bluuebunny/crossref_metadata_2025_split huggingface dataset:
158-LB: A Complete-Panel Islet Autoantibody Multiplex ECL Assay
Authors: HE LING , JIA XIAOFAN , MIAO DONGMEI , RASMUSSEN CRISTY GENO , REWERS MARIAN , YU LIPING 
Published: June 2021

Background: Type 1 diabetes (T1D), a major chronic autoimmune disease starting mostly from childhood, is now predictable with the measurement of four major islet autoantibodies (IAbs) including IAA, GADA, IA-2A and ZnT8A. Currently, there are approximately 1.4 million people affected with T1D in the United States and the incidence has doubled in the last 20 years, especially in young children. Mass screening for eligible subjects and the general population remains inefficiency and laborious bottleneck.
Methods: With the platform of our extensively validated high affinity electrochemiluminescence (ECL) assay, we have developed a simple multiplexed ECL assay to combine all four major IAb assays in a single well. Two cohorts were studied including 80 samples from newly diagnosed patients with T1D and 1,140 from Autoimmunity Screening for Kids (ASK) study. Both multiplex ECL assay and standard radio-binding assay (RBA) were performed in parallel.
Results: With &gt;99th percentile of specificity for both assays in over 1,000 samples from general population, sensitivity of multiplex ECL assay in new onset patients with T1D were similar to RBA, GADA 75% vs. 71%; IA-2A 91% vs. 90%; IAA 61% vs. 65%; ZnT8A 90% vs. 87%. In ASK cohort, multiplex ECL assay was concordant with RBA among children with multiple IAbs (42/44, 96%). In contrast, only 39% (21/54, p&lt;0.0001) of children with single IAb by RBA were positive by multiplex ECL assay.
Conclusion: Multiplex ECL assay illustrated its high sensitivity/specificity as RBA in T1D patients. In general population screening, multiplex ECL assay, similar to single ECL assay, is capable to discriminate high risk IAbs from low risk IAbs generated by RBA. With a multiplexing feature, it provides a high throughput tool with low cost and low sample volume for large scale of population screening for T1D.

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

Funding
JDRF (2-SRA-2018-533-S-B, 1-SRA-2016-208-S-B); National Institutes of Health (DK32083); Diabetes Research Center (P30DK116073)
159-OR: Changes of Plasma Phospholipid Fatty Acids in Pregnancy in Relation to the Diagnosis and Treatment of Gestational Diabetes
Authors: LI LING-JUN , ZHU YEYI , WU JING , TOBIAS DEIRDRE K. , HINKLE STEFANIE , MA RONALD C. , TSAI MICHAEL Y. , ZHANG CUILIN 
Published: June 2021

Background: Previous studies have shown that phospholipids fatty acid (FA) levels in early and mid-pregnancy were associated with incident gestational diabetes mellitus (GDM). However, the subsequent changes of such FAs profile following GDM diagnosis/treatment are understudied.
Methods: Within the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2,802 pregnant women, we ascertained 85 GDM cases according to Carpenter and Coustan criteria, and 85 non-GDM controls matched on maternal age, race/ethnicity, and gestational week at voluntary blood collection. We quantified participants’ plasma FAs concentrations via gas chromatography prior to GDM diagnosis (23-31 weeks) and after GDM treatment initiation (33-39 weeks), respectively. We estimated the GDM-specific FAs changes before and after GDM diagnosis, in reference to the controls using multiple linear mixed models adjusting for major confounders including pre-pregnancy BMI.
Results: Eleven FAs exhibited distinctive pre- and post-GDM diagnosis changes among GDM cases. Compared with controls, GDM cases tended to have greater reduction in GDM risk-related FAs such as 14:0 (β -0.22; 95% CI: -0.30, -0.14), 16:0 (-0.02; -0.04, -0.01) and palmitoleic acid (16:1n7) (-0.02; -0.04, -0.01), while greater increment in GDM protective FAs such as heptadecanoic acid (17:0) (0.17; 0.11, 0.22), vaccenic acid (18:1n7) (0.06; 0.03, 0.10) and DHA (22:6n3) (0.08; 0.02, 0.15).
Conclusion: Our data identified distinctive FAs changes between pre- and post GDM diagnosis among GDM subjects. These novel findings, along with prior evidence between antenatal FAs and incident GDM, shed lights on further understanding the FAs metabolism in the GDM etiological relevance.

Disclosure
L. Li: None. Y. Zhu: None. J. Wu: None. D. K. Tobias: None. S. Hinkle: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. M. Y. Tsai: None. C. Zhang: None.

Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development(HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C, HHSN275201000001Z)
165-LB: Development of Subsequent Diabetes Mellitus after Gestational Diabetes among Immigrant Women: Population-Based Cohort Study
Authors: HO JESSICA S.S. , READ STEPHANIE H. , ROSELLA LAURA , BERGER HOWARD , FEIG DENICE , FLEMING KAREN , RAY JOEL G. , SHAH BAIJU R. , SARMA SHOHINEE , LIPSCOMBE LORRAINE 
Published: June 2021

Objective: To evaluate which immigrant groups to Canada are at increased risk of diabetes (DM) after gestational diabetes (GDM), including the influence of time since migration.
Research Design and Methods: This retrospective cohort study used administrative data within a universal healthcare system. Included were women with GDM who had given birth in Ontario, Canada, 2006-2014. Women from each World region were compared to native-born/long-term residents of Canada for risk of DM using Cox regression. Results were further evaluated by time since immigration (0-5, 5-10, 10-20 years vs. native-born/long-term residents [referent]), adjusting for age at index pregnancy, income, BMI, parity and any hypertensive disorder of pregnancy.
Results: A total of 8630 women with GDM were followed for a median of 4.9 years. Relative to native-born/long-term residents (incidence rate 29.2 person-years), the age-adjusted hazard ratios (aHR) for DM were higher among women from South Asia (1.28, 95% confidence interval, CI 1.20-1.36), Latin America/the Caribbean (1.42, 95% CI 1.28-1.57), and Sub-Saharan Africa (1.59, 95% CI 1.39-1.83). Relative to native-born/long-term residents, the aHR for DM were 1.42 (95% CI 1.20-1.67) for those residing 0-5 years, 1.19 (95% CI 1.00-1.42) 5-10 years, and 1.41 (95% 1.20-1.65) 10-20 years since immigration.
Conclusions: Certain broadly-defined immigrant groups are at a significantly higher future risk of developing diabetes after having GDM, especially those who are recent immigrants.

Disclosure
J. S. S. Ho: None. L. Lipscombe: None. S. H. Read: Employee; Self; Certara. L. Rosella: None. H. Berger: None. D. Feig: Advisory Panel; Self; Novo Nordisk. K. Fleming: None. J. G. Ray: None. B. R. Shah: None. S. Sarma: None.
169-OR: Magnetogenetic Stimulation of Pancreatic Nerves Regulates Blood Glucose
Authors: LI ROSEMARY , GONZALEZ MARIA JIMENEZ , POMERANZ LISA E. , SCHWARTZ GARY J. , STANLEY SARAH 
Published: June 2021

There is substantial evidence that neural regulation plays a critical role in glucose metabolism and hormone release. Targeting neural populations innervating the pancreas could provide an alternative therapy for diabetes. However, our understanding of the precise physiological roles of pancreatic nerves is incomplete because we lack tools to study these populations in a non-invasive, targeted, temporally controlled manner. Here, we developed and validated a novel magnetogenetic neuromodulatory construct in vitro and in vivo then targeted defined pancreatic nerves to assess their roles in glucose metabolism and hormone secretion. The construct, coding for TRPV1 ion channel fused to a nanobody binding endogenous ferritin (NbTRPV1), was transfected into neural cell lines and primary neurons. Magnetic stimulation significantly increased intracellular calcium in cells expressing NbTRPV1. For in vivo delivery, the construct was packaged into AAV and infused into the pancreas through the pancreatic duct, using serotypes and promoters to target β cells or pancreatic nerves. Ex vivo calcium imaging confirmed magnet activation of pancreas-projecting neurons expressing NbTRPV1. In vivo, targeting NbTRPV1 to β cells improved glucose tolerance in male and female mice, validating the efficacy of this construct to regulate cell activity in the pancreas of freely moving mice. Magnet treatment of ChAT-CRE mice expressing NbTRPV1 in parasympathetic pancreatic neurons significantly improved glucose tolerance and increased insulin secretion. Conversely, targeting vagal sensory nerves from the pancreas in Advillin-iCRE mice impaired glucose tolerance with no significant effect on hormone secretion. These data demonstrate for the first time a method for remote, temporally controlled, targeted modulation of pancreatic islets and nerves to regulate blood glucose. This approach can be used to study the contribution of pancreatic nerves in a wide range of diseases, from diabetes to pancreatic cancer.

Disclosure
R. Li: None. M. Jimenez gonzalez: None. L. E. Pomeranz: None. G. J. Schwartz: None. S. Stanley: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); National Institutes of Health (R01NS097184, OT2OD024912)
17-LB: Disruption of Circadian Clocks Promote Progression of Alzheimer’s Disease in Diabetic Mice
Authors: HUANG JIAOJIAO 
Published: June 2021

Almost all plants and animals exhibit inherent 24-hour oscillations to adapt the Earth’s rotation. The main function of circadian rhythm was to prepare an organism for the potential outer opportunities and challenges. Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is more popular in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disorder on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability and AD-related pathophysiology. Our results indicated housing in these conditions had disrupted diurnal circadian rhythms in hippocampus and contributed to weight gain. In the brain, circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in Aβ deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under 6:18 light/dark cycle. In conclusion, circadian alterations could promote the development of AD in the patients of T2DM.

Disclosure
J. Huang: None.

Funding
National Natural Science Foundation of China (81670754, 81800686, 81974114)
170-LB: Obesity-Related Metabolites and Risk of Type 2 Diabetes in Chinese Adults
Authors: PAN XIONG-FEI , CHEN ZSU-ZSU , WANG THOMAS , ZHENG WEI , GERSZTEN ROBERT E. , SHU XIAO-OU , YU DANXIA 
Published: June 2021

The mechanisms linking overall/central obesity with type 2 diabetes are not fully understood. In a nested case-control study of 1039 incident cases and 1039 matched controls from two prospective cohorts of Chinese adults, we measured 142 plasma metabolites using LCMS platforms. We identified and validated 28 metabolites associated with body mass index (BMI) and 34 metabolites with waist circumference (WC) in multivariable-adjusted linear models at false discovery rate&lt;0.05. Using LASSO regression, we selected 15 and 21 metabolites, respectively, to create BMI- and WC-related metabolite composite scores (MCSs), including glutamate, branched-chain amino acids, tyrosine, uric acid, dimethylguanidino valeric acid, C5-carnitine, cis-aconitic acid, and homogentisic acid (positive associations) and 1,5-anhydrosorbitol, pyruvic acid, serine, glycine, and asparagine (inverse associations). Both MCSs showed strong linear associations with diabetes risk: OR (95% CI) in the highest vs. lowest quartiles was 3.92 (1.88, 8.15) for BMI-related MCS and 7.87 (3.53, 17.53) for WC-related MCS after adjusting for diabetes risk factors including plasma glucose (both P-trend&lt;0.001). Strikingly, the MCSs showed even stronger associations with diabetes among participants with normal BMI or WC: OR (95% CI) across quartiles was 6.99 (3.97, 12.3) and 9.98 (6.11, 16.3), respectively. The MCSs mediated 50-70% of the BMI/WC-diabetes association. MCSs alone achieved similar prediction performance as traditional risk factors, including age, sex, lifestyles, diet, family history, and BMI/WC (all C-statistics~0.75). Adding MCSs to traditional risk factors and plasma glucose improved the C-statistics from 0.79 to 0.83 (P&lt;0.001). In conclusion, we identified multiple obesity-related circulating metabolites strongly associated with diabetes risk, even among individuals with normal BMI or WC. Those metabolites could explain up to 70% of obesity-related diabetes risk and further improve diabetes risk prediction.

Disclosure
X. Pan: None. Z. Chen: None. T. Wang: None. W. Zheng: None. R. E. Gerszten: None. X. Shu: None. D. Yu: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK108159 to T.W., X-O.S., R.E.G.), (R01DK126721 to D.Y.); National Cancer Institute (UM1CA173640 to X-O.S.), (UM1CA182910 to W.Z.)
172-LB: Identification of Specific Risk Factors for Mortality in Patients with Diabetes Mellitus Hospitalized with COVID-19
Authors: PINÉS-CORRALES PEDRO J. , MOLINA MARIA , GARCÍA-BLASCO LOURDES , TOBOSO ROSA QUILEZ , ALCARAZ MARINA , GUTIÉRREZ LUIS VICENTE , MELLINAS GEMA PATERNA , CALBO MAYO JUAN MARIA , ALFARO-MARTÍNEZ JOSÉ-JOAQUÍN 
Published: June 2021

Introduction: Several studies have shown that diabetes mellitus (DM) is a risk factor for in hospital mortality due to COVID-19. The aim of our study was to analyze if prior clinical characteristics among DM patients affected the risk of in hospital mortality compared with nondiabetic patients hospitalized with COVID-19.
Material and Methods: The study was based on a retrospective, observational design and was conducted at two hospitals located in Albacete (Spain). All patients hospitalized with COVID-19 since the start of the pandemic until 7 July 2020 were included.
Results: During the study period, 1468 patients were hospitalized due to COVID-19; 402 of them had DM prior to hospitalization. DM was associated with higher in hospital mortality (28.6% versus 17.5%) in the univariate analysis. But, in a multivariate logistic regression analysis, after adjusting for age, presence of hypertension, smoking, presence of COPD, ACEI, ARB, antiplatelet, or anticoagulant therapy, DM was not a significant risk factor for death. Patients with DM2 receiving insulin treatment had a higher risk of in hospital death than nondiabetic patients (OR 1.78 [1.13-2.81], p=0.0126) after age was considered. The age-associated relative risk was 1.06 (1.05-1.07, p&lt;0.001) per year, whereas the relative risk associated with DM2 treated with insulin compared with no DM was 1.57 (1.11-2.23, p=0.0111) suggesting that DM2 treated with insulin entails a risk of in hospital COVID-19 death equivalent to being 9 years older. When previous logistic regression models included other variables related to personal history and prior nondiabetic treatments, the risks described showed no change.
Conclusion: This study confirms that pre-admission need for insulin therapy before hospitalization in patients with DM2 are associated with higher in hospital mortality due to COVID-19 in a large sample of DM inpatients with COVID-19.

Disclosure
P. J. Pinés-corrales: None. M. Molina: None. L. García-blasco: None. R. Quilez toboso: None. M. Alcaraz: None. L. Vicente gutiérrez: None. G. Paterna mellinas: None. J. Calbo mayo: None. J. Alfaro-martínez: None.
174-LB: Severe Hypoglycemia, High Anxiety, and Depressive Symptoms Are Associated with Erectile Dysfunction in Male Adults with Type 1 Diabetes in a Brazilian Tertiary Hospital
Authors: JASKULSKI PAULA R. , PAVIN ELIZABETH J. , SILVEIRA MÔNICA S. , KOELLE MARIA B. 
Published: June 2021

DM is the comorbidity that exerts the greatest risk for erectile dysfunction (ED). Studies have demonstrated a higher prevalence of sexual hormones’ disorders and depression in this population. There are few studies evaluating these aspects in persons with T1D (PWT1D). This study aimed to describe the frequency of ED in male adults with T1D (MAWT1D) followed in a Brazilian tertiary hospital and verify which sociodemographic, clinical, and laboratory factors were related to ED. In a cross-sectional study, 48 MAWT1D were evaluated. Inclusion criteria were T1D diagnosis for ≥ 5 years and age ≥ 18 years. We excluded MAWT1D in which other clinical conditions were present (e.g. COVID-19 infection, alcohol abuse). Patients’ characteristics were evaluated through medical records and a standard questionnaire displayed by Google Forms. Severe hypoglycemia was defined when PWT1D required another person assistance. Sexual hormones were measured by electrochemiluminescence and free androgen index (FAI) was calculated by multiplying total testosterone (ng/ml) by 347, then dividing by the sex hormone binding globulin (nmol/L). The scale 5-Item Version of the International Index of Erectile Dysfunction (IIEF-5) assessed ED. The Hospital Anxiety and Depression Scale - HAD measured anxiety and depressive symptoms (Cut point ≥ 8 indicated clinically relevant symptoms). Continuous and categorical measures were analyzed by Mann-Whitney, Kruskal-Wallis, chi-square, or Fisher’s exact test (p&lt;5%). The participants’ average age was 35.5 ± 12.6 years, and mean years of T1D diagnosis was 22.08 ± 11.2 years. The ED frequency was 52.08%. The associated factors were: severe hypoglycemia (p= 0.0007), HAD/D and HAD/A ≥ 8 (p=0.0184 and p = 0.0042, respectively). FAI was lower in ED group (0.0410).
Conclusion: ED frequency is high in MAWT1D and its associated factors should be mitigated to improve ED and quality of life in this population.

Disclosure
P. R. Jaskulski: None. E. J. Pavin: None. M. S. Silveira: None. M. B. Koelle: None.
174-OR: ADA Presidents’ Select Abstract: Epigenetic Regulation of Functional Beta-Cell Mass by Cohesin Smc3
Authors: WANG JEAN K. , PANDEY APARAMITA , HAM ALEXANDER P. , PARVEEN NAZIA , DHAWAN SANGEETA 
Published: June 2021

Both type 1 and type 2 diabetes are caused by insulin insufficiency due to inadequate functional beta-cell mass. The demise of beta-cells in diabetes is preceded by progressive impairment of beta-cell function. Several studies have shown that the regulation of beta-cell function and survival is tightly linked. However, the precise molecular mechanisms that link beta-cell function and survival remain far from clear. In this study, we report that the cohesin Smc3 is a novel epigenetic regulator of functional beta-cell mass. Smc3 is an ATPase that regulates the 3D chromatin architecture and chromatid cohesion, and plays an important role in cellular self-renewal, differentiation, and survival. Smc3 exists in a tripartite ring complex with proteins Smc1 and Rad21, and the association of this complex to the chromatin is regulated by Stag1. Our chromatin immunoprecipitation data suggest that the cohesin complex regulates beta-cell maturation and survival programs. Using transcriptomic profiling combined with histological and physiological analyses, we show that that the beta-cell specific Smc3 knockout mice (Smc3-BKO) become diabetic by 3 months of age, due to a progressive loss of beta-cell maturity and viability. Islets from the Smc3-BKO mice display impaired glucose stimulated insulin secretion (GSIS) around 1-2 months of age, with gene expression signatures that resemble functionally immature neonatal beta-cells. This is followed by progressive decline of beta-cell mass. At a molecular level, disruption of Smc3 leads to reduced protein levels of the other two subunits of the cohesin ring complex, Smc1 and Rad21. On the other hand, the mRNA levels of Stag1 are increased in the Smc3-BKO islets. Finally, we show that the cohesin regulatory program is disrupted in islets from humans with type 2 diabetes. Taken together, these studies provide a novel insight into the integrative epigenetic regulation of functional beta-cell mass.

Disclosure
J. K. Wang: None. A. Pandey: None. A. P. Ham: None. N. Parveen: None. S. Dhawan: None.
175-LB: Stress Hyperglycemia Predicts Mechanical Ventilation and Death in COVID-19 Infected Adults
Authors: MCDONNELL MARIE E. , SIMONSON DONALD C. , CROMWELL GRACE , GOPALAKRISHNAN GEETHA , GREENFIELD MARGARET , JOHNSON MATTHEW , KATTA SAI R. , LEBASTCHI JASMIN , MITRI JOANNA , PALERMO NADINE E. , RADHAKRISHNAN RAMYA , WESTCOTT GREGORY P. , WEINSTOCK RUTH S. , GARG RAJESH 
Published: June 2021

People with diabetes (DM) hospitalized with COVID-19 infection have a 2-3 fold higher risk of death compared with those without DM, and mechanical ventilation (MV) has been identified as a major risk factor for death. While stress hyperglycemia (StH) has been established as a risk factor for death in some critically ill cohorts, it is not a well-established risk factor for MV in COVID-19. The COVIDEastDM consortium pooled data from 5 academic hospitals on the East Coast of the US to study the relationship between hyperglycemia and COVID-19 outcomes. Data were obtained retrospectively from electronic records of adults with COVID-19 and either DM or StH (defined in this cohort as day-1 admission blood glucose &gt;180 mg/dl and A1c &lt;6.5%). This analysis included 3,435 individuals, of which 1,001 (29.1%) required MV and 748 (21.8%) died. The mean age was 67 ± 15 yrs., BMI 30.4 ± 7.7 kg/m2, A1c 7.98 ± 2.21 % and glucose 184 ± 104 mg/dl. Additionally, 57% were male, 4 % Asian,19% Black, 52% White, and 28% Hispanic. In a univariate analysis, risk factors for MV included younger age (OR 0.98 [95% CI 0.97, 0.99] per year older), male sex (OR 1.4 [1.2, 1.7]), BMI (OR 1.013 [1.003, 1.023] per kg/m2), Hispanic ethnicity (OR 1.16 [1.07, 1.28]) and the presence of diabetic ketoacidosis (n=38) at admission (OR 3.9 [2.0, 7.5]). Patients with StH were more likely to require MV (OR 1.93, [1.10, 3.39]). In a multivariate analysis, this relationship was continuous, with both lower A1c and higher glucose increasing risk of MV (p&lt; 0.01 for higher glucose, p&lt;0.001 for lower A1c). Patients who required MV were more likely to die than those who did not require MV (OR 5.1, [4.3, 6.1]) and StH predicted mortality in the multivariate analysis. Thus, in patients hospitalized with COVID19 infection, StH is a strong predictor of both MV and death in COVID-19 infected adults. While it is unclear if StH is a cause or effect of severe COVID-19, its presence early in the hospital course identifies higher risk patients and could potentially impact management.

Disclosure
M. E. Mcdonnell: Stock/Shareholder; Spouse/Partner; Abbott Diabetes. N. E. Palermo: None. R. Radhakrishnan: None. G. P. Westcott: None. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. R. Garg: None. D. C. Simonson: Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. G. Cromwell: None. G. Gopalakrishnan: None. M. Greenfield: None. M. Johnson: None. S. R. Katta: None. J. Lebastchi: None. J. Mitri: Consultant; Self; L-Nutra.

Funding
TechFoundation; Brigham Education Institute