFCS) produces greater metabolic dysfunction. However, the effects of sustained consumption of HFCS and sucrose have not been adequately compared in humans. The objective of this study was to compare HFCS-, sucrose-, or aspartame- sweetened beverage (-SB) consumption on hepatic lipid content and insulin sensitivity in young adults. In a parallel, double-blinded study, adult men and women (18-40 yrs) were assigned to beverage groups matched for sex, BMI and fasting triglycerides. Inpatient magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests were performed at baseline and intervention 15 days later. For 12 outpatient days subjects consumed their usual diets with 3 servings/day of HFCS- (n=28) or sucrose-SB (n=24) providing 25% energy requirement (Ereq), or aspartame-SB (n=23). Matched standardized diets were provided during inpatient testing with the sugar in beverages replacing complex carbohydrate during intervention.

Hepatic lipid content was increased by consumption of HFCS-SB (LS means of absolute Δ±SEM: 0.5%±0.2, P<0.05) and sucrose-SB (Δ: 0.5%±0.2, P<0.01) compared with baseline levels and compared with aspartame-SB (Δ: -0.2%±0.2, P<0.05 vs. HFCS- or sucrose-SB). The 3-hr Matsuda insulin sensitivity index was decreased by consumption of HFCS-SB (Δ: -0.3±0.2) and sucrose-SB (Δ: -0.5±0.2, P<0.01 vs. baseline) compared with aspartame-SB (Δ: 0.3±0.2, P<0.05 vs. HFCS- or sucrose-SB). The 2-hr Oral Glucose Insulin Sensitivity index was also decreased by consumption of HFCS-SB (Δ: -13.6±7.5) and sucrose-SB (Δ:-11.5±7.9) compared with aspartame-SB (Δ: +17.9±8.3, P<0.05 vs. HFCS- or sucrose-SB).

Consumption of SB providing 25% of Ereq as HFCS or sucrose for 2 weeks increased hepatic lipid content and reduced insulin sensitivity in young adults compared with consumption of aspartame-SB.

Disclosure

D. Sigala: None. B. Hieronimus: None. C. Price: None. V. Lee: None. M. Nunez: None. V. Medici: None. A.J. Chaudhari: None. J.P. McGahan: None. Y. Abdelhafez: None. N.L. Keim: None. M.I. Goran: Advisory Panel; Self; Yumi. Other Relationship; Self; Penguin Random House. G. Pacini: None. A. Tura: None. P.J. Havel: Research Support; Self; Arrowhead Pharmaceuticals, Inc., Magnamosis, Inc. Other Relationship; Self; None. K.L. Stanhope: None.

Funding

National Institutes of Health (R01HL091333, R01HL107256)
5-OR: Prior Bariatric Surgery and Perioperative Cardiovascular Outcomes following Noncardiac Surgery in Patients with Type 2 Diabetes Mellitus
Authors: JIN JIEWEN , LI HAI , ZHANG PENGYUAN , LI YANBING
Published: June 2020

Background: Diabetes mellitus is a risk factor for perioperative major adverse events. This study aims to evaluate the association between prior bariatric surgery (prior-BS) and perioperative cardiovascular outcomes following noncardiac surgery in patients with type 2 diabetes mellitus (T2DM).

Methods: We used the National Inpatient Database to identify major noncardiac surgery in T2DM patients from 2006 to 2014. The primary outcome is major perioperative adverse cardiovascular and cerebrovascular events (MACCE), which included death, acute myocardial infarction and acute ischemic stroke. In-hospital outcomes between patients with prior-BS and morbid obesity were compared using unadjusted logistic, multivariable logistic and propensity score matching analyses.

Results: A weighted of 152,6820 patients diagnosed with T2DM who underwent noncardiac surgery were included. Both rates of prior-BS and morbid obesity significantly increased during the study period (P<0.0001). Patients with prior-BS were younger, more likely to be female and had more smoking, alcohol abuse, anemia and prior venous thromboembolism and prior percutaneous coronary intervention. Incidence of MACCE was 1.01% and 3.25% in patients with prior-BS and morbid obesity, respectively. After multivariable adjustment, we found that prior-BS was associated with reduced risk of MACCE (odds ratio[OR]: 0.71; 95% confidence interval [CL]: 0.62-0.81), death (OR: 0.64; 95%CI: 0.52-0.78), acute kidney injury (OR: 0.66; 95%CI: 0.62-0.70) and acute respiratory failure (OR: 0.46; 95%CI: 0.42-0.50).

Conclusions: Prior bariatric surgery in diabetes mellitus patients who underwent noncardiac surgery is associated with lower risk of MACCE. Prospective studies are need to verify the benefits of bariatric surgery in noncardiac surgery.

Disclosure

J. Jin: None. H. Li: None. P. Zhang: None. Y. Li: None.

Funding

China Postdoctoral Science Foundation (2018M640871)
514-P: Adaptive Downregulation of NLRP3 Inflammasome Expression in Human Renal Tubular Epithelia in the Hyperglycemic and Hyperuricemic Culture
Authors: CIYING CHEN , RAN JIANMIN , CHEN CHUPING , ZHU PING , TAN RONGSHAO , LIU YAN
Published: June 2020

Background: Hyperuricemia has been an independent risk factor for diabetic kidney disease. Previous studies showed that hyperuricemia may induce interstitial infiltration of macrophages and activates its NLRP3 inflammasome. Meanwhile, there has been proved that an inner NLRP3 system exists in human tubular epithelia. Here we try to find how glucose and uric acid (UA) affect NLRP3 inflammasome in cultivating tubular epithelia.

Methods: HK-2 cells were cultivated. Experiment was designed according to a 2×3×2 multifactorial style. Double glucose concentrations (5.5MM and 25MM) crossed with three escalated UA concentration (0MM, 0.2MM, and 0.4MM), as well as Mcc950 (0MM and 0.1MM), an specific blocker for NLRP3 inflammasome. Morphology of HK-2 cells were observed. Supernatant concentrations and gene expressions of pivotal factors involved in NLRP3 inflammasome pathway including NLRP3, ASC, caspase-1, IL-1β and IL-18 were detected.

Results: 1) Morphology: As concentrations of glucose and UA increased, HK-2 cells obviously became floating and fragmental. 2) Genes: Except for Caspase-1, gene expressions of other four components were significantly inhibited in hyperglycemic state. Expressions of five genes were all decreased in euglycemic but unchanged in hyperglycemic state when UA increased. Mcc950 treatment significantly increased gene expressions of NLRP3, ASC, IL-1β and IL-18 in euglycemic but kept them unchanged in hyperglycemic state as UA increased. 3) ELISA: Supernatant IL-1β and IL-18, two effector molecules of NLRP3 inflammasome, were significantly decreased after stimulation with increased glucose or UA cascade. Interestingly, Mcc950 treatment further decreased concentrations of two molecules when UA stepwisely increased.

Conclusions: The inner NLRP3 inflammasome counter-regulates effects of hyperglycemia and hyperuricemia. Mcc950 may block the downstream points to reduce IL-1β and IL-18 production directly.

Disclosure

C. Ciying: None. J. Ran: None. C. Chen: None. P. Zhu: None. R. Tan: None. Y. Liu: None.

Funding

Guangdong Science and Technology Project Fund (2014B030303002); Guangdong Provincial Academician Workstation Fund (2017B090904027)
519-P: Comparison of Chronic Kidney Disease Risk Factors between Normoalbuminuric and Albuminuric Patients with Diagnosed Diabetes and Reduced Kidney Function
Authors: MOSSLEMI MITRA , HANNA RAMY M. , RHEE CONNIE , KALANTAR-ZADEH KAMYAR , STREJA ELANI
Published: June 2020

The prevalence of normoalbuminuric diabetic kidney disease (DKD) has increased in the past 20 years in the U.S. While previous studies reported the significance of nonalbuminurics pathway to kidney function loss in DKD, the factors associated with the nonalbuminuric kidney function decline remains to be elucidated. This study aimed to compare the CKD risk factors between nonalbuminuric and albuminuric DKD. Among NHANES participants (1999-2016) with diagnosed diabetes and reduced eGFR (< 60), we compared CKD risk factors (including demographics and CKD diagnosis status) between patients with normoalbuminuria (ACR<30) and albuminuria (ACR ≥ 30) using univariate and multivariable analyses. In our DKD cohort, there were 1479 (63%) normoalbuminuric and 1027 (37%) albuminuric cases. Risk factors that significantly differed between albuminuric statuses are presented in Table [Table]. In the multivariable model, age, gender, and DBP were not significantly associated with albuminuric status, while CKD diagnosis status was the strongest predictor followed by eGFR. Normoalbuminuria in patients with diabetes and reduced eGFR is associated with a seemingly healthier lab profile and lower odds of being diagnosed with CKD. Future studies should examine novel markers for detection of and protection against kidney function decline in nonalbuminuric DKD.

Disclosure

M. Mosslemi: None. R.M. Hanna: None. C. Rhee: Research Support; Self; Dexcom, Inc. K. Kalantar-Zadeh: None. E. Streja: None.
528-P: Relationship between Bone Mineral Density and Diabetic Nephropathy in Adults with Type 1 Diabetes
Authors: LARA CAROLINA , RODRIGUEZ FATIMA , VIVEROS-RUIZ TANNIA , ALMEDA-VALDES PALOMA , URIBE DANIEL , RIVAS BERNARDETTE , PEDRAZA NATALIA RAMIREZ , GARAY MORA JUAN A.
Published: June 2020

Objective: Osteoporosis is typically identified as a disease of postmenopausal women, however; it has been observed that in patients with type 1 diabetes (T1D) fractures associated with osteoporosis four to six times more common, in both sexes and at an early age (≈ 50 years). The objective of this study was to find associations between the bone mineral density (BMD), T-score and Z-score at the femoral neck, hip and spine and selected characteristics of patients with T1D.

Methods: BMD of patients with T1D was evaluated with DXA (GE Healthcare Lunar). A correlation analysis was performed to identify associations between glycated hemoglobin, 25-hydroxyvitamin D concentration, years since diagnosis and diabetic, estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR).

Results: We included 43 patients, with a mean age of 38.1 years, the mean BMD in the femoral neck was 0.94±0.13, in the hip 0.93±0.14 and the spine 1.11±0.13. We observed a negative correlation between the years since diagnosis of T1D and the BMD and T-score in the femoral neck and hip. There was a negative correlation between the ACR and the BMD, T-score and Z-score in the femoral neck and total hip and a positive correlation between the eGFR and the BMD and T-score in the femoral neck and hip.

Conclusions: In this study we identify some factors that might impact and decrease the BMD in patients with T1D including long time since diagnosis, older age of patients and presence of diabetic nephropathy. The ACR could be an indicator of early bone metabolic changes in patients with T1D. Further studies are required to confirm this association and to define the optimal age for BMD evaluation in patients with T1D.

Disclosure

C. Lara: None. F. Rodriguez: None. T. Viveros-Ruiz: None. P. Almeda-Valdes: None. D. Uribe: None. B. Rivas: None. N. Ramirez Pedraza: None. J.A. Garay Mora: None.
535-P: Neurotensin Improves Endothelial Progenitor Cell Function in Diabetic Wound Healing
Authors: LEAL ERMELINDO C. , FIGUEIREDO ANA , CARVALHO EUGENIA
Published: June 2020

Diabetic neuropathy plays an important role in the development of chronic wounds. Endothelial progenitor cells (EPCs) are known important regulators of wound angiogenesis. However, the role of neuropeptides in EPC function, and particularly Neurotensin (NT), is unknown in diabetic wound healing. EPCs isolated from normal mice were cultured in high glucose (25 mM) or normoglicemia (5.5 mM) and treated with NT (25-400 nM) for 3 days. Moreover, EPCs isolated from streptozotocin (STZ)-induced diabetic mice were treated with NT (100 nM) for 3 days. Subsequently, EPC viability, cell adhesion and reactive oxygen species (ROS) levels were evaluated. To the in vivo wound healing model, 6 mm wounds were created in the dorsum of diabetic mice and wound progression was followed up to day 10. The wound edges were injected with ex-vivo diabetic bone marrow derived EPCs treated in culture with NT (100 nM) for 3 days, or EPCs without NT treatment, or vehicle. Angiogenesis was evaluated by immunohistochemistry. The viability of EPCs cultured under high glucose or EPCs from diabetic mice was improved by NT treatment. Also, EPCs from diabetic mice showed decreased adhesion (58% of control, p<0.05) and increased ROS levels (148% of control, p<0.05) when compared to control EPCs, and these effects were reversed by NT treatment. In addition, NT-treated EPCs, from diabetic mice, improved wound closure (day 10, 4% of original wound size) when compared with non-treated EPCs or vehicle (day 10, 32% and 35% of original wound size, respectively, p<0.05). Furthermore, NT-treated EPCs, from diabetic mice, increased neovascularization at the wound site (153% of vehicle, p<0.05) when compared with non-treated EPCs (115% of vehicle) or vehicle. These results show that neurotensin is able to improve the function of EPCs from diabetic animals, which are able to improve wound healing by promoting angiogenesis. The restoration of EPC function by neurotensin could improve their therapeutic effect for the treatment of chronic diabetic wounds.

Disclosure

E.C. Leal: None. A. Figueiredo: None. E. Carvalho: None.

Funding

Portuguese Foundation for Science and Technology; European Foundation for the Study of Diabetes; Portuguese Society of Diabetology
56-LB: Trauma and Anxiety Effects on Adherence in Pediatric Type 1 Diabetes Mellitus
Authors: RAJ RISHI , NGUYEN MAI , MORALES ALBA , MEADOWS AMY L.
Published: June 2020

Background: Psychiatric factors, such as depression, anxiety, and life stressors, have been shown to negatively affect diabetes adherence and glycemic control in children and adolescents. However, less is known about how trauma exposure and symptoms of post-traumatic stress disorder (PTSD) may impact adherence and glycemic control.

Objectives: Determine the rates of trauma exposure and PTSD symptoms in patients ages 7-21 with type 1 diabetes (T1DM). Examine the relationship between trauma exposure, PTSD, Anxiety, behavioral adherence and glycemic control.

Methods: We enrolled 99 patients (mean age 13.8 ± 3.5 years, 51.5% female) who had been diagnosed with T1DM for at least 6 months and underwent standardized psychiatric screening questionnaires during their clinic visits. HbA1c at goal was defined by HbA1c < 7.5% and behavioral adherence were defined by self-monitoring of blood glucose (SMBG) ≥ 4/day or continuous glucose monitoring (CGM) calibration ≥ 2/day and/or CGM use ≥ 75%. All participants and/or their guardians provided assent and consent. Chi-square tests were used to assess the relationships between trauma, PTSD, anxiety and behavioral adherence. One-way ANOVA was conducted to examine group differences between HbA1c scores and the presence of suicidal ideation.

Results: 38.4% of participants had trauma symptoms and functional impairment. Rates of trauma secondary to accidental injury, medical traumatic stress, natural disaster and witness to family violence were 28.3%, 22.2%, 10.1%, and 6.1%, respectively. Neither trauma exposure nor PTSD predicted diabetes adherence. Anxiety was significantly associated with diabetes nonadherence (p=0.006). The group with suicidal ideation had higher HbA1c compared to the group without suicidal ideation (8.92 ± 1.40 vs. 8.30 ± 1.35, p=0.047).

Conclusions: Although trauma was common among young patients with T1DM, other factors, such as anxiety and suicidal ideation, maybe more important indicators of adherence and glycemic control.

Disclosure

R. Raj: None. M. Nguyen: None. A. Morales: None. A.L. Meadows: None.

Funding

Children’s Miracle Network/Kentucky Children’s Hospital Research Fund; National Institutes of Health (UL1TR001998)
562-P: Influence of Glycemic Control and Variability on Diabetic Retinopathy in Type 1 Diabetes Patients on Continuous Subcutaneous Insulin Infusion Therapy
Authors: LECUMBERRI EDURNE , BENGOA NURIA , ARGÜESO MARÍA FERNÁNDEZ , NATTERO CHÁVEZ LÍA
Published: June 2020

Introduction: There is scarce evidence demonstrating a relationship between glycemic control or glycemic variability with diabetic retinopathy (DR).

Objectives: We aimed to determine the prevalence of DR and its association with time in range (TIR), and other association factors.

Methods: We performed a retrospective observational study with 130 T1DM patients on continuous subcutaneous insulin infusion (CSII). Data of the three previous months were downloaded and analyzed.

Results: Mean age was 37±13 years-old. 51.5% were female. Mean BMI was 24.8±4.0 Kg/m2. Duration of T1DM was 21±10 years. The mean HbA1c was 7.1±0.8%; before CSII 7.4±1.0%. Mean LDL-c was 100±26 mg/dL. The prevalence of DR was 20.8% (95%CI: 14.7 - 28.5); 19.2% non-proliferative DR and 1.5% proliferative DR. Most glycemic control and variability parameters were significantly higher in the DR+ group (Table 1). After applying the stepwise logistic regression model (p<0.001, R2 0.561), the association factors for developing DR were: LDL-c, ExpB 0.97 (95%CI 0.95-0.99); duration of DM, ExpB 1.26 (95%CI 1.12-1.41); and HbA1c before CSII, ExpB 2.24 (95%CI 1.17-4.31).

Conclusions: Lower TIR and higher time in hyperglycemia were observed in patients with DR. LDL-c levels, long duration of DM and higher HbA1c before CSII were independent association factors for the development of DR.

Disclosure

E. Lecumberri: None. N. Bengoa: None. M. Fernández Argüeso: None. L. Nattero Chávez: None.
564-P: Differences in Diabetic Retinopathy Prevalence and Progression between Aboriginal and Anglo-Celt Australians: The Fremantle Diabetes Study Phase II
Authors: DRINKWATER JOCELYN J. , DAVIS WENDY A. , TURNER ANGUS W. , DAVIS TIMOTHY
Published: June 2020

Background: There are limited contemporary data on the prevalence and progression of diabetic retinopathy (DR) in urban-dwelling Aboriginal Australians. We therefore compared the prevalence of DR and cumulative incidence of new/worsening DR (NWDR) between Aboriginal and Anglo-Celt Australians with type 2 diabetes (T2D) in the representative community-based Fremantle Diabetes Study Phase II (FDS2).

Methods: From 2008 to 2011, 932 Anglo-Celt and Aboriginal FDS2 participants with T2D underwent comprehensive baseline assessments and were invited to biennial reviews. Ethnic status was based on self-selection, country/countries of birth and parents’ birth, language(s) spoken at home, and country of grandparents’ birth. Fundus photographs were graded according to the Early Treatment Diabetic Retinopathy Study protocol. Prevalence of DR and cumulative incidence of NWDR for each ethnic group, and unadjusted and adjusted odds ratios (ORs), were calculated.

Results: Baseline DR data was available for 911 (97.7%) participants (mean age 66.0 years, median T2D duration 8.4 years, 49.7% males). There were 817 Anglo-Celt and 94 Aboriginal participants. Of these, 56% had follow-up data. Baseline prevalence of any DR was 33.0% in Anglo-Celts and 52.1% in Aboriginals (P<0.001). During 4.2±0.4 years’ follow-up, the cumulative incidence of NWDR was 6.7% and 23.5%, respectively (P<0.001). The unadjusted OR (95% CI) for Aboriginals for any DR and NWDR were 2.21 (1.43-3.39) and 4.32 (1.33-13.98), respectively. These ORs were attenuated after age and sex adjustment (1.21 (1.10-1.33) and 4.1 (1.2-14.1), respectively) but were no longer significant after adjusting for other DR risk factors including HbA1c and systolic blood pressure.

Conclusions: Urban dwelling Aboriginal Australians have substantial DR prevalence and progression, highlighting the need for better access to culturally appropriate management.

Disclosure

J.J. Drinkwater: None. W.A. Davis: Advisory Panel; Spouse/Partner; Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Spouse/Partner; Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Proteomics International. Other Relationship; Spouse/Partner; Proteomics International. A.W. Turner: None. T. Davis: Advisory Panel; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Protemics International. Other Relationship; Spouse/Partner; Protemics International.

Funding

University of Western Australia; Australian Government Training Program; National Health and Medical Research Council of Australia
569-P: Plasma Metabolomic Profiling of Diabetic Macular Edema
Authors: XIAORONG ZHU
Published: June 2020

Background: Diabetic macular edema (DME), a sight-threatening retinopathy, is a leading cause of vision loss in persons with diabetes mellitus. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop DME, suggesting the existence of other potential pathogenic factors underlying DME. This study aimed to investigate the plasma metabotype of patients with DME and to identify novel metabolite markers for DME. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of DME.

Methods: To match clinical parameters between case and control subjects, patients with DME (DME, n=30) or those with diabetes but without DME (Control, n=30) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS).

Results: A total of 188 distinct metabolites between DME and Control groups were identified (VIP > 1, Fold Change > 1.5 or < 0.5, and P < 0.05). These metabolites mainly included Lipids and lipid-like molecules (71%), organic acids and derivatives (17%), Organic oxygen compounds (8%) and others. The distinct metabolites between DME and Control groups were enriched in 5 KEGG pathways, namely, lysine degradation, arachidonic acid metabolism, riboflavin metabolism, sulfur relay system, and thyroid hormone synthesis. Finally, 4 metabolites were selected as candidate biomarkers for DME, namely, Violaxanthin, uridine, D-Glucopyranuronic acid, and Capryloylglycine. The area under the curve for these biomarkers were 0.89, 0.85, 0.86, and 0.82, respectively.

Conclusions: This study suggested that impairment in the metabolism and 4 potential metabolites were identified as metabolic dysregulation associated with DME, which might provide insights into potential new pathogenic pathways for DME.

Disclosure

X. Zhu: None.

Funding

National Key Research and Development Program of China (2017YFC0909600)
583-P: Effects and Safety of Pemafibrate, a Novel Hypolipidemic Agent in Japanese Type 2 Diabetes Patients Receiving Statins
Authors: KUSUNOKI MASATAKA , SATO DAISUKE , SAKAZAKI TAKAHIKO , NATSUME YUKIE , MIYATA TETSURO
Published: June 2020

The combination therapy of statins and fibrates may increase the risk of hepatic dysfunction and myopathy, so this combination was contraindicated in patients with renal impairment and required careful administration even for patients with normal renal function. However, in Japan, patients with renal impairment were excluded from the relative contraindication category in 2018.

In the present study, we additionally administered 0.2 mg/day pemafibrate (PFB), a novel fibrate, for 6 months to 27 type 2 diabetes patients with dyslipidemia already receiving statins for 6 months (combination group), and examined the efficacy and safety of the combination therapy in comparison with a PFB monotherapy group.

In the combination group, a significant decrease in serum total cholesterol level was observed after 6 months of PFB treatment compared to baseline, along with increase in HDL-cholesterol. A significant decrease in serum triglyceride and a significant increase in HbA1c were observed in both groups. Significant decreases in serum creatinine kinase, which is an indicator of myopathy, and serum γ-GTP, a parameter of hepatic dysfunction, were observed in the combination group.

These results demonstrated that the statin-PFB combination therapy in type 2 diabetes patients with dyslipidemia improved lipid metabolism safely without increasing the risk of hepatic dysfunction and myopathy.

Disclosure

M. Kusunoki: Other Relationship; Self; Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. D. Sato: None. T. Sakazaki: None. Y. Natsume: None. T. Miyata: None.
589-P: Impaired Endothelial Nrf2 Expression Reduces Wound Neovascularization in Diabetic Mice
Authors: LEE JASMINE , VILLARREAL PONCE ALVARO P. , DAVID JOSHUA A. , KUHN JOSEPH , KWONG JENNIFER , CERADINI DANIEL
Published: June 2020

The global cost of diabetes in the U.S. is 1.3 trillion dollars, with chronic diabetic foot ulcers accounting for up to 13 billion dollars annually. An underlying factor that contributes to the chronicity of these wounds is poor vascular flow, which impedes physiologic wound healing. Here, using an in vivo murine model of wound healing, we demonstrate that Nrf2 expression in endothelial cells is necessary for physiologic neovascularization. Full-thickness 10 mm stented excisional wounds were created on the dorsa of double transgenic mouse with inducible conditional deletion of Nrf2 in cadherin 5 expressing endothelial cells (KO), wildtype (WT), and heterozygous mice. Time to wound closure was delayed in the KO compared to WT mice (KO 33.0±1.73 days vs. WT 14.0±0 days) and Nrf2 KO healed similarly to diabetic mice (KO 33.0±1.73 days vs. Diabetic 31.0±1.41 days). Endothelial cells isolated from the wounds of KO mice via flow cytometry demonstrated significantly decreased angiogenic functionality when compared to heterozygous controls. KO endothelial cells formed significantly fewer branches (KO 64.75±14.81 branches/cm2 vs. control 282.8±46.7 branches/cm2, p=0.014) and fewer branching points (KO 39.0±5.18 branching points/cm2 vs. Control 150.8±15.34 branching points/cm2, p=0.0031), indicating impaired angiogenic activity. Immunofluorescent staining of endothelial cells within the wound beds of KO also demonstrate decreased vascularity compared to WT controls. We looked at regulation of the CXCR4/SDF-1 axis, key to angiogenesis, using C166 mouse endothelial cells. Nrf2 knockdown cells in hypoxia, results in reduced Nrf2 levels by 76.5% (p=0.001) and that of downstream marker NQO1 by 66.4% (p=0.02). Expression of CXCR4 and SDF-1 decreased 61.7% (p=0.001) and 47.6% (p=0.02) respectively. These findings suggest that the Nrf2 dysregulation associated with diabetes may contribute to the impaired angiogenesis and decreased revascularization present in chronic diabetic wounds.

Disclosure

J. Lee: None. A.P. Villarreal Ponce: None. J.A. David: None. J. Kuhn: None. J. Kwong: None. D. Ceradini: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-08 to D.C.)
59-LB: Risk of Type 2 Diabetes Is Reduced in the Second Year of a Digital Diabetes Prevention Program in a Workplace Setting
Authors: BIRSE CHARLES E. , FRAGALA MAREN S. , ARELLANO ANDRE R. , BARE LANCE A. , SWEET CYNTHIA CASTRO , LAGIER ROBERT J.
Published: June 2020

Background: A digital Diabetes Prevention Program (dDPP) has been shown to reduce the 8-year risk of diabetes in the first year of implementation in a workforce setting. We asked whether the dDPP reduced the risk of diabetes in a second year.

Methods: Individuals were included in the study if they (i) participated in an employer-sponsored wellness program with year-end biometric screening for 4 consecutive years (2016 to 2019), (ii) had prediabetes-range fasting glucose (100 to 125 mg/dL) or Hb1Ac (5.7% to 6.4%), (iii) a BMI ≥25 kg/m2 at the end of 2017, and (iv) completed ≥9 lessons in a dDPP initiated at the beginning of 2018. In the first year of the dDPP, individuals participated in weekly online lessons. In the second year, no new content was introduced, but individuals had access to lessons delivered in year 1.

Results: The baseline characteristics from the 2017 year-end screen are provided (Table). On average, participants (n=401) completed 25.1 lessons (SD: 12.3). In the second year of intervention, levels of BMI, fasting glucose, triglycerides and HDL-C, all components of the 8-year diabetes risk score, improved relative to changes observed in the year before intervention. The 8-year risk of developing diabetes was also reduced (Table).

Conclusions: The risk of developing type 2 diabetes was reduced in the second year of a dDPP.

Disclosure

C.E. Birse: Employee; Self; Quest Diagnostics. M.S. Fragala: Employee; Self; Quest Diagnostics. A.R. Arellano: None. L.A. Bare: Employee; Self; Quest Diagnostics. C. Castro Sweet: Employee; Self; Omada Health. R.J. Lagier: Employee; Self; Quest Diagnostics. Employee; Spouse/Partner; Thermo Fisher Scientific.
59-OR: Lipoprotein Particle Distribution by NMR in Youth with Type 2 Diabetes (T2D) in the TODAY Study
Authors: KATZ LORRAINE E. , OTVOS JAMES D. , DREWS KIMBERLY , TESFALDET BEREKET , BACHA FIDA , WILLI STEVEN M. , MARCOVINA SANTICA M. , MCKAY SIRIPOOM , WEINSTOCK RUTH S.
Published: June 2020

T2D in adolescents is associated with an unfavorable lipid profile, but data on lipoprotein particle size and distribution in this population have yet to be published. The TODAY Study, a randomized treatment trial of T2D in youth, provided the opportunity to evaluate lipoprotein particle distribution and relate lipoprotein particle number and size to HbA1C, need for insulin treatment, gender, race/ethnicity, BMI, and blood pressure (BP). TODAY participants (n=348) with yearly samples available for NMR Lipoprofile assessments (baseline, 12, 24, 36 mos) were included. Baseline participant characteristics (mean±SD) were: age 13.7±2.0 yrs; BMI 34.3±7.6 kg/m2; 62.4% female; 20.7% White, 32.2% Non-Hispanic Black (NHB), 43.7% Hispanic. Analysis demonstrated increasing numbers of LDL, HDL, and VLDL particles over the three yrs (all ps<0.0001) with somewhat weaker trends for decreasing particle size (LDL p=0.0009, HDL p=0.02). HbA1c showed a strong positive correlation with LDL, VLDL, and HDL particle number (all ps<0.005). HbA1c was negatively associated with LDL (p<0.0001) and HDL size (p=0.001) but positively associated with VLDL size (p<0.0001). Need for insulin treatment did not impact these associations. Female subjects had larger HDL particle size than males at baseline (p=0.0004) and throughout (p<0.0001). NHBs had the largest LDL and HDL particle size and smallest VLDL particle size. BMI% and BP showed positive association with LDL, HDL, and VLDL particle numbers but negative association with LDL and HDL size. The preponderance of lipoprotein parameters were strongly associated with TG/HDL ratio and non-HDL-C after adjusting for baseline age, race, gender, BMI%, BP, and need for insulin treatment (p<0.0001).

In conclusion, these data demonstrate an atherogenic lipoprotein phenotype in youth with T2D and strong relationships with glycemic control and other cardiac risk factors. Concern regarding premature development of atherosclerosis in youth with T2D is warranted.

Disclosure

L.E. Katz: None. J.D. Otvos: Employee; Self; LabCorp. K. Drews: None. B. Tesfaldet: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Tolerion, Inc. Other Relationship; Self; Caladrius Biosciences, Inc. S.M. Marcovina: None. S. Mckay: None. R.S. Weinstock: Board Member; Self; JDRF. Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Jaeb Center for Health Research, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212)
594-P: Human Nrf2-Active Multipotent Stromal Cell Exosomes Promote Tissue Repair in a Wound Model of Type 2 Diabetes
Authors: KUHN JOSEPH , HASSAN ABSARA , SHARMA SONALI , KWONG JENNIFER , RAHMAN MONTAHA , ADAM SALMA , LEE JASMINE , VILLARREAL PONCE ALVARO P. , RABBANI PIUL S.
Published: June 2020

Exosomes, nanosized extracellular vesicles, may be key to translating multipotent stromal cell (MSC) therapy to the bedside. We previously found that nuclear factor erythroid 2-related factor 2 (Nrf2) regulates MSC promotion of tissue repair in diabetes. Here, we explore a novel role of Nrf2 in exosome biogenesis and investigate whether exosome treatment recapitulates the effects MSCs have on wound healing in mice with type 2 diabetes. Exosomes were harvested by differential ultracentrifugation of conditioned human bone marrow derived MSC media. For Nrf2-active exosomes, MSCs were incubated with potent Nrf2 activator, CDDO-Im. MSC characterization demonstrated robust tri-lineage differentiation, >95% expression of positive markers (CD44/CD73/CD90/CD105/CD106), and <5% expression of negative markers (CD45/CD31/CD14/CD19/HLA-DR). Immunoblotting of exosome isolates demonstrates enrichment for CD81, CD9 and TSG101. Nanoparticle tracking analysis demonstrates that Nrf2-active MSCs increase exosome secretion by 54%, compared to Nrf2-baseline MSCs (p<0.05). Exosomes were injected into the wound margin of full-thickness wounds on Leprdb/db (db/db) mice. Both Nrf2-baseline and Nrf2-active exosome treatment significantly reduced closure time to 15.5 and 14 days respectively, compared to 29.8 days for vehicle-treated wounds (p<0.05). This reduction eliminated the delay in closure time compared to wounds of C57/B6 mice. Nrf2-active exosome treatment of db/db wounds reduced closure time by a further 2.6 days compared to untreated C57/B6 wounds. At day 10, exosome treated db/db wounds have significant decreases in epithelial gap, expanded granulation tissue, and greater density of CD31+ vessels compared to vehicle-treated wounds. We conclude that activating Nrf2 in MSCs increases isolation efficiency by amplifying exosome yield and content. MSC exosome based therapies have potential for rapid translation to improve clinical wound healing outcomes.

Disclosure

J. Kuhn: None. A. Hassan: None. S. Sharma: None. J. Kwong: None. M. Rahman: None. S. Adam: None. J. Lee: None. A.P. Villarreal Ponce: None. P.S. Rabbani: None.

Funding

Plastic Surgery Foundation; Wound Healing Society; New York University Clinical and Translational Science Institute