bluuebunny/crossref_metadata_2025_split huggingface dataset:
186-OR: Novel Autoantibodies to Deamidated IA2 Extracellular Domain in Type 1 Diabetes
Authors: JIA XIAOFAN , MIAO DONGMEI , ZHANG CAIGUO , MICHELS AARON W. , YU LIPING , WENZLAU JANET M. 
Published: May 2022

Background: Insulinoma antigen-2 (IA2) is a major self-antigen in T1D with post translational modification (PTM) of the extracellular domain (IA2ec) by deamidation eliciting T cell responses in T1D patients. Yet the autoantibodies (Abs) to these IA2ec PTM epitopes in T1D has not been studied.
Methods: IA2ec protein containing all the four T-cell responsive deamidated Q&gt;E epitopes (aa 198-216, 467-482, 523-536 and 545-562) was produced. Sera from 269 new onset T1D children (median age= 12.6yrs) and 3age-matched healthy children were tested for Abs to IA2ecQ&gt;E and wide type (WT) IA2ec with radiobinding assay (RBA) .
Results: The assay cut-offs were set at the 99th percentile for both IA2ecQ&gt;E Ab and IA2ecWT Ab. In T1D children, positivity for IA2ecQ&gt;E Ab was 60.6% (163/269) vs. IA2ecWT Ab 19.3% (52/269, P&lt;0.0001) . In two subgroups of T1D patients who were positive (n=157) or negative (n=112) for current Abs to IA2 intra-cellular domain (IA2ic) , the positivity of IA2ecQ&gt;E Ab were significantly higher than IA2ecWT Ab (Fig) , 58% (91/157) vs. 15.3% (24/157, P&lt;0.0001) and 64.3% (72/112) vs. 25% (28/112, p&lt;0.0001) . However, the positivity of IA2ec Ab did not differ between the patients with or without IA2ic Ab.
Conclusion: IA2ecQ&gt;E Ab was detected in a large proportion of T1D patients, independent of the prototypical IA2ic Ab. IA2ecQ&gt;E Ab is potentially a new novel predictive and diagnostic biomarker for T1D.

Disclosure
X.Jia: None. D.Miao: None. C.Zhang: None. A.W.Michels: Employee; ImmunoMolecular Therapeutics, Stock/Shareholder; ImmunoMolecular Therapeutics. L.Yu: None. J.M.Wenzlau: None.

Funding
National Institutes of Health (R21- AI153665) National Institutes of Health (RDK032083) Diabetes Research Center (DRC) grant P30 DK116073
187-LB: Leveling Health Disparities through Digital Health—Associations between Risk for Health Inequity and Diabetes App Satisfaction, Use, and Outcomes
Authors: IMRISEK STEVEN D. , NAGRA HARPREET , HOY-ROSAS JAMILLAH R. , LEE MATTHEW , GOLDNER DAN , DACHIS JEFF , SEARS LINDSAY 
Published: May 2022

Introduction: Disparities in health outcomes are well documented in the literature, with factors such as race, education and income increasing the risk of inequity. Mobile health (mHealth) may help bridge the health equity gap. This study investigates use and attitudes toward One Drop's mHealth program for type 2 diabetes (T2D) as it relates to cumulative risk for health inequity.
Methods: Members with T2D using One Drop completed a health survey in exchange for a $20 gift card. We tested relationships between cumulative risk for inequity, calculated as a count of risks related to race/ethnicity, income, education, insurance and employment, and One Drop attitudes, use and outcomes.
Results: Members (N=149) reported a median of 1 risk factor. Risk was positively associated with reported helpfulness of the One Drop app, educational topics, reminders and actual views of lessons, while negatively related to past-month glucose logging (p’s&lt;.05) . No associations were found for helpfulness of glucose analysis or coaching, use of coaching, self-reported A1C and actual past-month blood glucose (p’s&gt;.05) .
Discussion: Higher risk for health inequity was associated with reporting greater helpfulness of One Drop's app and the use of some of its features. Combined with the absence of an association between risk for inequity and self-reported A1C and glucose, results suggest mHealth apps may be creating equitable outcomes by providing trusted content and greater accessibility. mHealth platforms should ensure this population has access to education emphasizing regular glucose monitoring as part of diabetes self-care.

Disclosure
S. D. Imrisek: Employee; One Drop. H. Nagra: Employee; One Drop, One Drop. J. R. Hoy-rosas: None. M. Lee: Employee; One Drop. D. Goldner: Employee; One Drop. J. Dachis: Board Member; One Drop, Employee; One Drop, Stock/Shareholder; One Drop. L. Sears: Employee; One Drop.
188-LB: Deep Learning–Based Population Screening of Type 1 Diabetes and Celiac Disease Genetic Risk from Blood Spots at Birth
Authors: SHARP SETH A. , LOCKE JONATHAN M. , XU YU , FRASER DIANE P. , FERRAT LAURIC A. , WEEDON MICHAEL N. , INOUYE MICHAEL , ORAM RICHARD A. , HAGOPIAN WILLIAM 
Published: May 2022

Introduction: Screening for type 1 diabetes (T1D) genetic risk in early life can prevent life threatening complications such as diabetic ketoacidosis and allow cost-effective recruitment into intervention and immunotherapy trials. Celiac disease (CD) frequently presents as a comorbidity in those with T1D and shares a strong genetic basis with T1D. Single nucleotide polymorphism (SNP) based genetic risk scores (GRS) for both T1D and CD have shown to be very predictive of future disease but are difficult to generate and typically require SNP array genotyping. We aimed to develop a combined GRS screening panel that could be genotyped from a single dried blood spot at birth.
Methods: We developed assays for proxy SNPs of common HLA-DQ haplotypes reported in previous GRS and additional loci from the most recent available genome-wide association studies (GWAS) . We used backwards stepwise regression to identify a subset of variants able to be genotyped with DNA eluted from 800 6mm dried blood spots. We developed and validated neural network models to quantify genetic risk of both T1D and CD using T1DGC and UK Celiac case-control SNP array data, validated in UK Biobank. Assays were developed with LGC Genomics and validated on 675 Seattle area samples.
Results: The complete panel consisted of 71 validated SNP assays, including 11 backup variants for key loci. We generated neural nework models which demonstrate equivalent or greater predictive power (AUC: T1D=0.914, CD=0.893) to previously published GRS yet require much less expertise to apply. We have developed an algorithm for preparation of raw genotyping data and subsequent generation of GRS requiring little expertise to apply.
Conclusion: A 71 SNP blood-spot screening panel is highly effective at screening genetic risk associated with T1D and CD at birth. Using a neural network model the panel enables widely available, easy to generate and inexpensive population screening of genetic risk for T1D and CD.

Disclosure
S. A. Sharp: None. J. M. Locke: None. Y. Xu: None. D. P. Fraser: None. L. A. Ferrat: None. M. N. Weedon: None. M. Inouye: None. R. A. Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. W. Hagopian: Research Support; Janssen Research & Development, LLC.

Funding
Diabetes UK (16/0005529) JDRF (3-SRA-2019-827-S-B)
188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes
Authors: CHAVEZ MIRANDA D. , MCDOWELL RUTH , TSE HUBERT M. 
Published: May 2022

Type 1 diabetes (T1D) is a result of insulin-secreting pancreatic β-cell destruction by autoreactive CD4 and CD8 T cells. There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. Systemically inhibiting glycolysis with 2-deoxyglucose (2-DG) can decrease autoreactive CD8 T cell islet infiltration. However, the effects of 2-DG on CD4 T cell diabetogenicity is unknown. Proinflammatory Th1 cells mediate β-cell destruction prefer glycolysis for maintaining effector responses, while immunosuppressive Treg cells prefer oxidative phosphorylation. We hypothesize that metabolic inhibition of glycolysis will diminish proinflammatory Th1 cell responses and delay β-cell destruction in T1D. Utilizing 2-DG, we performed an adoptive transfer of diabetogenic CD4+ T cells from NOD.BDC-2.5 or NOD.BDC-6.9 mice into NOD.scid mice. Recipient mice were systemically treated with 30 mM 2-DG in the drinking water beginning 4 days prior to adoptive transfer and monitored for hyperglycemia for 80 days post-transfer. NOD.scid mice treated with 2-DG had a significant delay in diabetes onset when transferred with either BDC-2.5 (n=14, p=0.0284) or BDC-6.9 (n=17, p=0.0249) CD4+ T cells compared to vehicle-treated groups. To define the effects of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were in vitro stimulated with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a decrease in T cell proliferation, T cell activation, and Th1 lineage commitment as shown by Ki67, CD25, and T-bet expression, respectively. Effector responses were also dampened as IFN-γ synthesis was decreased in our 2-DG treatment group compared to HIP only controls. Future studies will investigate the effects of 2-DG on CD4 T cell chemokine secretion, trafficking into the islet, and cellular metabolic profiles.

Disclosure
M.D.Chavez: None. R.Mcdowell: None. H.M.Tse: None.
198-OR: Altered Prandial Glucose Metabolism in Nondiabetic Subjects with Spinal Cord Injury Is Associated with Impaired Insulin Secretion and Clearance
Authors: TRBOVICH MICHELLE , DIMAS RUDI , SALEHI MARZIEH 
Published: May 2022

Patients with spinal cord injury (SCI) develop type 2 diabetes earlier and at 2-3 times higher frequency compared to the matched able-bodied persons (AB) . The difference in glucose abnormalities among SCI and AB cohorts remains after adjusting for known risk factors for DM, such as decreased physical activity, or lower body lean mass, or larger visceral fat mass. The mechanism for this dramatic effect of SCI on glucose metabolism is unknown but is consistent with endocrine-neurological alterations after injury. We hypothesized that SCI is associated with abnormalities in prandial glucose metabolism and β-cell function. To test this hypothesis glucose, insulin, and C-peptide levels were measured during 3-hr mixed meal tolerance test in 4 non-diabetic SCI (3M/1F, ages 33-61 years) and 6 age-matched AB with normal glucose tolerance test (2M/4F, ages 37-57 years) . SCI subjects had lower BMI (p=0.05) and A1C (p&lt;0.05) than AB (SCI vs. AB; BMI range: 19-29 vs. 25-39 kg/m2; A1C range: 5.0-5.3 vs. 5.3-5.9%) . Fasting values of glucose, insulin, C-peptide, insulin sensitivity (HOMA-IR) , and insulin clearance (CP/insulin) were similar between SCI and AB. Prandial glucose (AUCGlucose3h) and insulin (AUCInsulin3h) responses, however, were greater in SCI than AB (p&lt;0.01) . Despite larger prandial insulinemia β-cell output (AUCC-peptide3h) did not differ among 2 groups. This was consistent with a diminished insulin clearance (Total AUCC-peptide3h / Total AUCInsulin3h) in SCI compared to AB by 3-fold (p&lt;0.05) . Oral glucose insulin sensitivity (OGIS) was similar between 2 groups while β-cell glucose sensitivity and disposition index were smaller in SCI than AB by 2-fold (p=0.08) . These findings indicate that among subjects with normal glucose tolerance, those with SCI have larger prandial glycemic concentration despite lower BMI and A1C. This glycemic effect of SCI is associated with impaired β-cell function as well as insulin clearance.

Disclosure
M.Trbovich: None. R.Dimas: None. M.Salehi: None.
20-LB: Heart Failure Hospitalization among African American Compared with White Individuals with Type 2 Diabetes on Empagliflozin—Real-World Data
Authors: MISHRIKY BASEM M. , CUMMINGS DOYLE M. , FU YUANYUAN , HALLADAY JACQUIE , JONES WILLIAM S. , BOAN ANDREA , BERKELEY SARA JONES , PATIL SHIVAJIRAO P. , POWELL JAMES R. , ADAMS ALYSSA , IRISH WILLIAM 
Published: May 2022

While African Americans (AA) were underrepresented in the SGLT2i CVOT, the results from those trials were generalized to all, regardless of race. Our goal was to evaluate the risk of heart failure hospitalization (hHF) among AA vs. White (Wh) vs. Hispanic (His) patients with type 2 diabetes (T2D) initially prescribed empagliflozin (EMPA) .
We performed a multicenter retrospective study that extracted real world data for patients with T2D from 4 institutions in North & South Carolina who were ≥ 18 years, either AA or Wh or His, & were prescribed EMPA between Aug 2014 & Dec 2019. Our 1ry outcome was time to first hHF. Cumulative probability of hHF by race was estimated using the cumulative incidence function. The association of race with risk of hHF was evaluated using multivariable Cox hazards model.
A total of 9708 patients were eligible. Of these, 8994 patients had no history of hHF prior to EMPA administration (incident cohort) . Baseline characteristics & results are summarized in Table 1. AA patients were significantly younger, predominantly female, less likely to have pre-existing cardiac conditions, & more likely to have hypertension. When adjusting for age, gender, & baseline comorbidities, there was no significant difference in the risk of hHF between AA vs. Wh or His vs Wh.
Although clinical trials often misrepresent minorities, using real world data we found no significant difference in the risk of hHF in AA or His versus Wh patients with T2D taking EMPA.

Disclosure
B. M. Mishriky: Advisory Panel; AstraZeneca, AstraZeneca, Bayer AG, Bayer AG, Other Relationship; Lilly, Research Support; Lilly. A. Adams: None. W. Irish: Consultant; Eurofins Transplant Genomics, Taleris. D. M. Cummings: None. Y. Fu: None. J. Halladay: None. W. S. Jones: Research Support; Boehringer Ingelheim International GmbH. A. Boan: None. S. Jones berkeley: None. S. P. Patil: Research Support; Novo Nordisk. J. R. Powell: None.

Funding
Brody Brothers Endowment Grant (20-0922)
200-LB: Persistent cAMP Signaling Induces Adipocyte Browning through Biphasic Transcriptional and Epigenetic Remodeling
Authors: SO JISUN , TALEB SOLAEMA , WANN JAMIE , STROBEL OLIVIA , CHEOL ROH HYUN 
Published: May 2022

Beige adipocytes are inducible thermogenic cells formed in response to cold exposure and other environmental cues within white adipose tissue. Their capacity to produce heat would provide metabolic benefits against obesity and type 2 diabetes; however, the mechanisms underlying beige adipocyte recruitment, so-called adipocyte browning, induced by different stimuli remain unclear. Using our new adipocyte cell line with improved browning potentials, we compared adipocyte browning responses induced by cAMP (forskolin) versus PPARɣ activation (rosiglitazone) . Time-course RNA-seq revealed that chronic activation of cAMP but not PPARɣ resulted in a biphasic response. The cAMP signaling promoted tissue remodeling at the early phase and subsequently activated energy metabolism while inhibiting cell cycle, which resembles the kinetics of in vivo cold-induced browning. Those late-phase changes were highly correlated with those by PPARɣ activation. Consistently, the cAMP-driven effects were abolished by treatment with PPARɣ antagonists, suggesting PPARɣ as a converging point of its thermogenic actions. Assay for transposase-accessible chromatin sequencing (ATAC-seq) revealed unique dynamics of chromatin landscape distinct from transcriptional changes during cAMP-induced browning. Chromatin at early-induced genes opened acutely and stayed open until the late phase despite the rapid return of gene expression. The chromatin regions at late-induced genes also opened early, preceding transcriptional activation. Using a motif discovery method, we identified NFIL3 that was enriched in both early and late phases of cAMP-induced browning. Reduced thermogenic gene expression and mitochondrial respiration by NFIL3 knockdown suggest NFIL3 as a putative transcription factor mediating the biphasic response of adipocyte browning. These findings define new mechanisms that orchestrate transcriptional and epigenetic remodeling underlying beige adipocyte formation.

Disclosure
J. So: None. S. Taleb: None. J. Wann: None. O. Strobel: None. H. Roh: None.

Funding
American Diabetes Association (7-21-JDF-056) , National Institute of Health (DK129289)
200-OR: IER3IP1 Is Critical for Maintaining Glucose Homeostasis through Regulating the Endoplasmic Reticulum Function and Survival of ß-Cells
Authors: YANG JING , ZHEN JINYANG , FENG WENLI , FAN ZHENQIAN , HUANG YUMENG , SHU HUA , LI XIN , QIAO JINGTING , FAN YUXIN , SUN JINHONG , LI NA , LIU TENGLI , WANG SHUSEN , ZHANG XIAONA , ARVAN PETER , LIU MING 
Published: May 2022

Recessive mutations in IER3IP1 (Immediate Early Response 3 Interacting Protein 1) cause a triad of microcephaly, epilepsy, and permanent neonatal diabetes syndrome (MEDS) . IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development, however the role of IER3IP1 in β cell function and glucose homeostasis remains unknown. Herein, we established a new β cell-specific IER3IP1 knockout (IER3IP1-βKO) mouse model and found that IER3IP1 deficiency in β cells causes severe early onset insulin deficient diabetes. Functional studies revealed a markedly dilated ER along with significantly increased proinsulin misfolding and elevated expression of the ER chaperones including PDI, ERO1, BiP, and P58IPK. Transcriptome analysis confirmed by qRT-PCR revealed a markedly decreased expression of genes associated with β cell maturation, cell cycle, and anti-apoptosis, whereas there was a significantly increased expression of anti-proliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β cell maturation and proliferation, and promoted cell death. These data not only uncover a critical role of IER3IP1 in normal β cell function and survival, but they also provide insight into the mechanism (s) by which loss-of-function mutations of IER3IP1 lead to diabetes.

Disclosure
J.Yang: None. J.Sun: None. N.Li: None. T.Liu: None. S.Wang: None. X.Zhang: None. P.Arvan: n/a. M.Liu: None. J.Zhen: None. W.Feng: None. Z.Fan: None. Y.Huang: None. H.Shu: None. X.Li: None. J.Qiao: None. Y.Fan: None.

Funding
National Natural Science Foundation of China (81830025, 81620108004, 81870533, 81900720, 81800733, 82100865, 82070805, and 81870535)
202-LB: Insulin Regulation of Lipolysis in Adipocytes
Authors: STOECKLI JACQUELINE , ZADOORIAN ARMELLA , YANG GUANG , JAMES DAVID E. 
Published: May 2022

Adipocyte lipolysis is tightly regulated to provide fatty acids when needed and this is suppressed postprandially by insulin. This regulation remains incompletely understood. We have identified the abhydrolase ABHD15 as a key player in this process together with the phosphodiesterase PDE3B. In the absence of either ABHD15 or PDE3B, insulin is not able to suppress lipolysis. ABHD15 and PDE3B form a complex and in response to insulin they are both phosphorylated by Akt and bind to the adaptor protein 14-3-3. Insertion of a constitutive 14-3-3 binding site into either ABHD15 or PDE3B results in complete suppression of lipolysis even under pro-lipolytic conditions. Notably, we have discovered that the kinase Akt interacts with ABHD15 and insulin and/or 14-3-3 binding to ABHD15 abolishes the interaction. In summary we propose a model where ABHD15 binds to and suppresses the phosphodiesterase activity of PDE3B in the absence of insulin thereby facilitating unrestrained lipolysis and supply of fatty acids during starvation or crisis. Akt directly interacts with the ABHD15/PDE3B complex leading to phosphorylation and 14-3-3 binding upon insulin stimulation, which activates a pool of PDE3B thus repressing PKA and the lipolytic drive.

Disclosure
J. Stoeckli: Research Support; Pfizer Inc. A. Zadoorian: None. G. Yang: None. D. E. James: Research Support; Eli Lilly and Company, Novo Nordisk, Pfizer Inc.

Funding
Pfizer Inc.
206-LB: Increase of Hexokinase-2 Protein without Increase of Other Glycolytic Enzymes in Myotubes with High Glucose Concentration Supports the Hypothesis of Hexokinase-2-Linked Unscheduled Glycolysis as a Driver of Insulin Resistance
Authors: XUE MINGZHAN , RABBANI NAILA , THORNALLEY PAUL 
Published: May 2022

Insulin resistance in skeletal muscle is the major metabolic defect leading to the development of type 2 diabetes. The initiating dysfunction driving development of insulin resistance has not been disclosed. Recently, stabilization of hexokinase-2 (HK2) to proteolysis by increased glucose concentration, increasing flux through early-stage glycolysis without increase in expression and activity of other glycolytic enzymes, was identified as the initiator of metabolic dysfunction in hyperglycemia. This creates a wave of increased glycolytic intermediates activating hexosamine and protein kinase C pathways and increasing formation of methylglyoxal. Increased glucose-6-phosphate displaces HK2 from mitochondria, producing mitochondrial hyperpolarization and dysfunction. This is termed HK2-linked unscheduled glycolysis. Skeletal muscle exposed to increased fasting plasma glucose may stimulate this. To test this, we studied glycolytic enzyme abundance in murine C2C12 myotubes incubated with 5.5 and 25 mM glucose for 5 days, determining HK2 protein changes by Western blotting, normalized to ß-actin. Protein abundances in C2C12 myotube cultures with 5.5, 11.1 and 25.0 mM glucose determined by label-free quantitative mass spectrometry proteomics were mined from published data. In C2C12 myotubes, HK2 protein increased 46 ± 5 % in 25 mM glucose (P&lt;0.001, n = 3; Western blotting) . Proteomics corroborated this with 1.5 and 1.8 fold increase of HK2 in 11.1 and 25.0 mM glucose cultures, compared to 5.5. mM glucose control (P&lt;0.01, n = 3) . Abundances of other glycolytic enzymes, hexokinase-1, glucose-6-phosphate isomerase, phosphofructokinase, aldolase, triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase, were unchanged. This establishes the conditions for HK2-linked glycolytic overload. We conclude that high glucose concentration in C2C12 myotubes in vitro exhibits conditions producing hexokinase-2-linked unscheduled glycolysis

Disclosure
M. Xue: None. N. Rabbani: None. P. Thornalley: None.

Funding
Qatar Foundation, QB14Qatar University, QUHI-CMED-21_22-1