bluuebunny/crossref_metadata_2025_split huggingface dataset:
1485-P: Clinical Utility of Type 1 Diabetes and Type 2 Diabetes PGS for Informing Type 2 Diabetes Treatment and Disease Severity
Authors: BILLINGS LIANA K. , SHI ZHUQING , MULFORD ASHLEY , ASHWORTH ANNABELLE , XU JIANFENG , SANDERS ALAN R. 
Published: June 2024

Introduction: Type 1 diabetes (T1D) and type 2 diabetes (T2D) polygenic risk scores (PGST1D and PGST2D) can differentiate T1D and T2D, but it remains unclear whether PGST1D and PGST2D can inform T2D treatment and disease severity.
Methods: Among T2D patients in the Genomic Health Initiative (GHI) (N=2,716) and UK Biobank (UKB) (N=39,957), PGST1D and PGST2D were examined for association with anti-diabetes medications (ADM), number of ADM classes ever used, metabolic (BMI&gt;30, triglycerides&gt;150mg/dL, hypertension diagnosis) and autoimmune (hypothyroidism, celiac disease) phenotypes, and diabetic ketoacidosis with adjustment for HbA1c, age of recruitment and top 4 principal components.
Results: We confirmed previous UKB findings in the GHI that PGST1D and PGST2D differentiate T1D and T2D diagnoses. Among T2D patients in the GHI and UKB, a high vs. low PGST2D associated with more prevalent usage of insulin and non-insulin ADM, a greater number of ADM classes ever used, earlier age of T2D onset, and higher mean HbA1c. In the UKB, high PGST1D wasassociated with insulin treatment and number of ADM classes ever used (Table 1). Lastly, PGST1D associated with autoimmune phenotype and diabetic ketoacidosis, while the PGST2D associated with metabolic phenotype.
Conclusion: These findings emphasize the potential of polygenic risk scores to inform diabetes treatment and provide insights into disease onset and severity in T2D.

Disclosure
L.K. Billings: Advisory Panel; Novo Nordisk, Pfizer Inc. Z. Shi: None. A. Mulford: None. A. Ashworth: None. J. Xu: None. A.R. Sanders: None.

Funding
NorthShore Auxiliary Scholars Award (internal)
1488-P: A Novel Combination Therapy to Treat Autoimmune Type 1 Diabetes
Authors: HUSSEINY MOHAMED I. , COBB JACOB , RAWSON JEFFREY , GONZALEZ NELSON , KANDEEL FOUAD R. 
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) is a complex disease characterized by loss of immune tolerance to self-autoantigens and destruction of insulin-producing beta-cells. No single therapy confronts the several contributors to the disease. We developed an oral Salmonella-based vaccine that provides autoantigen in combination with TGFβ, IL10, and anti-CD3. The vaccine partially prevented and reversed autoimmune diabetes in mice. We also found that the hormone gastrin was beneficial to human islets in vitro and prevented, to a degree, autoimmune diabetes in mice. We hypothesized that the vaccine in combination with a gastrin analogue (GAST-17) would be more salutary in rodents with T1D than either agent alone.
Methods: The vaccine and GAST-17 combination were administered to autoimmune diabetic mice and outcomes compared with animals that received the vaccine or gastrin alone. Effects on glucose metabolism, islet cellular infiltration, and specific immune cells were characterized. The tolerogenic mechanisms of the combination therapy were examined.
Results: Administration of the vaccine with GAST-17 in combination reversed disease in 80% of diabetic mice compared to 63% of vaccine alone and 5% of GAST-17 alone treated animals. This was associated with increased antigen-specific regulatory T-cells, decreased islet-infiltrating lymphocytes, and increased beta-cell mass. As well, combination treated mice showed increased serum levels of the tolerogenic cytokine IL10 and decreased inflammatory cytokines (IFNγ, GM-CSF, IL1-alpha, IL12).
Conclusion: A novel combination treatment of an oral diabetes vaccine and GAST-17 was superior in the reversal of established T1D in mice. This combination strategy could be worthwhile examining in individuals with autoimmune diabetes.

Disclosure
M.I. Husseiny: None. J. Cobb: None. J. Rawson: None. N. Gonzalez: None. F.R. Kandeel: Advisory Panel; Vertex Pharmaceuticals Incorporated.

Funding
The Juvenile Diabetes Research Foundation (JDRF-2-SRA-2022-1214-S-B)
149-OR: Liver Health in Adolescents with Youth-Onset Type 2 Diabetes
Authors: SHAH AMY S. , XANTHAKOS STAVRA , TROUT ANDREW T. , KELSEY MEGAN M. , JENKINS TODD M. , HELMRATH MICHAEL , INGE THOMAS , BROWNE LORNA , SCHAAF LISA R. , BAUMGARTNER AMY , RIEGLER ALLEN , BAILEY ALEXANDER , DOBBS TYLER , WITT KAITLYN , HINES ASHTON , RUSK SHENA , NADEAU KRISTEN J. 
Published: June 2024

Introduction: Youth-onset type 2 diabetes (Y-T2D) and metabolic liver disease (MASLD) commonly coexist. MASLD can advance to fibrosis/cirrhosis with no treatments beyond lifestyle intervention. Limited liver data in Y-T2D led us to investigate MASLD in the ST2OMP study, which will compare metabolic bariatric surgery (MBS) to medical treatment for Y-T2D.
Methods: Liver fat (MRI proton density fat fraction (PDFF), liver stiffness (MR elastography), and ALT (inflammation) were measured in Y-T2D at ST2OMP enrollment. Linear regression examined differences in liver outcomes adjusted for sex, race/ethnicity, BMI, HbA1c and glucagon-like peptide 1 receptor agonists (GLP-1RA) use.
Results: At baseline, participants (n=56) had mean age 16.6yrs and BMI 43.8 kg/m2; median HbA1c 6.3% and diabetes duration 1.7 yrs. Elevated ALT occurred in 76.4%, PDFF in 89.0% and stiffness in 14.8%. Analyses adjusted for age, BMI and HbA1c (Table), found higher PDFF and ALT in males (vs. females) and in youth not taking GLP-1RA (each p&lt;0.05). Non-Hispanic White youth had the highest stiffness (p&lt;0.05).
Conclusions: MASLD is prevalent in Y-T2D with evidence of inflammation and stiffness. Males had higher measures of fat and inflammation, and non-Hispanic white youth had the highest stiffness. GLP-1RA use may be associated with less fat and inflammation, independent of BMI, but not stiffness. Future ST2OMP results will compare MASLD outcomes pre- and post-MBS.

Disclosure
A.S. Shah: None. S. Xanthakos: None. A.T. Trout: Research Support; Siemens Healthcare Diagnostics, GE Healthcare, Perspectum Ltd. Consultant; GE Healthcare. M.M. Kelsey: Other Relationship; Rhythm Pharmaceuticals, Inc., Lilly Diabetes. T.M. Jenkins: None. M. Helmrath: None. T. Inge: Consultant; Medtronic, Eli Lilly and Company, Brainstorm Therapeutics. Stock/Shareholder; Standard Bariatrics. Consultant; Teleflex. L. Browne: None. L.R. Schaaf: None. A. Baumgartner: None. A. Riegler: None. A. Bailey: None. T. Dobbs: None. K. Witt: None. A. Hines: None. S. Rusk: None. K.J. Nadeau: None.

Funding
National Institutes of Health (R01DK119450)
1493-P: Transglutaminase-Expressing Adipose Tissue Macrophages Positively Regulate Adipose Tissue Profibrotic Profile in Diet-Induced Obese Mice
Authors: HOLLIS MELANIE , ELIZONDO DIANA , P PATEL TUSHAR , ROBERSON ROBIN , CHEN JOCELYN , YANOVSKI JACK A. 
Published: June 2024

Introduction: Adipose tissue fibrosis (ATF) in obesity-driven diabetes is characterized by increased extracellular matrix (ECM) deposition. Cell populations that induce ATF in diabetes have yet to be fully elucidated. Transglutaminase 2 (TGM2) is known to contribute to ECM stabilization. The objective of this study was to investigate adipose tissue macrophage (ATM)-derived TGM2 as a potential modulator of ATF in diabetes.
Methods: C57BL/6 mice were placed on chow diet (CD) or high-fat diet (HFD) for 10 weeks and evaluated for ATF and TGM2 expression in epididymal white adipose tissue (eWAT). Next, TGM2 was silenced in HFD mice via in vivo RNAi silencing to evaluate effects on ATF. Lastly, TGM2 CRISPR-silenced macrophages were co-cultured with differentiating adipocytes and evaluated for adipo/lipogenesis. Readout indices included, picrosirius red, qPCR, western blot, RNAscope, and flow cytometry.
Results: TGM2 and Col6A1 eWAT expression were increased in HFD mice compared to CD. TGM2 was increased within the ATMs from HFD mice, suggesting ATMs as the main TGM2 contributor in eWAT during obesity. Successful silencing of TGM2 within HFD ATMs decreased eWAT fibrosis, plausibly caused by observed changes in abundance of AT pro-inflammatory immune cells in TGM2 silenced mice. Finally, differentiating adipocytes co-cultured with TGM2-silenced macrophages showed reduced adipocyte expansion, supporting the notion that macrophage-derived TGM2 contributes to AT ECM alterations also involved in adipocyte growth.
Conclusion: Results suggest that ATMs secreting TGM2 in HFD mice contribute to ATF in obesity. We identify TGM2 in ATMs as a potential cell-specific candidate marker for therapeutics directed at obesity-associated ATF.

Disclosure
M. Hollis: None. D. Elizondo: None. T. Patel: None. R. Roberson: None. J. Chen: None. J.A. Yanovski: Research Support; Rhythm Pharmaceuticals, Inc., Soleno Pharmaceuticals, Inc, Versanis Bil, Hikma Pharmaceuticals, Inc., National Institutes of Health.
1496-P: The Highly Immunodeficient SRG Rat for Modeling Diabetes
Authors: WALTON GRACE 
Published: June 2024

Immunocompromised rodents are essential for pre-clinical testing of cell-based therapies. The SRG rat (Sprague Dawley Rag2-/-, Il2rg-/-) lacks mature B, T, and NK cells, and is normoglycemic under standard conditions. Compared to mice, the SRG rat offers more human-like metabolism, easier surgical manipulations, and greater volume and frequency of blood collection. Compared to nude rats, the SRG is more permissive to a wider range of human xenografts. Given the advantages of the SRG rat, we determined whether it could serve as a model of streptozotocin-induced (STZ) Type 1 Diabetes or diet-induced obesity (DIO) as a model of Type 2 Diabetes. We compared the effects of STZ on blood glucose levels in SRG versus wild-type Sprague Dawley (SD) male rats. Rats were given vehicle, STZ 40 mg/kg, or STZ 65 mg/kg. After low dose STZ, day 6 non-fasting glucose was 262 ± 41 (SEM) mg/dL in SD rats and 565 ± 64 (SEM) mg/dL in SRG rats. After high dose STZ, day 6 non-fasting glucose was 679 ± 23 (SEM) mg/dL in SD rats and 505 ± 72 mg/dL in SRG rats. Weight loss associated with hyperglycemia was more pronounced in SRG rats compared to SD rats. To induce T2D, obesity, and insulin resistance, SRG rats were fed control or high fat diet (60% kcal from fat). Food intake and body weight were measured weekly. SRG rats underwent IPGTT (after 10 and 24 weeks of high fat diet) and ITT (after 11 weeks of high fat diet). Compared to low fat diet, DIO rats had increased caloric intake and body weight throughout the study. After 10 weeks, DIO rats had impaired glucose tolerance without elevated fasting insulin. Insulin tolerance did not differ at 11 weeks. At 24 weeks, glucose tolerance did not differ between diet groups, but DIO SRG rats displayed elevated fasting insulin (P &lt; 0.01).
In conclusion, SRG rats display increased sensitivity to 40 mg/kg STZ when compared to SD rats, with rapid induction of weight loss and hyperglycemia. The SRG glycemic response to chronic DIO is complex and changes over time, likely due to compensatory hyperinsulinemia.

Disclosure
G. Walton: None.
1498-P: Intermittent Hypoxia Increased the Expression ofIL-1ß, IL-6, and IL-8 in Human Monocytes through the Downregulation of MicroRNA-146a
Authors: TAKASAWA SHIN , MAKINO MAI , SHOBATAKE RYOGO , YAMAUCHI AKIYO , SAKURAMOTO-TSUCHIDA SUMIYO , UCHIYAMA TOMOKO , TAKEDA MAIKO , TAKEDA YOSHINORI , MIZUTA KEITA , ASAI KEITO , OTA HIROYO 
Published: June 2024

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for systemic inflammation. Serum inflammation markers such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, and C-X-C motif chemokine ligand 10 (CXCL10) in SAS patients have been reported to be elevated. However, the details of why IH leads to induce the elevations remain unclear. We investigated inflammation-related transcripts in human monocytes (HL-60 and THP-1 cells) exposed to IH by real-time RT-PCR and found that IL-1 β, IL-6, and IL-8 mRNAs were significantly increased. ELISA confirmed that IL-1β, IL-6, and IL-8 in the HL-60 and THP-1 culture media were significantly increased by IH (P=0.011 and 0.0339 in IL-1β, P=0.0419 and 0.369 in IL-6, P&lt;0.0001 and &lt;0.0001 in IL-8, respectively). We next investigated promoter activities of the genes and revealed that they were not increased by IH. On the other hand, target mRNA search of microRNA (miR)s revealed that the mRNAs have a potential target sequence for miR-146a. The miR-146a level of IH-treated cells was significantly decreased than that of normoxia-treated cells. Thus, we introduced miR-146a mimic and non-specific control RNA (miR-146a mimic NC) into HL-60 and THP-1 cells and measured the mRNA and protein levels of IL-1β, IL-6, and IL-8. The IH-induced expression of IL-1β, IL-6, and IL-8 was abolished by introduction of miR-146a mimic but not by miR-146a mimic NC. Our results demonstrate that IH stress up-regulates the levels of IL-1β, IL-6, and IL-8 in human monocytes to accelerate systemic inflammation including diabetes through the miR-146a mediated mechanism, resulting in onset or aggravation of systemic inflammation.

Disclosure
S. Takasawa: None. M. Makino: None. R. Shobatake: None. A. Yamauchi: None. S. Sakuramoto-Tsuchida: None. T. Uchiyama: None. M. Takeda: None. Y. Takeda: None. K. Mizuta: None. K. Asai: None. H. Ota: None.
1500-P: Oral Exposure to Cigarette Smoke Condensate Leads to Glucose Intolerance and Immune-Cell Alterations in the Gut
Authors: BOSCH ANGELA J.T. , KELLER LENA , LOW ANDY J.Y. , KELLENBERGER WANJA T. , CAVELTI-WEDER CLAUDIA 
Published: June 2024

Introduction & Objective: Smoking is associated with an increased risk for diabetes, yet the underlying mechanism remains elusive. Since smoking correlates with many gastrointestinal tract diseases, we aimed to investigate whether cigarette smoke influences metabolic health through gut exposure.
Methods: Male C57Bl/6N and Rag2-/- mice were exposed to cigarette smoke condensate (CSC) by oral gavage (5 days/week; 0.5mg/day). Metabolic health was evaluated by glucose and insulin tolerance tests. At the end of the experiment, immune cells of different organs were characterized by flow cytometry.
Results: Mice treated with CSC exhibited impaired glucose tolerance combined with increased insulin secretion and reduced insulin sensitivity, indicative for insulin resistance. Additionally, oral exposure to CSC led to changes in colonic immune cells as characterized by increased eosinophils and inflammatory macrophages. In the liver, macrophages and monocytes were elevated, while in the adipose tissue, there was an increase in Th2 and regulatory T-cells. Rag2-/- mice, lacking mature T- and B-lymphocytes, were not protected from metabolic impairment, but rather developed glucose intolerance after a shorter period of CSC exposure.
Conclusion: Gut exposure to CSC results in glucose intolerance and insulin resistance. Additionally, oral CSC exposure leads to gut and liver inflammation. Innate immunity seems to play a central role in driving this inflammation, as mice lacking B- and T-cells demonstrate early onset of glucose intolerance. These findings point towards an immune-mediated mechanism of CSC-induced diabetes through gut exposure.

Disclosure
A.J.T. Bosch: None. L. Keller: None. A.J.Y. Low: None. W.T. Kellenberger: None. C. Cavelti-Weder: None.

Funding
Swiss National Science Foundation (SNSF) (32003B_204937 / 2)
1506-P: Genomic Monitoring of Islet Graft Injury in Type 1 Diabetic Patients after Islet Transplantation
Authors: HUSSEINY MOHAMED I. , COBB JACOB , ORR CHRIS , HACKER-STRATTON JEANNETTE , FOROUHAR ELENA , EL-SHAHAWY MOHAMED A. , KANDEEL FOUAD R. 
Published: June 2024

Introduction & Objective: Early detection of islet graft injury after islet transplantation (IT) may allow timely intervention to preserve islet graft health and function. We hypothesized that in response to IT injury, islet beta-cells will release cell-free DNA (cfDNA) into the circulation allowing for early detection of graft injury.
Methods: Real-time bidirectional pyrophosphorolysis-activated PCR (Bi-PAP) and methylation-specific PCR (MSP) assays were developed to detect donor cfDNA and beta-cell specific unmethylated insulin DNA in plasma of individuals with type 1 diabetes who received IT. Under approved protocols at the City of Hope National Medical Center, blood samples from type 1 diabetic IT individuals (n=22) were collected before and after the procedure and analyzed using the Bi-PAP and MSP assays. The longitudinal relationships between the metabolic and immunologic parameters and the appearance of donor-specific cfDNA in circulation of individuals after IT were analyzed.
Results: All individuals that underwent IT showed donor-specific cfDNA in plasma (by both methods) on day one after the procedure. Donor-specific cfDNA decreased gradually and was no longer detected in the plasma by day 18 post-IT. Insulin independence and less variation in blood glucose levels after IT was associated with minimal to no plasma donor cfDNA during the study period. In contrast, individuals that did not achieve insulin independence, had wide swings in blood glucose, or that had immune activation after IT were found to have increases in donor cfDNA.
Conclusion: Donor islet cfDNA persisted in individuals with poorer outcomes after IT. These findings suggest that donor cfDNA may be markers of islet injury after allo-transplantation. It remains to be seen if donor cfDNA levels provide more insights sooner than other techniques currently employed to monitor islet health after transplantation.

Disclosure
M.I. Husseiny: None. J. Cobb: None. C. Orr: None. J. Hacker-Stratton: None. E. Forouhar: None. M.A. El-Shahawy: None. F.R. Kandeel: Advisory Panel; Vertex Pharmaceuticals Incorporated.
1507-P: Mixed-Meal Tolerance Test (MMTT) C-Peptide and BETA-2 Score Predict Underlying ß-Cell Secretory Capacity following Islet Transplantation for Type 1 Diabetes (T1D)
Authors: FLATT ANNELIESE , MATUS AUSTIN M. , GALLOP ROBERT J. , MARKMANN EILEEN M. , DALTON-BAKES CORNELIA V. , PELECKIS AMY , LIU CHENGYANG , NAJI ALI , RICKELS MICHAEL R. 
Published: June 2024

Introduction and Objective: Assessment of β-cell secretory capacity by glucose-potentiation of arginine-induced insulin secretion (AIRpot) provides a gold-standard measure of functional β-cell mass post-islet transplantation. However, glucose-potentiated arginine (GPA) testing procedures are intensive and not feasible for routine islet graft monitoring. We examined the association between simple measures of islet graft β-cell function (MMTT C-peptide and BETA-2 score) and β-cell secretory capacity (AIRpot) in a longitudinal cohort.
Methods: Individuals with T1D complicated by problematic hypoglycemia underwent intrahepatic allogeneic islet transplantation under the Clinical Islet Transplantation 07 (CIT07) protocol between 2008 - 2012. MMTT and GPA procedures were completed on adjacent days at 2.5 months and yearly up to 7 years post-transplant. Relationships between measures were assessed by repeated-measures correlation analysis.
Results: 11 individuals (mean±SE age: 45±3 years; T1D duration: 28±4 years; and BMI: 25±1 kg/m2) received 694,895±48,498 islet equivalents over one (n=7) or two (n=4) transplants. 63 paired procedures in individuals with sustained islet graft function were assessed, representing an average of 5.73 repeated measures per participant. MMTT C-peptide correlated moderately with AIRpot at 60-min (r2=.16; P&lt;0.01), 90-min (r2=.24; P&lt;0.001) and at peak (r2=.22; P&lt;0.001). Assessment of C-peptide/glucose ratio improved the relationship at 60-min (r2=.20; P&lt;0.001). BETA-2 score was a better predictor of AIRpot (r2=.23; P&lt;0.001) than fasting C-peptide/glucose (r2=.14; P&lt;0.01).
Conclusion: MMTT C-peptide and BETA-2 score predict underlying β-cell secretory capacity however with only moderate effect sizes. The BETA-2 score holds additional value as a fasting measure that can inform changes in β-cell secretory capacity.

Disclosure
A. Flatt: None. A.M. Matus: None. R.J. Gallop: None. E.M. Markmann: None. C.V. Dalton-Bakes: None. A. Peleckis: None. C. Liu: None. A. Naji: None. M.R. Rickels: Consultant; Vertex Pharmaceuticals Incorporated, Sernova, Corp. Research Support; Dompé.

Funding
National Institutes of Health Public Health Services Research Grants (R01 DK091331; U01 DK070430; UL1 TR000003; UL1 TR001878; and P30 DK19525)
1518-P: HMGA1 Deficiency—A Common Causal Link between Tau Pathology and Insulin Resistance?
Authors: MIRABELLI MARIA , CHIEFARI EUSEBIO D. , SAVERIO BRUNETTI FRANCESCO , PATRIZIA FOTI DANIELA , BRUNETTI ANTONIO 
Published: June 2024

Consistent evidence supports a link between neurodegeneration, insulin resistance (IR) and type 2 diabetes (T2D). The molecular mechanisms for this association are unclear. It has been previously shown that the transacting factor HMGA1 is needed for proper expression of the insulin receptor. Also, IR and T2D were reported earlier in humans and mice with HMGA1 gene defects. Here, we focused on HMGA1 as a potential novel pathogenic factor of Tauopathies, including Alzheimer’s disease.
Investigations were performed in vitro, in human and mouse neuronal cell models, and in vivo, in Hmga1-/- mice. Immunoblot analyses, combined with protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays in living cells were carried out, in addition to Tau immunohistochemistry in Hmga1-/- mouse brain. Also, a case-control study was used to explore the relationship between HMGA1 and Tau pathology in Tauopathy patients, carrying or not the rs146052672 variant, which negatively impacts HMGA1 protein production and increases the risk of IR and T2D.
We show that HMGA1 plays a role in controlling Tau protein expression. This function was mediated primarily through the specific repression of MAPT gene transcription. Thus, Tau mRNA and protein levels were inversely related to HMGA1 in both human neuronal cells and primary mouse neurons. This inverse relationship was confirmed in the brain of Hmga1-/- mice, in which Tau was overexpressed, compared to Hmga1+/+ mice. Furthermore, genetic analysis indicated that the rs146052672 variant was more common among patients with Tauopathy (17%) than among controls (5%). Adjusted logistic regression analysis revealed a strong association of this variant with Tauopathy (OR, 5.56 [95% CI, 2.08-14.87]; P = 0.001).
HMGA1 is a repressor of the MAPT gene. As such, HMGA1 deficiency may be a causative factor of Tauopathy. We hypothesize that a shared causal link between Tau pathology and insulin resistance is plausible, that is, via downregulation of HMGA1 function.

Disclosure
M. Mirabelli: None. E.D. Chiefari: None. F. Brunetti: None. D. Foti: None. A. Brunetti: None.