bluuebunny/crossref_metadata_2025 huggingface dataset:
399-P: Association of Social Determinants of Health with Initiation of Novel Glucose-Lowering Drugs in Patients with Diabetes—A Post Hoc Analysis of the Kidney-CHAMP Trial
Authors: MOSSLEMI MITRA , WELTMAN MELANIE , LAVENBURG LINDA-MARIE U. , ALGHWIRI ALAA , YABES JONATHAN , HAN ZHUOHENG , COSTACOU TINA , JHAMB MANISHA
Published: June 2024

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are recommended but underutilized in patients with diabetic kidney disease, with different patterns of disparities reported. How social determinants of health (SDOH) shape disparities in SGLT-2i/GLP-1 RA initiation remains to be elucidated. We investigated the SDOH factors associated with SGLT-2i/GLP-1 RA initiation vs. nonuse, among participants with type 2 diabetes and chronic kidney disease enrolled in the Kidney Coordinated HeAlth Management Partnership (Kidney-CHAMP) trial (2019-2022). In the Kidney-CHAMP subpopulation of 890 participants with type 2 diabetes who were not using SGLT-2i/GLP-1 RA at baseline (age: 18-85 yrs., eGFR: 15-30 mL/min/1.73m2), 32% initiated SGLT-2i/GLP-1 RA during the 3-year follow-up period. In multivariable mixed model analysis, age, primary insurance category, and distance to nearest health clinic were the SDOH factors that remained significantly associated with SGLT-2i/GLP-1 RA initiation (Table 1). Our results suggest that access-to-care factors may play a pivotal role in the inadequate adoption of SGLT-2i/GLP-1 RA, emphasizing the need for further research into the mechanisms underlying the impact of SDOH factors on SGLT-2i/GLP-1 RA uptake.

Disclosure

M. Mosslemi: None. M. Weltman: None. L.U. Lavenburg: None. A. Alghwiri: None. J. Yabes: Other Relationship; Bayer Inc. Z. Han: None. T. Costacou: None. M. Jhamb: Research Support; Bayer Inc., Pfizer Inc. Advisory Panel; Eli Lilly and Company, Boehringer-Ingelheim, Xcenda LLC, CKD Networks of Excellence.
40-OR: The Association of Continuous Glucose Monitoring Metrics with Hospital-Related Clinical Outcomes
Authors: FLINT KRISTEN L. , O'CONNOR MOLLIE , SABEAN AMY , ASHLEY ANNABELLE , ZHENG HUI , YAN JOYCE , STEINER BARBARA , ANANDAKUGAN NILLANI , CALVERLEY MELISSA M. , BARTHOLOMEW RACHEL , GREAUX EVELYN , CASTELLANOS LUZ E. , LARKIN MARY E. , RUSSELL STEVEN J. , PUTMAN MELISSA S.
Published: June 2024

Introduction: Few studies have examined the association between continuous glucose monitoring (CGM) metrics and hospital-related clinical outcomes in the inpatient setting.

Methods: In this prospective observational study, patients admitted on non-intensive care floors receiving fingerstick glucose monitoring wore blinded Dexcom G6 Pro CGM during their hospital stay. Clinical data were extracted from the medical record including a composite of infection, DKA/HHS, renal replacement therapy, or thrombosis. Readmissions and emergency department (ED) visits within 30 days of discharge were identified through record review and participant phone interview. The associations between CGM metrics and clinical outcomes were assessed with multivariable logistic regression.

Results: In this cohort of 326 adults (78% type 2 diabetes, 12% type 1 diabetes, 10% other), median % time in range 70-180 mg/dL was 44.5% (17.1, 70.2%), % time >180 mg/dL (TAR) was 54.8% (28.8, 82.3%), and % time <70 mg/dL (TBR) was 0% (0, 0.2%). Multivariable regression analyses demonstrated a significant association of 30-day ED visits with increased %TAR (p = 0.01) and borderline association of 30-day readmissions and %TBR (p = 0.06) (Table 1).

Conclusion: Hyperglycemia identified by CGM was associated with 30-day ED visits, suggesting CGM could help identify patients that may benefit from increased support after hospital discharge.

Disclosure

K.L. Flint: None. M. O'Connor: None. A. Sabean: None. A. Ashley: None. H. Zheng: None. J. Yan: None. B. Steiner: None. N. Anandakugan: None. M.M. Calverley: None. R. Bartholomew: None. E. Greaux: None. L.E. Castellanos: None. M.E. Larkin: None. S.J. Russell: Employee; Beta Bionics, Inc. Stock/Shareholder; Beta Bionics, Inc. Other Relationship; Beta Bionics, Inc. Consultant; Beta Bionics, Inc. Research Support; Beta Bionics, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Other Relationship; Novo Nordisk. M.S. Putman: Research Support; Dexcom, Inc. Other Relationship; Vertex Pharmaceuticals Incorporated. Research Support; Vertex Pharmaceuticals Incorporated. Advisory Panel; Anagram Therapeutics.

Funding

National Institutes of Health (R01 DK119699-02S1); National Institutes of Health (T32DK007028); Dexcom Investigator Initiated Study Grant
400-P: KidneyIntelX Impact on ADA DKD Prevention Model Metrics
Authors: TOKITA JOJI , MCNICHOLAS TONY , NADKARNI GIRISH N. , COCA STEVEN , DONOVAN MICHAEL J.
Published: June 2024

The ADA DKD Prevention Model was developed to define key concepts for DKD prevention and treatment. We sought to describe and quantify specific outcome measures outlined in the ADA model following deployment of a system-wide interdisciplinary approach that centered around KidneyIntelX, a prognostic test that utilizes combines prognostic biomarkers and clinical variables to generate patient-specific risk assessment for kidney function decline. We assessed the changes in various process measures, including clinical assessments, referrals, and changes in short- and intermediate-term metrics. 6258 patients were tested with KidneyIntelX across the Mount Sinai Health System between 2021 and 2023. The median age was 67 years, with 51% females and 25% identified as African American. Baseline eGFR was 65 ml/min/1.73 m2, UACR 56 mg/g, and HbA1c 7.2%. Among tested patients scoring intermediate (40%) or high (10%) risk, UACR testing increased by 25%, NSAID prescriptions decreased by 11%, and use of SGLT2i and GLP1-RAs increased by 14-37%. Hypertension control and control of HbA1c improved by 12 to 27%, and albuminuria decreased by 19%.

In conclusion, risk assessment in patients with stages G1-3b DKD resulted in improvements in several process measures including UACR testing, guideline-recommended therapies, less nephrotoxin usage, and better control of hypertension, glycemia, and albuminuria.

Disclosure

J. Tokita: Research Support; Renalytix. T. McNicholas: None. G.N. Nadkarni: Stock/Shareholder; Renalytix. S. Coca: Stock/Shareholder; Renalytix. Consultant; Bayer Inc., Takeda Pharmaceutical Company Limited, 3ive Labs, Vifor Pharma Management Ltd., Boehringer-Ingelheim. M.J. Donovan: Employee; Renalytix.

Funding

Renalytix
404-P: Characterization of the Differential Effects of Oxyntomodulin (GLP-1/Glucagon) and GLP-1 on Body Weight, Glucose Metabolism and Renal Function in db/db Mice
Authors: ANVARI GOLNAZ , POCAI ALESSANDRO
Published: June 2024

Introduction: Oxyntomodulin (OXM) is a peptide hormone released from the gut in post-prandial state that activates both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Because GLP-1 agonism has been reported to have a renoprotective effect in animal models and humans, we compared the effect of simultaneous GCGR and GLP-1 activation to matched GLP-1 agonism on kidney function in mice.

Methods: Male 16 wk old db/db BLKS/J mice (n=30) with increased serum creatinine (~3-fold) were selected and treated once daily with saline, OXM or OXM-Q3E (a peptide analog to OXM without GCGR activity) for 6 weeks. Body weight and food intake were monitored weekly. An intraperitoneal glucose tolerance test (IPGTT) was performed on week 1 after food was removed for 6h. Plasma levels were collected before and at the end of the study to evaluate plasma creatinine and ketone bodies. OXM, but not OXMQ3E, activates the GCGR in vivo as shown by increased plasma ketone bodies (OXM 7.7±0.4, OXMQ3E 4.1±0.3, Vehicle 3.5±0.4 mg/dL). During the IPGTT, OXM and OXMQ3E had similar improvement in glucose tolerance while OXM reduced body weight and serum creatinine to a greater extent than OXMQ3E.

Results: OXM, but not OXMQ3E, activates the GCGR in vivo as shown by increased plasma ketone bodies (OXM 7.7±0.4, OXMQ3E 4.1±0.3, Vehicle 3.5±0.4 mg/dL). During the IPGTT, OXM and OXMQ3E had similar improvement in glucose tolerance while OXM reduced body weight and serum creatinine to a greater extent than OXMQ3E.

Conclusions: Our results provide new insights into the mechanism of action of OXM and suggest that activation of GCGR may have beneficial effect on kidney function when delivered together with GLP-1.

Disclosure

G. Anvari: None. A. Pocai: None.
405-P: Pharmacological Activation of Kidney AMPK Promotes Diuresis and Natriuresis in Rats
Authors: ANVARI GOLNAZ , POCAI ALESSANDRO
Published: June 2024

Introduction: In vitro and in vivo genetic studies have demonstrated that AMP-activated protein kinase (AMPK) controls renal epithelial electrolyte transport stimulating renal sodium and water reabsorption. Using a selective small molecule pan AMPK activator, cpd 1, we characterize the contribution of AMPK to the regulation of renal transport, the final composition of excreted urine and potential mechanisms involved.

Methods: Sprague-Dawley (SD) rats were injected subcutaneously with vehicle (20% Hydroxypropyl-beta-cyclodextrin), cpd 1, or the loop diuretic furosemide as a diuretic positive control, dissolved in 5ml/kg injection volume. Urine and blood samples were collected for measurement of creatinine, sodium, blood urea nitrogen (BUN). Transcutaneous glomerular filtration rate (GFR) was assessed at 5-7 hours post treatment using fluorescein-isothiocyanate-(FITC)-sinistrin clearance in conscious rats. Glycoprotein non-metastatic melanoma protein B (GPNMB) and pAMPK were evaluated in plasma and kidney lysate, respectively.

Results: Sustained elevation of renal AMPK and upregulation of plasma GPNMB were observed in rats treated with cpd 1 (10 mg/kg). After 24 hours, similar to furosemide, cpd 1 increased the urine output and BUN/creatinine ratio. Natriuresis was also increased for both treatments while GFR was reduced.

Conclusion: Pharmacological activation of renal AMPK resulted in a strong effect on diuresis and natriuresis in rats.

Disclosure

G. Anvari: None. A. Pocai: None.
406-P: Kidney Disease and Risk of Diabetic Ketoacidosis in Type 1 Diabetes
Authors: BAKHSH ABDULMOHSEN M.K. , BUDHRAM DALTON R. , BAPAT PRIYA , ABUABAT MOHAMMAD I. , VERHOEFF NATASHA , MUMFORD DOUG , ORSZAG ANDREJ , CHERNEY DAVID , FRALICK MICHAEL , WEISMAN ALANNA , ERIK LOVBLOM LEIF , PERKINS BRUCE A.
Published: June 2024

Introduction & Objective: Sodium glucose linked transporter inhibitors (SGLTi) in T1D raise DKA risk but hold potential for kidney protection, especially with impaired renal function [eGFR <60 ml/min/1.73m2]. We aimed to determine if those with eGFR impairment have higher DKA risk, perhaps owing to lower buffering capacity, thereby reducing safety of SGLTi use.

Methods: Previously collected data from the DCCT/EDIC Study was obtained through the NIDDK central repository. We assessedtime-varying eGFR over 34 years as exposures and subsequent time-to-first DKA event as the outcome in Cox proportional hazard models.

Results: Of 1441 participants, 297 experienced 488 DKA events over 34-year follow-up. Unadjusted nonlinear association between eGFR categories indicated a “J-shaped” relationship (Figure). Using eGFR of 100 ml/min/1.73m2 as the reference, there were no differences in the relative hazard for eGFR ≤ 110 ml/min/1.73m2 while eGFR > 110 ml/min/1.73m2 had progressively higher risk of DKA. This relationship was only partially explained by covariates in an adjusted model.

Conclusion: Impaired kidney function did not increase DKA risk, implying that use of interventions that increase DKA risk (such as SGLTi) should not cause greater concern than in those with normal eGFR. However, hyperfiltration (eGFR ≈ >120ml ml/min/1.73m2) may impart greater DKA risk and requires further study.

Disclosure

A.M.K. Bakhsh: None. D.R. Budhram: None. P. Bapat: None. M.I. Abuabat: None. N. Verhoeff: None. D. Mumford: None. A. Orszag: None. D. Cherney: Other Relationship; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK an. Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. M. Fralick: Consultant; singal1, proofdx. A. Weisman: None. L. Lovblom: None. B.A. Perkins: Advisory Panel; Abbott. Other Relationship; Novo Nordisk. Advisory Panel; Insulet Corporation, Nephris. Other Relationship; Medtronic. Advisory Panel; Sanofi, Vertex Pharmaceuticals Incorporated, Dexcom, Inc.

Funding

Diabetes Canada (Operating Grant OG-3-21-5572-BP)
409-P: Evaluating the Agreement between CKD-EPI Calculated eGFR and mGFR in People with Diabetes—An International Individual Participant Data Meta-analysis
Authors: KWOK RODNEY , KISHORE KARTIK , ZAFARI TINA , HACHEM MARIAM , KOYE DIGSU , BJORNSTAD PETTER , RESEARCH GROUP DCCT/EDIC , SCHAEFFNER ELKE , JEONG TAEDONG , MIN WON-KI , MACISAAC RICHARD , CHURILOV LEONID , EKINCI ELIF I.
Published: June 2024

Introduction: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. We and others have shown that CKD-EPI equation is less accurate in estimating glomerular filtration rate (eGFR) in people with diabetes. This study aimed to assess the agreement between directly measured glomerular filtration rate (mGFR) and eGFR (2021 CKD-EPI) in individuals with type 1 or type 2 diabetes, especially in clinically relevant ranges of GFR.

Methods: Datapoints (n=16,182) were collected from people with type 1 and type 2 diabetes from six international cohorts (Diabetes Control and Complication Trial [DCCT, USA], Colorado [USA], Germany, Korea, Spain, and Australia), with mGFR assessed using exogenous filtration markers. The intra-class correlation coefficient between mGFR and eGFR was estimated using (a) a one-step intra-individual participant data meta-analysis approach, and (b) a four-level mixed-effect linear model which included studies and individual participants as first and second level random effects, method of measurement as third level fixed effect and time as fourth level random effect.

Results: Whilst overall mGFR and eGFR agreement was good (ICC: 0.82, 95%CI: 0.79, 0.84), subgroup analyses based on clinically relevant GFR ranges(<30, 30-59, 60-89, ≥90 ml/min per 1.73m2) revealed poor agreement between mGFR and eGFR measurements (ICC: 0.38, 0.40, 0.29, 0.34 respectively).

Conclusion: Our data suggest the need for alternative methods to calculate eGFR in people with diabetes, particularly across clinically relevant GFR ranges, to improve early detection and management of kidney impairment and optimize intervention strategies for DKD.

Disclosure

R. Kwok: None. K. Kishore: None. T. Zafari: None. M. Hachem: None. D. Koye: None. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc. E. Schaeffner: Consultant; AstraZeneca. Other Relationship; National Kidney Foundation. T. Jeong: None. W. Min: None. R. MacIsaac: None. L. Churilov: None. E.I. Ekinci: Advisory Panel; Lilly Diabetes. Research Support; Novo Nordisk, Boehringer-Ingelheim, Eli Lilly and Company. Board Member; Eli Lilly and Company. Advisory Panel; Abbott. Research Support; Endogenex, Versanis, AstraZeneca.

Funding

Australian Government Research Training Program (RTP) Scholarship
412-P: Kidney Shape in Magnetic Resonance Imaging—A Possible Biomarker for Diabetic Kidney Disease?
Authors: KYWE SOE KYWE , SHARMA KANISHKA , PERIQUITO JOAO , SHORE ANGELA , GOODING KIM M. , SELVARAJAH DINESH
Published: June 2024

Introduction: With advancement in medical imaging, magnetic resonance imaging (MRI) is considered as an alternative source of biomarkers. The aim of this study was to explore the potential of kidney shape factors measured by MRI as biomarkers for DKD progression as early DKD tends to have larger kidney volume due to hypertrophy and hyper-filtration.

Methods: Total 134 participants with type 2 diabetes and eGFR>30 ml/min/1.73 m2 from iBEAt study were examined. This EU-funded, multi-centre renal imaging study seeks to identify novel biomarkers for DKD. All MRI data was acquired on 3T Siemens scanners. Each kidney was segmented using in-house software. Significant threshold was set at p<0.01. Hierarchical cluster analysis (HCA) among 15 shape parameters was conducted by centroid clustering method (SPSS V29.0).

Results: The mean (SD) age of study participants was 70(8) years, eGFR 76.7(13.6) ml/min/1.73 m2, UACR 4.3(14.4) mg/mmol and 35.8% women. Several shape factors (mean (SD)) such as bounding box volume (495(126) ml), convex hull volume (212(48) ml), short (5.3(0.6) cm) and long axis length (12(1.2) cm) and surface area (227(36) cm2) correlated strongly with kidney volume (KV) (Range r = -0.54 to 0.99). Two distinct clusters were identified in HCA; cluster 1 include compactness and extent which were 3D shape features with low correlation to KV (r = 0.03 and -0.03 respectively, p<0.01). Conversely, cluster 2 parameters mainly consisted of shape measures which were more closely correlated to KV.

Conclusion: Compactness and extent were statistically independent of KV.Extent is the ratio of KV to its bounding box volume; compactness is the surface area-to-volume ratio relative to that of an equivalent sphere, which has 100% compactness. Reduction in compactness indicates an irregular kidney shape secondary to ageing, cortical thinning and compression by surrounding structures. These measures may serve as independent prognostic markers that predict increased risk of future renal decline.

Disclosure

K. Soe: None. K. Sharma: Employee; Antaros Medical. J. Periquito: None. A. Shore: None. K.M. Gooding: None. D. Selvarajah: Research Support; Abbott. Speaker's Bureau; Grunenthal. Research Support; Impeto medical.

Funding

The Innovative Medicines Initiative 2 Joint Undertaking (115974)
413-P: Comparative Effectiveness of Glucose-Lowering Agents on Kidney Outcomes in Adults with Type 2 Diabetes at Moderate Cardiovascular Risk
Authors: NEUMILLER JOSHUA J. , HERRIN JEPH , SWARNA KAVYA , POLLEY ERIC , GALINDO RODOLFO J. , UMPIERREZ GUILLERMO , DENG YIHONG , MICKELSON MINDY , MCCOY ROZALINA G.
Published: June 2024

Introduction & Objective: Guideline-directed care of people with type 2 diabetes (T2D) and high risk of cardiovascular disease (CVD) is informed by robust outcome trials. Little is known about the impact of T2D drugs in adults with T2D with moderate CVD risk, particularly on key kidney outcomes.

Methods: We used claims data from OptumLabs® Data Warehouse, linked to 100% sample of Medicare claims, for adults ≥21 years with T2D and moderate baseline CVD risk initiated on a GLP-1RA, SGLT2i, DPP4i, or sulfonylurea between 1/1/2014 and 12/31/2021. We used Cox models in a target trial framework to compare incident rates of a kidney composite outcome, including stage 3-5 chronic kidney disease, kidney failure, or initiation of kidney replacement therapy.

Results: We identified 364,714 adults with T2D, moderate CVD risk, and without stage 3 or greater CKD at baseline (mean age 65.5 years, 48.9% female). Compared to DPP4i, sulfonylurea therapy was associated with increased risk (HR:1.04; 95% CI:1.02-1.06), while SGLT2i (HR:0.70; 95% CI:0.67-0.73) and GLP-1RA (HR:0.87; CI:0.83-0.92) use were associated with lower risks for the kidney composite outcome (Figure).

Conclusion: SGLT2i and GLP-1RA are associated with lower risks, and sulfonylureas are associated with higher risk, for incident kidney disease in people with T2D and moderate CVD risk.

Disclosure

J.J. Neumiller: Advisory Panel; Bayer Inc., Boehringer-Ingelheim, Eli Lilly and Company, Proteomics International. J. Herrin: None. K. Swarna: None. E. Polley: None. R.J. Galindo: Consultant; Abbott. Other Relationship; Dexcom, Inc. Consultant; Bayer Inc. Other Relationship; Novo Nordisk, Eli Lilly and Company. Consultant; Boehringer-Ingelheim, AstraZeneca. G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc. Y. Deng: None. M. Mickelson: None. R.G. McCoy: Research Support; American Diabetes Association. Other Relationship; American Diabetes Association. Consultant; Wolters Kluwer Health. Research Support; National Institutes of Health, Patient-Centered Outcomes Research Institute. Consultant; Yale New Haven Health System.

Funding

Patient-Centered Outcomes Research Institute (PCORI) award (PCS-1409-24099)
414-P: A Novel Mutation in HNF1B Promotes Ferroptosis-Mediated Renal Mesangial Cells Fibrosis
Authors: CHEN XIN , WEI QIANYING , HUANG MEI , LI YUXIAO , ZHANG MEI
Published: June 2024

Objective: In this study, we identified a novel HNF1B gene mutation (c.445C>A) in a young male MODY5 patient with and elevated serum creatinine levels and albuminuria.

Method: We constructed the HNF1B wild type (HNF1B-WT) and the novel missense mutation (c.445C>A) Mutant (HNF1B-Mut) plasmid and no-loaded control plasmid (pCDH) were transfected into mouse mesangial cells (MMCs) and identified successfully by real-time fluorescent quantitative PCR (RT-qPCR). The changes of cell proliferation activity were detected by CCK-8, the changes of intracellular reactive oxygen species (ROS) were detected by DCFH-DA probe, and the expressions of fibronectin (FN) and iron death index 4-HNE were detected by immunofluorescence staining. The expression levels of long chain fatty acyl-CoA synthetase 4 (ACSL4) and GPX4, key regulatory proteins of iron death, were detected by RT-qPCR.

Results: RT-qPCR confirmed that compared with the control group, the expression levels of CycD1, FN, COLI and other indicators of proliferation and fibrosis decreased in the HNF1B-WT group, but increased in the HNF1B-Mut group. Immunofluorescence co-staining indicated that FN and 4-HNE decreased in HNF-WT cells and increased in HNF1B-Mut cells. CCK-8 assay confirmed that HNF1B-Mut plasmid restored the proliferation activity of MMCs inhibited by HNF-1B. After loading with DCFH-DA probe, it was found that HNF1B-Mut group had higher ROS level than HNF1B-WT group, suggesting that HNF1B-Mut promoted cellular oxidative stress. RT-qPCR showed that the expression of ACSL4 was

increased and GPX4 was decreased in HNF1B-Mut group compared with wild control group.

Conclusion: HNF1B c.445C>A mutation can promote MMCs proliferation and fibrosis by improving intracellular oxidative stress and iron death sensitivity. These abnormal changes may be related to the abnormal renal function impairment of the clinical progenitor.

Disclosure

X. Chen: None. Q. Wei: None. M. Huang: None. Y. Li: None. M. Zhang: None.

Funding

National Natural Science Foundation of China (Approval No.81974103), the Improvement of Clinical Ability Project of Jiangsu Province Hospi-tal (JSPH-MA-2021-3), Jiangsu Provincial Medical Key Discipline (Laboratory) (ZDXK202202).
419-P: Association of Remnant Cholesterol (rem-C) with Kidney Disease Progression in People with Type 2 Diabetes (T2D)
Authors: YAMAMOTO YUI , HANAI KO , MORI TOMOMI , BABAZONO TETSUYA
Published: June 2024

Objective: A study using diabetic mice demonstrated that cholesterol deposition in the kidneys provokes apoptosis of podocytes and albuminuria; however, most studies in people with diabetes have failed to demonstrate significant association of higher LDL cholesterol (LDL-C) levels with progression of diabetic nephropathy (DN). Accumulating evidences reveal a strong atherogenicity of cholesterol in triglyceride-rich lipoproteins, called rem-C. Currently, data on the association between rem-C and DN are limited. Here, we examined whether rem-C can predict kidney disease progression in people with diabetes.

Methods: This was a retrospective cohort study of 5161 Japanese adults with T2D (mean age: 61 years, women: 36.4%). The exposure was serum rem-C levels at baseline, treated as a categorical variable and classified into four categories based on the quartile of rem-C. Rem-C was calculated as total cholesterol minus LDL-C minus HDL cholesterol, referencing previous studies. The outcome was a composite of a ≥30% decline in eGFR or the initiation of kidney replacement therapy. The hazard ratios (HRs) for the outcome were estimated using the multivariable Cox proportional hazards model. In the analysis treating rem-C as a continuous variable, the multivariable-adjusted restricted cubic spline model was used.

Results: The median (interquartile range: IQR) baseline rem-C (mg/dL) was 25 (18-35). During a median (IQR) follow-up of 7.6 (3.0-11.6) years, 1172 people reached the outcome. In setting the first quartile group (n= 1257) as the reference, the HRs (95% CIs) of the second (n= 1302), third (n= 1304), and fourth quartile groups (n= 1298) were 1.13 (0.92-1.39), 1.38 (1.10-1.74), and 1.36 (1.01-1.81), respectively. A similar trend was also shown by the spline model.

Conclusion: Rem-C levels were identified as a risk factor for kidney disease progression in people with T2D. Future interventional studies are needed to clarify the potential of rem-C as a therapeutic target for DN.

Disclosure

Y. Yamamoto: None. K. Hanai: None. T. Mori: None. T. Babazono: None.
42-OR: A Small Intestinal Bile Acid Modulates the Gut Microbiome to Improve Glucose Regulation following Bariatric Surgery
Authors: CHEN YINGJIA , CHAUDHARI SNEHAL N. , HARRIS DAVID A. , TAVAKKOLI ALI , DEVLIN SLOAN , SHEU ERIC
Published: June 2024

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide the most effective and durable therapy for type 2 diabetes (T2D). This work is aimed at identifying molecule mediators of bariatric surgery’s metabolic effects, in order to develop non-invasive interventions for T2D. Our previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we investigate the metabolic effects of LCA and the mechanisms of its downregulation post-SG. We find that LCA feeding to chow-fed mice worsens glucose tolerance, decreases respiratory exchange ratio, and increases adiposity. We also show that taurodeoxycholic acid (TDCA) is the only bile acid whose concentration is increased in the murine small intestine post-SG. Moreover, TDCA abundance is decreased in small intestinal tissue from patients with T2D. Treatment of cecal cultures with SG small intestinal contents or TDCA in vitro reduces the expression of bacterial bile acid-inducible (bai) operon and production of LCA. In vivo treatment of diet-induced obese mice with TDCA also suppresses the bai operon, reduces LCA levels and leads to improvements in host glucose handling. Abolishing gut microbiota or co-feeding LCA to TDCA-treated mice substantially diminishes the beneficial effects of TDCA on glucose regulation, demonstrating that TDCA’s glucoregulatory effects require the microbiota. This work has revealed that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.

Disclosure

Y. Chen: None. S.N. Chaudhari: None. D.A. Harris: None. A. Tavakkoli: Consultant; AltrixBio. S. Devlin: None. E. Sheu: Other Relationship; Intuitive Surgical. Consultant; Vicarious Surgical Inc. Speaker's Bureau; Cine-Med.

Funding

National Institutes of Health (R01 DK126855R35, GM128618); Alfred P. Sloan Fellowship; National Institutes of Health (K99/R00 DK128503)
420-P: Effects of Nonalbuminuric Type 2 Diabetes Mellitus on Renal Outcomes
Authors: CHOI DUGHYUN , PARK SAMEL , YOUNG LEE EUN
Published: June 2024

Introduction & Objective: The classic pattern of diabetic kidney disease is typically followed by microalbuminuria. However, the pure impact of type 2 diabetes mellitus (T2D) without albuminuria on renal outcomes is not fully understood. This study aimed to investigate the renal outcomes in non-albuminuric T2D compared to non-albuminuric non-T2D subjects.

Methods: Data from the National Health Insurance Service-National Sample Cohort of Korea from 2009 to 2015 were analyzed. Subjects with an estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2 at baseline and within the normal range of albuminuria were included. They were divided into T2D and non-T2D groups. The primary outcome was a composite renal outcome, consisting of the initiation of renal replacement therapy and a decline of ≥ 40% in eGFR from baseline.

Results: A total of 77,267 patients were analyzed (11,957 in the T2D group vs. 65,310 in the non-T2D group). In a linear mixed model, the T2D group showed a significantly greater annual decline in eGFR of -0.113 ml/min/1.73 m2 (95% CI: -0.222 to -0.003, p = 0.044) compared to the non-T2D group. The primary outcome, the adjusted hazard ratio for the composite renal outcome, was 1.57 (95% CI: 1.28-1.92, p < 0.001).

Conclusion: Non-albuminuric T2D was associated with a greater annual decline in renal function and had a 1.5-fold increased risk of adverse renal outcomes compared to non-albuminuric non-T2D subjects.

Disclosure

D. Choi: None. S. Park: None. E. Lee: None.

Funding

National Research Foundation of Korea grant funded by the Korean government (2021R1G1A1009254)
421-P: Ferritin and COVID-19 Infection and Outcomes in American Indian and Alaska Native Dialysis Patients with Diabetes
Authors: HU MING , QUANDELACY TALIA , WANG YUEDONG , KOTANKO PETER , CONWAY REBECCA B.
Published: June 2024

American Indians/Alaska Natives (AIAN) bear the greatest burden of diabetes and are overrepresented in the dialysis population. They were also hardest hit by COVID-19, w/higher mortality rates than any U.S. racial/ethnic group. Early in the pandemic, hyperferritinemia was prognostic of poor COVID-19 outcomes, including death. We determined the association of ferritin w/ COVID-19 infection, hospitalization, and mortality in AIAN dialysis patients w/ diabetes. We followed 1,065 AIAN in-center hemodialysis patients w/ diabetes from January 2020 to March 2022. For incident COVID infection, baseline ferritin was defined as the average from one year prior to two weeks prior to RT-PCR confirmed COVID-infection (days-365,-14). Change in ferritin was defined as the difference between the baseline average and two week prior average (-14,0) to the PCR positive test date. For non-infected patients, a randomly selected date following the distribution of PCR positive dates of COVID patients was chosen as the test date. Logistic regression assessed the association of ferritin and its change w/ COVID-19 infection, hospitalization and mortality, adjusting for age, sex, race, vaccination status, vintage, and lab values. During follow-up, the cumulative incidence of infection was 35.7%; in the infected, 26.7% were hospitalized and 12.6% died. While baseline ferritin was not linked to infection risk (p=0.42), TSAT (p=0.02) and ferritin change (p=0.09) were marginally. In the infected, ferritin two weeks prior to RT-PCR confirmed diagnosis were linked to hospitalization (p=0.02), while ferritin change was not (p=0.59). Neither baseline nor ferritin change was linked w/ mortality; but lower baseline hgb (p=0.09), higher neutrophils (p=0.09) and neutrophil to lymphocyte ratio (p=0.06) showed weak relationships w/ mortality. Ferritin was associated w/ future risk of COVID-19 infection and hospitalization but not mortality in AIAN dialysis patients w/ diabetes.

Disclosure

M. Hu: None. T. Quandelacy: None. Y. Wang: None. P. Kotanko: Other Relationship; Fresenius Medical Care. R.B. Conway: None.
43-PUB: A Bibliometric Analysis of Machine Learning and Type 2 Diabetes from 2010 to 2023
Authors: YANG YANLING , LIU ZHIGU , LIN BEISI , CHEN DANRUI , YAN JINHUA , ZENG LONGYI , XU WEN
Published: June 2024

Objective: Machine learning in the research on type 2 diabetes (T2D) has garnered attention in recent years. Nonetheless, few studies offer a thorough picture of the knowledge generation landscape in this field. This comprehensive bibliometric analysis was conducted to discover global research trends and networks and to emphasize the most prominent countries, institutions, and key topics in this domain.

Methods: Articles on the link between machine learning and T2D from 2010 to 2023 were searched in the Science Citation Index-Expanded of Web of Science Core Collection. The results were classified into categories of prediction, screening and management. CiteSpace software, Vosviewer, the R package "bibliometrix" and the Online Analysis Platform of Literature Metrology were used to analyze the data.

Results: A total of 611 articles were retrieved on the link between machine learning and T2D. The number of publications increased dramatically in the past 5 years, with a sharply increase in the last 3 years. The United States dominated the field until 2021, and the dominance of China started in 2022. The United States was the most frequently involved country in international cooperation. Harvard Medical School was the most productive university. The co-citation keyword clustering labels displayed eight main clusters: precision medicine, counterfactual prediction, risk scoring, diabetic retinopathy, predictive model, gut microbiome, clinical decision support system, and bariatric surgery. The keyword bursts analysis indicated that validation, risk prediction, predictive model, predictor, and metabolomics were the research hotspots with high strength.

Conclusion: Machine learning is now being increasingly applied in the field of prediction, screening and management of T2D, especially over the last years with exponential growth. This bibliometric study provided systematic information and guidance to help explore the application and practice of machine learning in T2D for future research.

Disclosure

Y. Yang: None. Z. Liu: None. B. Lin: None. D. Chen: None. J. Yan: None. L. Zeng: None. W. Xu: None.

Funding

Natural Science Foundation of Guangdong Province (2022A1515012364)
450-P: Pulse Pressure as a Predictor of Cardiovascular Events in Cardiovascular Disease Patients with Differing Glycemic State
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2024

Pulse pressure, i.e. the difference between systolic and diastolic blood pressure is a measure of arterial stiffness, which is a strong predictor of cardiovascular risk. The power of pulse pressure to predict cardiovascular events in patients with differing glycemic state is unclear and is addressed in the present study. We prospectively recorded cardiovascular events in a high-risk cohort of 1787 patients with cardiovascular disease (1472 patients with angiographically proven coronary artery disease and 315 with sonographically proven peripheral artery disease), over a mean follow-up period of 10.7±5.0 years. At baseline, pulse pressure significantly increased from patients with NFG (n=690) over those with IFG (n=505) to those with T2DM (n=592; 56±17 mmHg, 58±15 mmHg and 59±18 mmHg, respectively; ptrend=0.002). During follow-up, 913 of our patients suffered cardiovascular events; the incidence of cardiovascular events increased significantly from subjects with NFG over those with IFG to those with T2DM (49.9%, 44.2% and 60.3%, respectively; ptrend<0.001).Pulse pressure in the total study population predicted cardiovascular events (standardized adjusted HR 1.13 [1.05-1.22], p<0.001) in Cox regression models adjusting for age, sex, hypertension, smoking, body mass index and LDL cholesterol and also after additional adjustment for the baseline glycemic state (HR=1.12 [1.04-1.21], p=0.002). In subgroup analyses, standardized adjusted HRs were 1.15 [1.02-1.30], p=0.027), 1.00 [0.85-1.17], p=0.971) and 1.17 [1.05-1.31], p=0.006) in patients with NFG, IFG and T2DM, respectively. An interaction term puls pressure by glycemic state was not significant (p=0.310), indicating that the glycemic state did not significantly impact the power of pulse pressure to predict cardiovascular events. From our data we conclude that pulse pressure is a predictor of cardiovascular events in CVD patients irrespective of the baseline glycemic state.

Disclosure

T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
456-P: The ApoB/LDL-C Ratio Predicts Cardiovascular Events in Coronary Artery Disease Patients Independent of Type 2 Diabetes Status
Authors: LARCHER BARBARA , PLATTNER THOMAS , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2024

A high ApoB/LDL-C ratio reflects small LDL particle size which like type 2 diabetes (T2DM) is associated with insulin resistance. Whether the ApoB/LDL-C ratio and the presence of T2DM are mutually independent predictors of cardiovascular events is unclear and is addressed in the present study. We enrolled a large high-risk cohort of 1200 patients with coronary artery disease. T2DM was diagnosed according to current ADA guidelines. Prospectively, cardiovascular events were recorded over a mean follow-up period of 10.5±4.9 years. At baseline, the ApoB/LDL-C ratio was significantly higher in patients with T2DM (n=422) than in subjects who did not have T2DM (0.81±0.18 vs. 0.74±0.15 p<0.001). During follow-up, 662 patients suffered cardiovascular events. The Apo B/LDL-C ratio predicted cardiovascular events in univariate analysis (HR=1.11 [1.03-1.20] p= 0.006), and the event rate was higher in patients with than in those without T2DM (62.2% vs. 52.3%; p=0.001). In a multivariate adjusted Cox regression model both the ApoB/LDL-C ratio and T2DM significantly predicted cardiovascular events in a mutually independent manner, with standardized adjusted HRs of 1.11 [1.03-1.20]; p=0.008 and 1.39 [1.18-1.64]; p<0.001, respectively. We conclude that in subjects with coronary artery disease the ApoB/LDL-C and T2DM are mutually independent predictors of cardiovascular events.

Disclosure

B. Larcher: None. T. Plattner: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
464-P: The Visceral Adiposity Index Predicts Cardiovascular Events Both in Coronary Artery Disease Patients With and in Those Without Diabetes
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2024

The Visceral Adiposity Index (VAI) is calculated based on waist circumference, BMI, triglyceride and HDL-cholesterol levels and is a validated measure of visceral adiposity. In the general population, the VAI has been shown to be an independent risk factor for premature mortality. Its power to predict cardiovascular events in patients with coronary artery disease (CAD) with or without type 2 diabetes mellitus (T2DM) is not known and is addressed in the present study. We prospectively investigated 927 patients with angiographically diagnosed CAD over a mean follow-up time of 8.2±4.3 years. At baseline, the VAI was significantly higher in patients with T2DM (n=303) than in those who did not have diabetes (6.5±5.2 vs. 4.8±4.9; p<0.001). During follow-up, we recorded 385 cardiovascular events. The VAI significantly predicted the incidence of cardiovascular events both univariately (standardized HR 1.09 [1.02-1.16]; p=0.011) and after adjustment for age, gender, smoking, LDL cholesterol, hypertension and T2DM (standardized adjusted HR 1.11 [1.04-1.18]; p=0.002); also T2DM significantly predicted cardiovascular events in this fully adjusted model (adjusted HR 1.26 [1.04-1.52]; p=0.018) independently from the VAI. We conclude that the VAI and T2DM are mutually independent predictors of cardiovascular events in patients with CAD.

Disclosure

T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
47-PUB: FRAME—An Education Program for Newly Diagnosed Youth with Type 2 Diabetes
Authors: VAKHARIA MILI , ELISA DIAZ MARIA , MCKAY SIRIPOOM , LYONS SARAH , SONABEND RONA Y. , KIM GRACE K.
Published: June 2024

Background: We launched a new multidisciplinary pediatric type 2 diabetes (T2D) inpatient education program, FRAME (Follow a Balanced Meal, Reduce Insulin Resistance with Lifestyle Change, Adhere to Medication, Monitor Blood Glucose & Comorbidities, and Engage Support System). It focused on MyPlate method and fixed insulin dosing rather than based on grams of carbohydrates. Our quality improvement (QI) aim was to decrease the percentage of youth with new onset T2D, diagnosed less than 6 months, placed on carbohydrate-based insulin dosing from baseline of 19% to 14% by December 2023.

Methods: Our team implemented the following Plan-Do-Study-Act cycles: 1. Created a FRAME Works T2D education program 2. Educated providers and ancillary staff 3. Implemented the education at all three hospitals 4. Initiated a post-hospitalization discharge knowledge assessment test.

Results: P-chart showed shift in center line with percentage of patients with T2D, diagnosed less than 6 months, on a carbohydrate-based dosing regimen decreasing from baseline of 19% to 10%, from December 2022 to December 2023 (Figure 1).

Conclusions: Our QI project successfully facilitated interprofessional led patient education for youth with T2D using the FRAME program. Our next steps are to develop an outpatient education curriculum with treatment algorithm and outcomes.

Disclosure

M. Vakharia: None. M. Diaz: None. S. Mckay: None. S. Lyons: None. R.Y. Sonabend: None. G.K. Kim: None.
471-P: Anti-NFKB Inhibitor Beta Antibody Correlates with Cardiovascular Disease in Type 1 Diabetic Patients with Autoimmune Disease
Authors: PARK KYOUNGMIN , PHAM LINDA , LI QIAN , GREGORY YU MARC , FU JIALIN , VISHVA TEJA JANGOLLA SURYA , WU I-HSIEN , KING GEORGE L.
Published: June 2024

Cardiovascular disease (CVD) is a major cause of mortality in Type 1 diabetes (T1D). Studies suggest that autoimmunity may influence CVD development in T1D. We created a novel T1D-CVD mouse model by deleting ApoE via CRISPR/Cas9 editing in nonobese diabetic (ApoE-/-/NOD) mice, an autoimmune T1D model, and observed that both diabetic and nondiabetic ApoE-/-/NOD mice showed autoimmune insulitis and greater atherosclerotic lipid deposition and plaque formation compared to CongApoE-/‘- wild type (WT) mice. Plasma studies with autoantigen proteomic microarray from people with long-duration T1D>50 years (“Medalists”), identified potential autoantibodies (AAb) targeting antigens in aortic plaques, which correlated to coronary artery calcium (CAC). One protein, nuclear factor-KB inhibitor beta (NFKBIB, p=0.0017), was higher in plasma of Medalists positive for HLA T1D risk alleles (HLA+) compared to HLA(-) Medalists. To quantify circulating anti-NFKBIB in Medalist samples, we developed an immunoassay using novel electrochemiluminescence technology. Our findings showed higher anti-NFKBIB AAb in HLA(+) versus HLA(-) Medalists. Moreover, in the HLA(+) group, higher anti-NFKBIB AAb was seen in those with CVD. To corroborate these findings from Medalist patients, we analyzed plasma from ApoE-/-/NOD mice with autoimmune T1D, as well as control nondiabetic CongApoE/NOD mice. Immunoblot analysis showed that only isolated IgG from plasma of ApoE-/-/NOD mice detected NFKBIB in aortic lysates and/or purified recombinant NFKBIB protein in a concentration-dependent manner, relative to IgG from control mice. Flow cytometry analysis of immunocytes revealed twofold increases in blood and para-aortic B- (CD19+, p=0.012) and T-cell (CD4+, p=0.008) populations of ApoE-/-/NOD mice compared to WT mice. These suggest that anti-NFKBIB AAb is a novel AAb present in people and mouse models with T1D and atherosclerosis, and may contribute to CVD development in T1D.

Disclosure

K. Park: None. L. Pham: None. Q. Li: None. M. Yu: None. J. Fu: None. S. Jangolla: None. I. Wu: None. G.L. King: None.

Funding

5R01HL161864-02, Beatson foundation #5R01HL161864-02
472-P: Molecular Pathogenesis of Sex-Specific Vascular Contributions to Cognitive Impairment and Dementia and in Type 1 Diabetes
Authors: WILSON SANTOS ED , KHATOON SUBIKA , ZHENG YUN-MIN , WANG YONG-XIAO
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) is a serious disease that affects millions of people worldwide and is a major factor for vascular contributions to cognitive impairment and dementia (VCID). However, whether and how sex affects VCID in diabetics is rarely reported. In this study, we compared cognitive and memory impairments in male and female mice with T1D and evaluated the underlying molecular mechanisms.

Methods: We injected streptozotocin (STZ) and then measured cerebral blood flow, ROS production, Tau, and Chk2 expression by Western blotting.

Results: Our findings indicate that intraperitoneal STZ-injection induced T1D in both genders of mice, showing largely elevated blood glucose, and decreased body weight. However, male diabetic mice showed greater cognitive impairment determined by an open-field test and memory loss measured by a novel object recognition test. Interestingly, ROS generation in isolated mitochondria and mitochondrial complex III from cerebral arterial smooth muscle (CASM) tissues was greater in male diabetic mice. ROS production in isolated mitochondria and mitochondrial complex III from cerebral cortex tissues was increased similarly in both male and female diabetic mice. We further found that male diabetic mice had higher DNA damage, as demonstrated by greater check kinase 2 (Chk2) phosphorylation in CASM tissues. Tau phosphorylation in CASM tissues was also largely increased in diabetic mice; this diabetic increase was no different between males and females. Noticeably, mitochondrial and complex III ROS production, Chk2, and tau phosphorylation all had similar increases in cerebral cortex tissues from both male and female diabetic mice.

Conclusion: Taken together, we conclude that T1D may cause greater mitochondrial complex III ROS production, greater DNA damage and greater Chk2 phosphorylation in male CASM tissues, thereby leading to more serious cognitive impairment and memory loss in male than female T1D.

Disclosure

E. Santos: None. S. Khatoon: None. Y. Zheng: None. Y. Wang: None.

Funding

R01HL122865R03AG070784R01HL108232
477-P: Peripheral Neuropathy—Evaluation of DPNCheck vs. mTCNS in Type 1 Diabetes
Authors: MARION LIPI A. , NEVAREZ CRYSTABELLA E. , MURTHY ANANYA B. , YU ELAINE W.
Published: June 2024

Introduction: The handheld DPNCheck (DPNC) nerve conduction study (NCS) device has shown high sensitivity (SENS) and specificity (SPEC) against classical NCS for detecting peripheral neuropathy (PN), but studies comparing DPNC to clinical assessments are lacking. We aimed to evaluate DPNC against a validated clinical reference standard in adults with T1D.

Methods: Among 88 adults >50 yrs with T1D, we assessed PN with the modified Toronto Clinical Neuropathy Scale (mTCNS) and bilateral sural nerve conduction velocity (VEL) and action potential amplitude (AMP) with DPNC. Abnormal AMP or VEL >1 leg=DPNC+. We used McNemar’s test and calculated SENS and SPEC to compare DPNC to mTCNS (score >3=PN+) as the reference.

Results: Mean age was 63+6 yrs, T1D duration 46±10 yrs and A1c 7.1±1%; 52% were male. Mean mTCNS score was 5.2+5, AMP 42+10 m/s and VEL 4.8+3 µV. Correlation between mTCNS and worse leg AMP and VEL was -0.36 and -0.52, respectively (p<0.001). The proportion of subjects PN+ by mTCNS was similar to those DPNC+ using standard manufacturer cutoffs (DPNC-std; p=0.85) but significantly higher in those DPNC+ using age and height adjusted cutoffs (DPNC-adj; p<0.001). DPNC-adj had 94% SENS but 28% SPEC; DPNC-std had 71% SENS and 63% SPEC.

Conclusion: DPNC has high SENS for detecting PN in T1D. Lower SPEC may reflect detection of subclinical PN rather than misclassification of true negatives. DPNC alone or combined with mTCNS may aid in early PN detection.

Disclosure

L.A. Marion: None. C.E. Nevarez: None. A.B. Murthy: None. E.W. Yu: Research Support; Amgen Inc.

Funding

National Institutes of Health (T32DK007028)