bluuebunny/crossref_metadata_2025_split huggingface dataset:
159-LB: High-Affinity ZnT8 Autoantibodies by Electrochemiluminescence Assay Improve the Risk Prediction for Type 1 Diabetes
Authors: JIA XIAOFAN , HE LING , MIAO DONGMEI , WAUGH KATHLEEN , RASMUSSEN CRISTY GENO , DONG FRAN , REWERS MARIAN , YU LIPING 
Published: June 2021

Background: A cohort of children with single ZnT8 autoantibody (ZnT8A) positivity were identified in two large clinical trials, Autoimmunity Screening for Kids (ASK) and Diabetes Autoimmunity Study in the Young (DAISY), and their risk of type 1 diabetes (T1D) have never been studied.
Methods: Three cohorts were analyzed using a high-affinity electrochemiluminescence (ECL) ZnT8A assay including 302 new onset T1D patients, 135 children positive for ZnT8A by standard radio-binding assay (RBA) from 23400 children screened in ASK study, and 123 children with multiple autoantibodies or single ZnT8A by RBA from 2547 children in DAISY study.
Results: ECL-ZnT8A had a similar sensitivity with RBA-ZnT8A in the cohort of 302 new onset T1D patients (62.3% vs. 61.9%). In ASK, 135/23400 of general population children were positive for RBA-ZnT8A and 64/135 were found as single ZnT8A only without other islet autoantibodies. Of 64 children with single ZnT8A, only 14.1% (9/64) were detectable by ECL-ZnT8A. Antibody-affinity analysis revealed that the ZnT8A in RBA but not confirmed by ECL were of low affinity and they were easily disappeared during the follow-up behaving as ‘transient’ positivity. In terms of T1D classification from stage 1 to stage 3, positive predictive value (PPV) of ECL-ZnT8A (61/70 [87.1%]) was significantly higher than that of RBA-ZnT8A (73/137 [53.3%]; P&lt;0.0001). The cumulative risk of clinical T1D development with ZnT8A confirmed by ECL (16/66) was significantly enhanced during a short time of follow-up, compared with ZnT8A not confirmed by ECL (1/43; p=0.023). Similarly in DAISY participants, 11/2547 children were identified as single ZnT8A by RBA while only three who developed T1D were detected ECL-ZnT8A.
Conclusions: Large proportion of ZnT8A by current standard RBA are single ZnT8A with majority at low risk in population-based screening while ECL-ZnT8A can discriminate high risk from low risk and are highly predictive for T1D development.

Disclosure
X. Jia: None. L. He: None. D. Miao: None. K. Waugh: None. C. Geno rasmussen: None. F. Dong: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research & Development, LLC, JDRF. L. Yu: None.

Funding
Diabetes Research Center (P30DK116073); JDRF (2-SRA-2018-533-S-B, 2-SRA-2020-965-S-B, 1-SRA-2016-208-S-B); National Institutes of Health (DK32083)
160-OR: Increased Adiposity and Low Height-for-Age in Early Childhood Is Associated with Later Metabolic Risk in American Indian Children and Adolescents
Authors: RAMIREZ-LUZURIAGA MARIA J. , KOBES SAYUKO , SINHA MADHUMITA , KNOWLER WILLIAM C. , HANSON ROBERT L. 
Published: June 2021

Background: Growth abnormalities in early childhood have been related to later metabolic risk, but little is known about these associations in populations at high risk of diabetes.
Methods: We linked anthropometric data collected at ages 0-&lt;5 y from 2928 routine clinical examinations conducted 1990-2000 to metabolic data from a longitudinal study in a southwestern American Indian population at high risk of diabetes. A total of 701 participants with ≥1 follow-up examination at ages 5-16 y were included. We derived age and sex-specific z-scores (from WHO Child Growth Standards) of weight-for-height (WHZ) and height-for-age (HAZ) at ages 0-&lt;5 y. We selected the highest observed WHZ and the lowest HAZ and analyzed associations of categories of WHZ and HAZ with metabolic data at ages 5-9 y and 10-16 y. Linear mixed effects models were used to account for repeated measures.
Results: In age and sex-adjusted models, overweight and obesity (WHZ &gt; 2) at ages 0-&lt;5 y was significantly associated with higher BMI and with greater height at ages 5-16 y relative to normal weight (WHZ ≤ 1). It was also associated with increased fasting glucose, 2-h glucose, fasting insulin, 2-hr insulin, total cholesterol, triglycerides, SBP, DPB and decreased HDL. For example, at ages 5-9 y 2-h glucose was 10.4 mg/dl higher (95% CI: 5.6, 15.3) and fasting insulin was 1.88 times higher (95% CI: 1.58, 2.24). Associations were attenuated and no longer significant when adjusted for BMI. Low height-for-age (HAZ&lt; -2) at ages 0-&lt;5 y was associated with lower BMI and lower height at ages 5-16 y relative to normal height (HAZ ≥ 0). With adjustment for BMI, low height-for-age was associated with 1.40 times higher 2-h insulin (95% CI: 1.05, 1.87) and 5.47 mg/dL lower HDL (95% CI: 2.68, 8.62) at ages 10-16 y.
Conclusion: These analyses suggest that both overweight/obesity and low height-for-age in early childhood can influence subsequent metabolic risk in American Indian children and adolescents.

Disclosure
M. J. Ramirez-luzuriaga: None. S. Kobes: None. M. Sinha: None. W. C. Knowler: None. R. L. Hanson: None.
161-LB: Role of Child Physical Activity and Sleep Efficiency in Relation to Prenatal Exposure to Gestational Diabetes on Adiposity
Authors: ALVES JASMIN M. , DEFENDIS ALEXIS W. , CHOW TING , NGUYEN-RODRIGUEZ SELENA T. , XIANG ANNY , PAGE KATHLEEN A. 
Published: June 2021

Introduction: Little is known on the role of child physical activity (PA) and sleep in relation to maternal gestational diabetes mellitus (GDM) and child adiposity. We explored these relationships using data collected from the BrainChild Study.
Method: Data included 88 children (mean ± SD, age 9.5 ± 1.7 years; 52% GDM exposed; 56% female) born at Kaiser Permanente Southern California. GDM exposure was obtained from electronic medical records. Anthropometric measurements, time spent in moderate and vigorous PA and actigraphy-based sleep parameters were measured during daily life for 7 days using wrist-worn accelerometers.
Results: GDM exposed vs. unexposed children had higher BMI z-scores (1.3 ± 1.0 vs. 0.7 ± 1.1, p=0.015), total body fat (29.7 ± 9.6 vs. 25.0 ± 8.3%, p=0.017) and waist to height ratios (WHR) (0.52 ± 0.08 vs. 0.47 ± 0.07, p=0.002). Linear regression showed that children who engaged in more VPA had lower measures of adiposity, independent of age and sex (BMI z-score: β=-0.39, p=0.033; body fat%: β=-3.25, p=0.037; WHR: β=-0.23, p=0.068). Further adjusting for sleep efficiency did not affect the results. Similar patterns were observed for MVPA but were not significant. There was no interaction between GDM exposure and PA on adiposity. Sleep efficiency was not associated with adiposity, but there was a significant interaction between GDM exposure and sleep efficiency on child adiposity (p=0.042). GDM exposed children who had better sleep efficiency had marginally lower body fat (β=-0.56, p=0.098), while this relationship was not observed in unexposed children (β=0.50, p=0.14).
Conclusion: Our findings demonstrate that VPA is associated with lower child adiposity measures regardless of GDM exposure, and sleep efficiency is associated with lower adiposity among GDM exposed children. These findings suggest that strategies to increase VPA and improve sleep efficiency may be beneficial for ameliorating the adverse effects of GDM exposure on child adiposity.

Disclosure
J. M. Alves: None. A. W. Defendis: None. T. Chow: None. S. T. Nguyen-rodriguez: None. A. Xiang: None. K. A. Page: None.

Funding
American Diabetes Association (1-14-ACE-36 to K.A.P.); National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116858)
165-OR: Antioxidant-Based Encapsulation Strategies to Enhance Islet Allotransplantation
Authors: BARRA JESSIE , KOZLOVSKAYA VERONIKA , KHARLAMPIEVA EUGENIA , TSE HUBERT M. 
Published: June 2021

The destruction of insulin-producing cells is a hallmark of type 1 diabetes (T1D) and results in a loss of glycemic control. Islet transplantation can restore glucose homeostasis and prevent hypoglycemic events; however, long-term graft survival is low. Oxidative stress mediates islet transplant rejection. Therefore, suppressing oxidative stress with nanothin encapsulation materials comprised of alternating layers of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), a scaffold polymer, may allow for improved graft survival. We hypothesize that (PVPON/TA)-encapsulation of islets will prolong graft function and delay allotransplantation rejection in the absence of systemic immunosuppression. We recently published that allogeneic transplantation of encapsulated C57BL/6 islets into NOD mice significantly delayed graft failure, decreased free radical-adduct formation, and reduced infiltrating immune cell effector responses. These data suggest local immunosuppression with (PVPON/TA)-encapsulation may be a promising technique to prolong islet graft function in islet allotransplants. To enhance immunosuppression, we conjugated CTLA-4-Ig to the outer surface of (PVPON/TA) layers. (PVPON/TA/CTLA-4)-encapsulated islets display significantly delayed allograft rejection compared to (PVPON/TA) controls. Flow cytometry analysis demonstrated reduced CD80/CD86 costimulatory receptor and MHC-II expression on innate immune populations, enhanced FOXP3+ regulatory T cells, and enhanced PD1+ CD8 T cells within (PVPON/TA/CTLA-4)-encapsulated grafts. To monitor graft integrity in vivo, we conjugated (PVPON/TA) layers with the fluorophore Cy5.5. Transplantation of (PVPON/TA/Cy5.5)-encapsulated islets restored glucose tolerance and was detected in vivo for up to eight weeks post-transplant. The ability to modify our (PVPON/TA) coatings opens the door for endless possibilities to improve clinical islet transplantation.

Disclosure
J. Barra: None. V. Kozlovskaya: None. E. Kharlampieva: None. H. M. Tse: None.

Funding
National Science Foundation (1608728); National Institute of Diabetes and Digestive and Kidney Diseases (DK-099550); JDRF (SRA-2016-270-S-B, 2-SRA-2019-692-S-B)
166-LB: Targeting Deprescribing in Type 2 Diabetes Mellitus Using a Pragmatic Electronic Health Record Measure of Frailty
Authors: USOH CHINENYE , LENOIR KRISTIN M. , PAJEWSKI NICHOLAS M. , CALLAHAN KATHRYN E. 
Published: June 2021

Background: Guidelines recommend less stringent glycemic goals for older adults with type 2 diabetes mellitus (T2DM) and frailty or comorbidity. However, pragmatic, scalable approaches to identify candidates for de-intensification of T2DM regimens are lacking.
Methods: Analysis of electronic health record (EHR) data for patients ≥65 years with T2DM from an accountable care organization as of 11/1/2020. Frailty was determined based on a 54-item electronic Frailty Index (eFI) derived from the EHR. Other data included the level of glycemic control, use of higher-risk medications regimens (active prescription of insulin, sulfonylurea, or combinations of the two), the incidence of emergency department (ED) visits and hospitalizations, and all-cause mortality.
Results: Amongst 16973 patients, 53.9% were female, 77.8% white, with a mean age of 75.5 (SD=6.9) years. Based on the eFI, 6218 (36.6%) patients were classified as frail (eFI&gt;0.21). During short-term follow-up (median=116 days), compared to fit patients (eFI≤0.10), patients classified as frail exhibited a higher incidence of ED visits and hospitalizations (hazard ratio = 3.05, 95% CI: 2.35 to 3.95) and all-cause mortality (hazard ratio = 7.33, 95% CI: 3.61 to 14.88). A large number of patients classified as frail based on the eFI had HbA1c levels &lt;7.5% based on their most recent measure (N=4544, 73.1%). In this population, 1408 (31%) were prescribed no T2DM medication, 1013 (22.3%) were prescribed metformin alone, and 1755 (38.6%) were on a higher-risk T2DM medication (sulfonylurea or insulin). In frail patients with HbA1c&lt;7.5%, patients taking metformin only exhibited the lowest rate of ED visits and hospitalizations (hazard ratio = 0.58, 95% CI: 0.44 to 0.77 compared to all other groups).
Conclusions: The eFI is a pragmatic and scalable tool to identify vulnerable older adults with T2DM that may benefit from de-prescribing consistent with guideline recommendations.

Disclosure
C. Usoh: None. K. M. Lenoir: None. N. M. Pajewski: None. K. E. Callahan: None.
167-LB: Pandemic Changes and Usage of At-Home Collected Hemoglobin A1c and Lipid Profiles
Authors: DION EMMA J. , HUMPHREYS DEVON , OLDS KAYLAN , SIRIWARDHANE THUSHANI , BAUER TIMOTHY 
Published: June 2021

Background: Routine health screening and monitoring declined when COVID-19 was declared a global pandemic on March 11, 2020. Early reports found Hemoglobin A1c (HbA1c) testing declined nearly 50% among patients with diabetes from March to May in 2020 compared with 2019. At-home sample collection aligns with social distancing practices and mitigates potential exposure to SARS-CoV-2 in public settings, including clinics. This study sought to characterize utilization of at-home lab tests and resulting HbA1c and lipid profiles in pre-pandemic and pandemic cohorts.
Methods: Results from individuals who used at-home collection to measure HbA1c, total cholesterol, calculated LDL-C, HDL, triglycerides, and hs-CRP between October 2017 and December 2020 were identified from a commercial consumer database. A total of 19,076 test-takers were included, of which 12,587 had HbA1c measurements and 13,624 had lipid measurements.
Results: Use of tests measuring HbA1c increased 60.3% in February-May 2020, around the time of pandemic declaration, and to a lesser degree from June-December when compared with 2019 use. Use of tests measuring lipids increased 61.9% during the same time periods. The mean HbA1c (%) in the pre-pandemic vs. pandemic cohort was 5.47 ± 0.72 (N = 3476) vs. 5.69 ± 0.87 (N = 2851) among users ages 18-44, 5.85 ± 1.04 (N = 2740) vs. 6.12 ± 1.17 (N = 1709) among users ages 45-64, and 6.05 ± 0.91 (N = 703) vs. 6.47 ± 1.34 (N = 513) among users ages 65+. Overall, the percent of individuals with an HbA1c characteristic of prediabetes and diabetes (HbA1c ≥ 5.7% and ≥ 6.5%, respectively) was 23.4% and 7.0% in 2018 (N = 2342), 26.6% and 8.5% in 2019 (N = 3751), and 38.8% and 14.7% of total users in 2020 (N = 6173).
Conclusions: The impact of the COVID-19 pandemic on at-home lab testing demonstrates the feasibility and increased usage of at-home sample collection for routine health monitoring particularly among people with elevated HbA1c.

Disclosure
E. J. Dion: Employee; Self; Everlywell, Inc.. D. Humphreys: None. K. Olds: Employee; Self; Everlywell, Inc. T. Siriwardhane: None. T. Bauer: Employee; Self; Everlywell, Inc.
177-OR: The Swi/Snf Chromatin Remodeling Complex Controls the Specification, Expansion, and Differentiation of Pancreatic Endocrine Progenitor Cells
Authors: SPAETH JASON , DAVIDSON REBECCA K. , CASEY NOLAN 
Published: June 2021

A key feature of type 1 and type 2 diabetes is insufficient functional β-cell mass. Strategies to augment functional β-cell mass include directed differentiation of embryonic stem cells towards a β-cell fate, which requires extensive knowledge of the transcriptional programs governing endocrine cell differentiation in vivo. Pdx1, an essential transcription factor involved in pancreas formation, endocrine progenitor cell expansion and β-cell function, dynamically recruits coregulators to drive gene expression programs in those cells vital for its activity. Pdx1 binds to numerous coregulators in the β-cell, including the ATP-dependent Swi/Snf chromatin remodeling complex. Previous work by our group revealed a critical role for Pdx1:Swi/Snf in both the developing pancreas and mature β-cell. Here we interrogate the role of Swi/Snf on governing Pdx1-dependent gene expression programs and chromatin accessibility in pancreatic endocrine cell development. We developed a mouse model to eliminate the activity of the two core ATPase subunits of Swi/Snf, Brg1 and Brm from endocrine progenitor cells using Neurogenin3-Cre (Δendo). Conditional knockout of Brg1 (Brg1ΔendoBrm+/-) from endocrine progenitor cells leads to severe glucose intolerance, ad-libitum fed hyperglycemia, reduced serum insulin, compromised glucose stimulated insulin secretion from isolated islets and reduced islet mass in 4-week old animals. Whereas Brg1Δendo/+Brm-/- mice are normal, remarkably, no DKOΔendo (double knockout (DKO): targeted both Brg1 and Brm) mice have been found at weaning, suggesting loss of all Swi/Snf activity from the endocrine progenitor cell pool is postnatally lethal. Future experiments will be directed at determining how Swi/Snf controls Pdx1-dependent gene expression programs and chromatin accessibility in endocrine progenitor cells that are critical for islet cell expansion, differentiation and maturation.

Disclosure
J. Spaeth: None. R. K. Davidson: None. N. Casey: None.

Funding
National Institutes of Health (R03DK127129, K01DK115633)
18-LB: Histone Modifications and CXCR4 Chemokine Receptor Signaling in Hyperglycemic DRG Neurons
Authors: SATTERFIELD NATALIE , THAKUR VIKRAM , CHATTOPADHYAY MUNMUN 
Published: June 2021

Diabetes is a global epidemic that affects many individuals throughout the world and presents a major health challenge to society. The state of chronic hyperglycemia can have many devastating secondary effects including neuropathy, nephropathy, retinopathy, and cardiovascular disease. The diabetes mediated neuropathic complications are a substantial burden to society due to a lack of therapies as well as decreased quality of life and increased mortality. Approximately 50% diabetic patients suffer from neuropathy which is described as alterations of pain sensation in the feet that leads to increased risk for infection, ulcers, non-traumatic amputations and ultimately death. Painful diabetic neuropathy (PDN) affects individuals within 20 years after the onset of disease, mediated by the gradual degeneration of axonal structures in sensory neurons. It is known that hyperglycemia is involved in the pathogenesis of this disease, but specific mechanisms are not well understood. Previous studies have shown that inflammation and epigenetic changes may play a role in the development of PDN. Specifically, it has been demonstrated that the chemokine receptor CXCR4 is involved in inflammation relating to PDN while the histone deacetylases HDAC4 and HDAC6 are involved in mediating the epigenetic changes in sensory neurons under hyperglycemic conditions. This study investigated the alterations in inflammatory mediators and epigenetic changes in sensory neurons under normal glucose and high glucose environments. Western blot and immunocytochemistry techniques were used to measure any differences in these two conditions. The results from this study demonstrated an upregulation of histone deacetylases and CXCR4 in hyperglycemic conditions, while histone acetyltransferases were shown to be down-regulated in high glucose environments. These findings may lead to potential therapeutic targets for PDN since it is a life altering condition with minimal treatment options available today.

Disclosure
N. Satterfield: None. V. Thakur: None. M. Chattopadhyay: None.

Funding
Texas Tech University Health Sciences Center El Paso (183381SEED)
180-LB: Effects of Proton Pump Inhibitors on Glycemic Control and Risk of Incident Diabetes: A Systematic Review and Meta-analysis
Authors: PENG CAROL CHIUNG-HUI , BUKHARI KHULOOD , HUANG HUEI-KAI , TU YU-KANG , LEE GIN YI , CHANG HUAI-EN , HUANG YUTING , FU YUNTING , MUNIR KASHIF M. 
Published: June 2021

Background and Aims: Whether proton pump inhibitors (PPI) can improve glycemic control is unclear. Also, incident diabetes from PPI use has not been elucidated. We conducted a meta-analysis and systematic review to determine the impact of PPI on glycemic control in individuals with diabetes and the risk of diabetes in those without diabetes.
Methods: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. Studies reporting a change of glycemic indices, including glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG), in individuals with diabetes taking add-on PPI compared to standard therapy were included. Also, studies evaluating risk of incident diabetes in individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences or relative risks were imputed using random-effects models.
Results: Seven studies (n = 342) for glycemic control, and five studies (n = 244,439) for risk of incident diabetes were included. Compared to standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD = −0.36 %; 95% CI: −0.68 to −0.05; p = 0.025), and FBG (WMD = −10.0 mg/dL; 95% CI: −19.4 to −0.6; p = 0.037). However, PPI use was not significantly associated with the risk of incident diabetes (pooled RR = 1.10; 95% CI: 0.89 to 1.34; p = 0.385).
Conclusions: PPI along with standard care improved glycemic indices in individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when treating upper gastrointestinal symptoms in patients with diabetes.

Disclosure
C. Peng: None. K. Bukhari: None. H. Huang: None. Y. Tu: None. G. Lee: None. H. Chang: None. Y. Huang: None. Y. Fu: None. K. M. Munir: None.
182-OR: Genetic Susceptibility to Diabetic Kidney Disease Is Linked to C/EBP-XOR Axis
Authors: WANG QIN , QI HAIYING , LI SHUYU , CASALENA GABRIELLA , YU LIPING , DAEHN ILSE S. 
Published: June 2021

Diabetic kidney disease (DKD) is the leading single cause of end-stage renal disease in the United States. Approximately 30% of diabetics develop DKD with comparable blood glucose levels, indicating a significant genetic contribution for susceptibility. However, the underlying mechanisms that contribute to differential susceptibility are poorly understood. The glomerulus is the primary site of injury with hypertrophy and podocyte depletion being the hallmarks for progressive DKD. We have demonstrated that mitochondrial oxidative damage accumulation in glomerular endothelial cells, leads to podocyte loss via endothelial-to-podocyte crosstalk in DKD susceptible DBA/2J (D2) mice compared to DKD resistant C57BL/6J (B6) mice. To map genetic loci associated with podocyte depletion after long-term diabetes (6mth), we used the 39 strains of BXD, and parental B6 and D2 mice. We identified a significant cis-acting variant in the promoter of xanthine oxidoreductase (XOR). XORs catalyze the oxidation of purine substrates produce uric acid and reactive oxygen species. XOR expression in the kidney and circulating activity were significantly higher in diabetic D2 compared to B6. XOR inhibition significantly reduced albuminuria, oxidative damage in glomeruli and prevented podocyte depletion in diabetic D2 mice. We used CRISPR/Cas9 to knock-in the XOR risk variant into DKD-resistant B6 mice and generated mutant B6-XORem1 mice with significantly higher XOR activity than B6. This risk variant is a transcription factor binding site to C/EBPβ, we show higher C/EBPβ expression in glomerular endothelium from diabetic B6-XORem1 mice but not in diabetic B6. B6-XORem1 mice had increased mitochondrial oxidative stress in endothelial cells, podocyte depletion, basement membrane thickening, albuminuria, glomerulosclerosis and tubular injury, and these changes were prevented with XOR inhibition. Our data suggest that the identified promoter variant is causal for DKD susceptibility via the C/EBPβ-XOR axis.

Disclosure
Q. Wang: None. H. Qi: None. S. Li: None. G. Casalena: None. L. Yu: None. I. S. Daehn: None.

Funding
National Institutes of Health