bluuebunny/crossref_metadata_2025_split huggingface dataset:
131-LB: Diabetes and Disparities in Continuous Glucose Monitoring in Community Health Care Settings
Authors: WALLIA AMISHA , AGARWAL SHIVANI , OWEN ANDREW L. , LAM EMILY L. , DAVIS KA'DERRICKA , BAILEY STACY , DELACEY SEAN E. , PACK ALLISON , ESPINOZA JUAN , BRIGHT DANA , EGGLESTON ALICE , O'BRIEN MATTHEW J. 
Published: June 2023

Federally qualified health centers (FQHCs) serve vulnerable DM patients in primary care in underserved settings. The state of DM (glycemic control, complications) may differ and utilization of technologies (e.g. continuous glucose monitoring [CGM]) may be essential. But the current state of DM and CGM is poorly characterized. Using EHR data from a national FQHC network (2015-2021) we examined baseline demographic characteristics, CGM prescriptions, and their association. We included 47,579 with DM: n=1630 with T1D [3%], n= 45,949 T2D [97%], 38% Hispanic, 34% Black (Table 1). Notably, T1D pts [mean age 43 SD 16], had poor glycemic control (HbA1c 9.4 SD 2.4) with elevated DM complications severity index scores [mean DSCI 2.3 SD 4.7]. Overall CGM prescriptions were extremely low; 9% in T1D and only 1% in T2D. Among T1D, those who were Hispanic [OR 0.39, (CI 0.23, 0.66), p &lt; 0.001] or Black [OR 0.52, (CI 0.33, 0.81), p = 0.003] were less likely to have CGM prescribed than White adults, after adjustment. Among T2D, those who were Hispanic [OR 0.42, CI 0.33, 0.55, p &lt; 0.001] or Black [OR 0.68, CI 0.54, 0.85, p = 0.001] were similarly less likely to have CGM. Non-private insurance was also a significant factor. DM severity (poor control, complications) is notable in FQHCs, yet CGM is exceptionally low. These findings underscore the major translation gap in standard of care for FQHCs and the critical need to understand inequities.

Disclosure
A. Wallia: Research Support; UnitedHealth Group, Novo Nordisk, Eli Lilly and Company. D. Bright: None. A. Eggleston: None. M. J. O'brien: None. S. Agarwal: Advisory Panel; Medtronic, Consultant; Beta Bionics, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. A. L. Owen: None. E. L. Lam: None. K. Davis: None. S. Bailey: Advisory Panel; Gilead Sciences, Inc., Consultant; Lundbeck, Pfizer Inc., Research Support; Eli Lilly and Company, Merck Sharp & Dohme Corp., Gilead Sciences, Inc., Lundbeck, Pfizer Inc. S. E. Delacey: None. A. Pack: Consultant; Gilead Sciences, Inc., Research Support; Merck & Co., Inc., Pfizer Inc., Gordon and Betty Moore Foundation, RRF Foundation for Aging, Lundbeck, Eli Lilly and Company, Gilead Sciences, Inc. J. Espinoza: Consultant; Sanofi, Research Support; NIH - National Institutes of Health, FDA, Speaker's Bureau; Glooko, Inc.

Funding
Centers for Diabetes Translation Research (5P30DK020541, 472P30DK092949-11A); National Pilot and Feasibility Grant for Diabetes Research Centers; Center for Diabetes Translation Research
133-OR: Insulin Dynamics across the Glucose Tolerance Spectrum in Youth with Obesity
Authors: CHO WONHEE , BACHA FIDA , TFAYLI HALA M. , LEE SOJUNG , MICHALISZYN SARA , YOUNG KIM JOON , ARSLANIAN SILVA A. 
Published: June 2023

Despite β-cell failure in youth with dysglycemia (DYSG) (IGT + T2D), fasting insulin concentrations are elevated. Here, we examined 1) metabolic clearance rate of insulin (MCRI) in youth with normal glucose tolerance (NGT) and DYSG, 2) racial/ethnic differences in insulin dynamics and 3) physical and metabolic correlates of MCRI. In 95 Black (B) + 111 White (W) youth, age 14.4 ± 2.0 [SD] yrs., BMI 34.7 ± 6.4 kg/m2, MCRI and peripheral insulin sensitivity (PIS) were calculated from the hyperinsulinemic-euglycemic clamp, 1st-phase insulin (1stPhI) from the hyperglycemic clamp, disposition index (DI=PIS x 1stPhI), % body fat by DXA, visceral adipose tissue (VAT) by MRI. In DYSG vs NGT, MCRI was lower (261.6 ± 11.9 vs 334.1 ± 8.5 ml/m2/min, p&lt;0.001) and fasting insulin was higher (46.9 ± 4.4 vs 32.9 ± 1.2 μU/mL, p&lt;0.001). In B vs W youth (Image), MCRI was lower driven by DYSG. Lower PIS, lower MCRI and higher 1stPhI were characteristics of B youth with DYSG vs W with equally impaired DI. In B and W youth, positive correlates of MCRI were PIS and DI and negative correlates were fasting insulin, % body fat and VAT.
In conclusion, higher fasting insulin concentrations in DYSG despite a failing β-cell could be explained by decreased MCRI. Racial/ethnic contrast in insulin dynamics differs by glycemic status and is more pronounced in DYSG manifested by lower PIS and lower MCRI in B vs W youth with no difference in β-cell function relative to insulin sensitivity.

Disclosure
W.Cho: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. H.M.Tfayli: Other Relationship; Novo Nordisk, Research Support; Sanofi, Novartis. S.Lee: None. S.Michaliszyn: None. J.Kim: None. S.A.Arslanian: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Consultant; Société des Produits Nestlé SA,, Other Relationship; Eli Lilly and Company, AstraZeneca, Research Support; Novo Nordisk, Eli Lilly and Company.

Funding
American Diabetes Association (7-08-JF-27 to S.L.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (K24HD01357, R01HD27503); National Center for Advancing Translational Sciences (UL1TR000005); National Center for Research
1342-P: Are Plasma Aminotransferases of Value in Screening Patients with T2DM for NAFLD or Fibrosis?
Authors: ORTIZ ROCHA ANDREA , GODINEZ LEIVA EDDISON , KALAVALAPALLI SRILAXMI , LOMONACO ROMINA , SHETTY SHWETHA S. , MARANGI STEPHEN A. , VALDEZ SAENZ ENRIQUE , SHRESTHA SULAV , GONZALEZ MARIA A. , CHI XIAOFEI , GURKA MATTHEW J. , BARB DIANA , CUSI KENNETH 
Published: June 2023

The ADA recommends to screen for NASH and liver fibrosis individuals with type 2 diabetes (T2DM), obesity (OB) and/or elevated alanine aminotransferase (ALT). However, recent studies have questioned the clinical value of measuring ALT and AST for the detection of patients at risk of nonalcoholic fatty liver disease (NAFLD) or advanced liver fibrosis or cirrhosis. The aim of this study was to assess the clinical value of ALT and AST ≥40 IU/L, or their lower cut-offs ≥30 IU/L as recommended by recent AACE guidelines, to screen populations at risk. To this end, we recruited 714 participants (age: 56 ± 11 years, male: 42%; BMI: 30.8 ± 6.5 kg/m2; T2DM: 35%; A1c: 6.0 ± 1.2%) from primary care or endocrinology clinics, unaware of having NAFLD/fibrosis. Screening for NAFLD included laboratory tests and imaging with elastography (steatosis by controlled attenuation parameter [CAP]; fibrosis by liver stiffness measurement [LSM]). Elevated transaminases were more common in patients with vs. without T2DM, with ALT ≥40 IU/L occurring in 13% vs. 8% and AST in 9% vs. 3% of patients (both p&lt;0.05). If using a cutoff of ≥30 IU/L: 25% vs. 18% and 20% vs. 13%; respectively (both p&lt;0.05). Elevated ALT ≥30 IU/L was the highest in patients with T2DM and OB (n=164) vs. controls (without T2DM or OB; n=269; 27% vs 15%; p=0.02). The sensitivity for diagnosing steatosis by ALT or AST was very low, with ALT and AST ≥40 IU/L present in only 16% and 9%, respectively. However, steatosis by imaging (CAP) was often present if ALT or AST were high (81 and 90%, respectively). An ALT ≥40 IU/L was also not useful for diagnosing patients with fibrosis of any stage (LSM ≥7.0), missing the diagnosis in 63% of patients, and this did not improve when examining only those with more advanced fibrosis (≥F3) being elevated in only 40%. Conclusions: Plasma aminotransferases are of limited diagnostic value when screening patients with T2DM for NAFLD or fibrosis. This supports the ADA recent guidelines for using FIB-4 and additional noninvasive testing for screening.

Disclosure
A. Ortiz Rocha: None. E. Godinez Leiva: None. S. Kalavalapalli: None. R. Lomonaco: None. S.S. Shetty: None. S.A. Marangi: None. E. Valdez Saenz: None. S. Shrestha: None. M.A. Gonzalez: None. X. Chi: None. M.J. Gurka: None. D. Barb: None. K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns.

Funding
National Institutes of Health (R01120331-01A1)
135-LB: A Variable Impact of the Wave 1 and Wave 2 Lockdowns of the COVID-19 Pandemic on Glycemic Control—A Longitudinal Analysis of FGM Adult Users From Poland
Authors: HOHENDORFF JERZY , KAO KALVIN , BRANDNER LAURA , MALECKI MACIEJ 
Published: June 2023

WHO declared COVID19 pandemic in March 2020. In Poland, the particularly severe restrictions related to COVID19 pandemic were implemented during Wave 1. All activities were prohibited except necessary everyday ones. From late May to July 2020 restrictions were gradually lifted. In October 2020, due to Wave 2 of COVID19 pandemic some restrictions were reimplemented, however, their impact on everyday life was smaller than during the Wave 1. The aim of the study was to analyze the impact of different phases of COVID19 pandemic on glycemic control in patients with diabetes using FGM. Longitudinal data of 469 adults aged 18-64 were analyzed. Analyzed time periods were every first 45 days of each quarter of the year 2020. Q1 stands for the first pre-pandemic quarter of 2020, Q2 correspondences to the severe lockdown of Wave 1, Q3 to time of most restrictions lifted, and Q4 to less strict lockdown of Wave 2. Mean glycemic indices are shown in Table 1.
In summary, Wave 1 and Wave 2 of COVID19 pandemic had different impact on glycemic control in patients with diabetes. The severe lockdown of the first wave resulted in adults with diabetes in improvement of glycemic indices, particularly TIR. Common findings during both lockdowns were reduction in TBR and lower glycemic variability as compared to the preceding periods.

Disclosure
J. Hohendorff: Speaker's Bureau; Abbott, Novo Nordisk, Ascensia Diabetes Care, Dexcom, Inc., Bayer Inc. K. Kao: Employee; Abbott Diabetes. L. Brandner: Employee; Abbott Diabetes. M. Malecki: Advisory Panel; Abbott Diabetes. Speaker's Bureau; AstraZeneca, AlfaSigma. Advisory Panel; Novo Nordisk, Lilly, Sanofi. Speaker's Bureau; Merck & Co., Inc. Research Support; Medtronic. Advisory Panel; Dexcom, Inc. Speaker's Bureau; BIOTON S. A., Servier Laboratories, KRKA. Advisory Panel; Bayer Inc.
1350-P: Risk Models for the Development of Cardiovascular and Microvascular Events in Adults with Type 2 Diabetes in the FIELD Study
Authors: LEUNG ONG KWOK , O'CONNELL RACHEL L. , JANUSZEWSKI ANDRZEJ S. , DONOGHOE MARK W. , GEBSKI VAL , SULLIVAN DAVID , ANN RYE KERRY , SCOTT RUSSELL S. , BEST JAMES D. , TASKINEN MARJA-RIITTA , SIMES ROBERT J. , JENKINS ALICIA , KEECH ANTHONY C. 
Published: June 2023

Background: There are a few prediction models for chronic complications in people with type 2 diabetes (T2D). This study developed such risk models.
Methods: Data from 9795 adults with T2D in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were used to develop risk prediction models for total CVD events, cardiovascular mortality, amputations and new microvascular events using 27 candidate traditional risk factors and additional novel biomarkers (incl. vascular and systemic inflammation, oxidative stress; n=26) using exhaustive search methods.
Results: There were 1295 total first CVD events, 267 CVD deaths, 115 amputations and 1530 new microvascular events. A total of 19 and 18 traditional risk factors were selected in the clinical risk models for total CVD events and CVD mortality, with AUC of 0.723 and 0.821 respectively. For individual microvascular complications, the AUC of their models ranged from 0.656 to 0.895. The addition of novel biomarkers to the clinical risk models only resulted in modestly higher AUC (Table below).
Conclusion: New clinical risk models can be implemented as risk prediction tools for chronic complications in adults with T2D, including for sight-threatening retinopathy and amputations. Novel biomarkers may guide future research on disease mechanisms, but had limited predictive value over clinical variables.

Disclosure
K.Ong: None. M.Taskinen: Board Member; Novo Nordisk, Consultant; Eli Lilly and Company, Novartis, Akcea, Research Support; Novo Nordisk. R.J.Simes: None. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health. A.C.Keech: None. On behalf of the field study investigators: n/a. R.L.O'connell: None. A.S.Januszewski: None. M.W.Donoghoe: None. V.Gebski: None. D.Sullivan: None. K.Rye: None. R.S.Scott: None. J.D.Best: None.

Funding
Laboratories Fournier; National Health and Medical Research Council of Australia (457103, 1024105, 1037786)
1351-P: Caffeine Intake Is Associated with a Lower Risk of Nonalcoholic Fatty Liver Disease–Related Fibrosis in Patients with Type 2 Diabetes
Authors: HAN JIAHAO , LIU CHUAN , YANG HUANHUAN , GAO RUIXIA , LI ZHIHUI , LI JIA , QI XIAOLONG 
Published: June 2023

Background: Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are conditions closely associated, the prevalence of which is continuously growing, providing a heavier socioeconomic and disease burden. Lifestyle modification is still considered the cornerstone of nonalcoholic liver steatohepatitis (NASH). We aimed to investigate the association between caffeine and NAFLD-related fibrosis in populations with different diabetes conditions.
Methods: Adult participants in NHANES from 2005 to March 2020 pre-pandemic were included with three group: T2DM group, prediabetes group and diabetes-free group. Liver fibrosis was assessed by Fibrosis-4 (FIB-4) index. Logistic regression was employed to interrogate the association between caffeine and liver fibrosis.
Finds: A total of 23711 participants were included. The proportions of high risk (FIB-4&gt;2.67) for liver fibrosis in T2DM group was significantly higher than that of prediabetes group and diabetes-free group (5.9% vs 3.2% vs 2.4%, P&lt;0.001). However, the proportions of high risk in prediabetes group is equal with that of diabetes-free group (3.2% vs 2.4%, P&gt;0.05). Notably, the proportions of intermedium risk (FIB-4&gt;1.3, and&lt; 2.67) for liver fibrosis in prediabetes group was significantly higher than that of diabetes-free group (32.3% vs 24.2%, P&lt;0.001). Participants with caffeine intake≤78mg/day had a high risk for liver fibrosis than that with caffeine intake &gt;78mg/day in all groups (Diabetes-free group: OR 1.312[1.086-1.585]; Prediabetes group: OR 1.641[1.192-2.259]; T2DM group: OR 1.373[1.066-1.769]; all P&lt;0.05).
Interpretation: Prevalence of liver fibrosis is high in patients with T2DM and prediabetes. And caffeine intake more than 78mg per day is associated with a lower risk for liver fibrosis in T2DM and prediabetes.

Disclosure
J.Han: None. C.Liu: None. H.Yang: None. R.Gao: None. Z.Li: None. J.Li: None. X.Qi: None.
1352-P: Ethnic Disparities in Diabetic Complications in the U.S.
Authors: YOSHIDA YILIN , FONSECA VIVIAN , ZU YUANHAO 
Published: June 2023

Objective: To estimate the prevalence of diabetes (DM) complications and assess risk factors for complications by ethnicity and DM duration.
Methods: We used National Health and Nutrition Examination Survey data, 1999-2018. We defined cardiovascular disease (CVD) as a history of heart failure, stroke, or heart attack; chronic kidney disease (CKD) as an eGFR &lt;60, albuminuria, or both; retinopathy as retinal microaneurysms or blot hemorrhages; and lower extremity disease (LED) as peripheral neuropathy, peripheral artery disease, or ulcers. We assessed the age-adjusted prevalence of each complication and multivariable logistic regressions for risk factors related to any complication by ethnicity in new (DM&lt; 10 y without insulin) and established patients (DM≥10 y).
Results: Non-Hispanic Whites (W) had the highest CVD rates, followed by Blacks (B), Mexican Americans (M), and Asian Americans (A) in both new (31% W, 21% B, 14% M, 11% A) and established patients (38% W, 36% B, 29% M, 28% A). Blacks had the highest CKD rates in both new (40% B, 33% W, 31% A, 30% M) and established patients (63% B, 52% M, 51% W, 40% A). For retinopathy, in new patients, Mexican Americans had the highest rate (27% M, 20% B, 12% W), while in established patients, Whites had the most (62% W, 61% B, 57% M). Blacks had the highest rates for LED in both new (52% B, 47% W, 45% M) and established patients (78% B, 68% W, 59% M). Male gender was a risk factor for any DM complication in Asian Americans (new patients, odds ratio 3.9, 95% CI 2-7.5; established, 2.5, 1.1-5.4). Obesity was a risk factor in Black new patients (1.4, 1-1.8). Poor glycemic control was a risk factor in Asian American (4, 2.2-7.6) and White new patients (1.5, 1.1-2.1), and Black established patients (1.7, 1.2-2.4).
Conclusions: White patients had the highest rate of CVD, while Blacks had the most CKD and LED. Mexican Americans with &lt; 10 y of DM had more retinopathy than their ethnic counterparts. Interventions to integrate the male sex and promote weight and glycemic control may reduce DM complications in ethnic minorities.

Disclosure
Y.Yoshida: None. V.Fonseca: Consultant; Abbott, Corcept Therapeutics, Eli Lilly and Company, Other Relationship; BRAVO4HEALTH, LLC, Research Support; Fractyl Health, Inc., Stock/Shareholder; Amgen Inc. Y.Zu: None.
1355-P: Risk of Chronic Kidney Disease in Early-Onset Type 2 Diabetes in Mexico
Authors: SILVA-TINOCO RUBÉN , CUATECONTZI-XOCHITIOTZI TERESA , GUZMAN-OLVERA EILEEN B. , DELATORRE-SALDAÑA VIRIDIANA , GALINDEZ-FUENTES ANA , CASTILLO-MARTINEZ LILIA , BERNAL-CEBALLOS FERNANDA , RIOS-CARBAJAL VIANEY , TORRES-SANDOVAL NARDA , MANUEL MEJIA-VILET JUAN , OCHOA-MORENO JORGE , SERNA JAVIER , LOPEZ-ARELLANO OLIVA 
Published: June 2023

Patients with early onset type 2 diabetes (EOD) seem to be at increased risk of developing complications. Screening and diagnosis for CKD is poorly executed in primary care (PC) of low-and-middle income countries. Thus, we aimed to analyze the presence of CKD in EOD in comparison with later-onset diabetes (LOD). Data were obtained from the largest cohort of patients with T2D evaluated for CKD within the PC in Mexico (DIABEMPIC). EOD and LOD were defined as the age of diagnosis &lt;40 and ≥40 years, respectively. CKD assessment included albuminuria through urinary albumin-creatinine ratio (≥30mg/g for CKD) and estimated glomerular filtration rate (eGFR≤60 ml/min/1.73m2 for CKD). A total of 1,592 patients were included. The burden of CKD at different diabetes durations are shown in Table 1. The prevalence of overall CKD was significantly higher in the EOD group (p&lt;0.008), associated to a greater presence of albuminuria; a higher prevalence of albuminuria was observed after 10 years of diagnosis in the EOD (p&lt;0.0001). In the univariate analysis, EOD was associated with an increased risk of CKD (OR 1.33, 95%CI 1.08-1.65). In conclusion, EOD patients presented a higher risk of CKD, particularly on account for albuminuric-CKD phenotype, even though they are comparatively younger. Our results enhance the need for the management of risk factors and proper screening of CKD in T2D, especially in EOD, in PC settings, and through albuminuria measurement.

Disclosure
R.Silva-tinoco: Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Inc., Novo Nordisk. J.Mejia-vilet: None. J.Ochoa-moreno: None. J.Serna: None. O.Lopez-arellano: None. T.Cuatecontzi-xochitiotzi: None. E.B.Guzman-olvera: None. V.Delatorre-saldaña: None. A.Galindez-fuentes: None. L.Castillo-martinez: None. F.Bernal-ceballos: None. V.Rios-carbajal: None. N.Torres-sandoval: None.
1357-P: Conflicting Significance of High BMI as a Predictor of Individual Diabetic Complications
Authors: YAGUCHI YUTA , FUJIHARA KAZUYA , MON KHIN LAY , WU SIJIA , FERREIRA EFREM D. , SATO TAKAAKI , HORIKAWA CHIKA , MATSUBAYASHI YASUHIRO , KATO KIMINORI , SONE HIROHITO 
Published: June 2023

Although weight management plays a central role in diabetes treatment, the association between body weight and diabetic complications is not fully elucidated. Therefore, we investigated the relationship between BMI and risk of diabetic complications in patients with diabetes mellius (DM) using nationwide claims data. Analyzed were 91097 patients with DM without prior treatment-requiring diabetic eye disease (TRDED), initiation of dialysis (dialysis), coronary artery disease (CAD), cerebrovascular disease (CVD), heart failure (HF) or amputation (mean age 52 y, HbA1c 7.2%, median follow-up 4.5 y). Participants were divided into 6 groups according to BMI (BMI&lt;20.0, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.0, ≥30.0). Risk of diabetic complications was examined by Cox regression analysis. There was an inverse correlation between the risk of dialysis and BMI; hazard ratio (HR) for dialysis in patients with BMI ≥30.0 was 0.46 (0.29-0.74). There was a U-shaped relationship between the risk of HF and BMI; HRs for HF in patients with BMI &lt;20.0 and ≥30.0 were 1.97 (1.15-3.37) and 1.76 (1.27-2.45), respectively (Figure). High BMI was significantly associated with a higher risk of HF, but lower risks of TRDED and dialysis. The relationship between BMI and diabetic complications was inconsistent among complications, suggesting that the target weight should be individualized according to diabetic complications.

Disclosure
Y.Yaguchi: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. L.Khin: None. S.Wu: None. E.D.Ferreira: None. T.Sato: None. C.Horikawa: None. Y.Matsubayashi: None. K.Kato: None.
136-OR: The MDA5627X Variant Is Associated with Type 1 Diabetes Protection via Attenuated Inflammatory Antiviral Responses
Authors: IWALOYE OPEOLUWA , ARMITAGE LUCAS H. , MEACHAM AMY M. , MATHEWS CLAYTON E. 
Published: June 2023

Type 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β cells. Genetics and environmental factors play crucial roles in T1D development. Four single nucleotide polymorphisms in IFIH1, encoding the viral sensor MDA5 have been linked to T1D. MDA5 promotes anti-viral responses and may link genetics with environmental factors to promote or suppress T1D. A stop-gain mutation in IFIH1 (rs35744605) results in a non-functional MDA5 protein (MDA5627X). We hypothesized that MDA5627X protects against T1D by dampening inflammatory anti-viral responses resulting in reduced autoimmunity. We gene edited human induced pluripotent stem cells at rs35744605 using a CRISPR/Cas9 strategy to generate iPSC encoding the stop-gain variant (MDA5627X). Macrophages (Mφ) have been demonstrated to be indispensable for T1D-initiation and regulate anti-viral responses. We differentiated iPSCs into Mφ and studies responses to high molecular weight Poly I:C to mimic viral infection. The outcome measures were Type 1 Interferon (IFN1) production, antigen presentation, and immune activation markers. Treatment of MDA5 intact Mφ with Poly I:C resulted in 60-fold increase in IFN1 production and a 3-fold elevation in human leukocyte antigen Class I (HLA-I) expression. In contrast, treated MDA5627X Mφ failed to increase IFN1 or HLA-I at any Poly I:C dose. While Poly I:C did not increase HLA-I expression, untreated MDA5627X Mφ had elevated HLA-1 compared to MDA5 intact Mφ (P=0.0306). Also, we assessed the expression of CD80, CD86, CD40, and MHC-II, however there were no differences in the expression between Mφ with intact MDA5 or MDA5627X. In contrast, IFNg and LPS treatment elevated expression of CD80, CD86, CD40, and MHC-II in both Mφ populations. In conclusion, our data point to a protective effect of the MDA5627X variant in T1D through decreased inflammatory IFN1 levels and T cell activation by Mφ.

Disclosure
O.Iwaloye: None. L.H.Armitage: None. A.M.Meacham: None. C.E.Mathews: None.

Funding
National Institutes of Health (R01DK127497, P01AI042288, UH3DK122638)