bluuebunny/crossref_metadata_2025_split huggingface dataset:
246-OR: Association of Erythritol and Erythronate with Cardiovascular Outcomes and Death
Authors: ABUSHAMAT LAYLA A. , SUN CAROLINE W. , YU BING , HOOGEVEEN RON C. , CHENG CHAO , HARTIG SEAN M. , HERMAN MARK A. , REUSCH JANE E.B. , SELVIN ELIZABETH , NDUMELE CHIADI E. , NAMBI VIJAY , BALLANTYNE CHRISTIE M. 
Published: June 2024

Introduction & Objective: Erythritol, an endogenously produced sugar alcohol, is a commonly used artificial sweetener since 2002. However, circulating erythritol is associated with cardiovascular (CV) disease at visit 1 (1987-89) of the Atherosclerosis Risk in Communities (ARIC) study. The objective was to assess the association of erythritol and its metabolite erythronate with CV outcomes in older adults at ARIC visit 5 (2011-13).
Methods: Fasting erythritol and erythronate were measured in ARIC participants by mass spectrometry and were analyzed continuously and by tertiles. Cox proportional hazard models assessed associations with CV outcomes and death.
Results: Top tertile erythritol or erythronate levels were associated with older age, diabetes, hypertension, hyperlipidemia, higher body mass index, lower estimated glomerular filtration rate, microalbuminuria, and higher cardiac biomarkers (p&lt;0.001). Over mean follow-up of 7.7±2 years, higher erythritol and erythronate relative concentrations were associated with CV events after adjustment for covariates (Figure). Erythronate associated more strongly than erythritol.
Conclusion: Erythritol and erythronate may serve as biomarkers of poor cardiac-kidney-metabolic syndrome (CKM) health and CV outcomes. Future studies should assess the contribution of endogenous production via the pentose phosphate pathway versus exogenous intake.

Disclosure
L.A. Abushamat: None. C.W. Sun: None. B. Yu: None. R.C. Hoogeveen: Consultant; Denka Seiken. Research Support; Denka Seiken. C. Cheng: None. S.M. Hartig: None. M.A. Herman: Research Support; Eli Lilly and Company. J.E.B. Reusch: Advisory Panel; Medtronic. E. Selvin: None. C.E. Ndumele: None. V. Nambi: Board Member; American Society of Preventive Cardiology. Stock/Shareholder; Insera. Other Relationship; American College of Cardiology. C.M. Ballantyne: Research Support; Abbott Diagnostics. Consultant; Abbott Diagnostics. Research Support; Akcea Thearpeutics, Inc., Amgen Inc. Consultant; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Consultant; Arrowhead Pharmaceuticals, Inc., AstraZeneca, Denka Seiken, Eli Lilly and Company, ESPERION Therapeutics, Inc., Genentech, Inc., Illumina. Research Support; Ionis Pharmaceuticals. Consultant; Ionis Pharmaceuticals. Research Support; Merck & Co., Inc. Consultant; Merck & Co., Inc. Research Support; New Amsterdam. Consultant; New Amsterdam. Research Support; Novartis Pharmaceuticals Corporation. Consultant; Novartis Pharmaceuticals Corporation. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Research Support; Regeneron Pharmaceuticals Inc., Roche Diagnostics. Consultant; Roche Diagnostics, TenSixteen Bio, Alnylam Pharmaceuticals, Inc.
27-OR: Effect of Acute Exercise and Exercise Training on the Ability of Insulin to Clear Branched-Chain Amino Acids from Plasma in Obesity and Type 2 Diabetes
Authors: MØLLER PAULINE M. , KJØBSTED RASMUS , HOUBORG PETERSEN MARIA , WOJTASZEWSKI JØRGEN F.P. , HOJLUND KURT 
Published: June 2024

Introduction & Objective: Insulin resistance in obesity and type 2 diabetes (T2D) is associated with elevated plasma branched-chain amino acid (BCAA) levels. Whether insulin action on plasma BCAA and the ability of acute exercise or exercise training to alter insulin action on plasma BCAA are intact in obesity and T2D remains to be established.
Methods: In studies (STs) of persons with T2D and glucose-tolerant, obese (OB), and lean (LE) controls examined by hyperinsulinemic-euglycemic clamps (insulin infusion 40 mU/min/m2), we studied the effect of insulin for 4-h (ST1) and insulin for 2-h before and after an acute exercise (1-h, VO2max 70%) bout (ST2) and before and after exercise training for 8 weeks (ST3) on plasma BCAA using a BCAA detection kit.
Results: Insulin-stimulated glucose disposal in T2D was 30-50% lower than in OB (ST1-3) and 40-60% lower than in LE (ST1+3), and 20% lower in OB than in LE (ST1), with p&lt;0.05. Exercise training (ST3) increased insulin-stimulated glucose disposal by 30-40% in all groups (all p&lt;0.01). Plasma BCAA was increased in T2D compared with OB and LE (ST1+3), and in OB compared with LE (ST1), in particular, in the insulin-stimulated state (all p&lt;0.05). In line, the ability of insulin to reduce plasma BCAA was significantly attenuated (~30%) in T2D compared with OB and LE both before (ST1+3) and after exercise training (ST3), with p&lt;0.05. Prior acute exercise (ST2) reduced plasma BCAA (10-15%) and attenuated (20-25%) the ability of insulin to further reduce plasma BCAA in both T2D and OB (all p&lt;0.05).
Conclusion: An impaired ability of insulin to clear BCAA from plasma in T2D and, to a lesser extent, in OB may contribute to elevated plasma BCAA and is not improved after exercise training. An acute bout of exercise lowers plasma BCAA but does not augment insulin action on plasma BCAA in T2D or OB.

Disclosure
P.M. Møller: None. R. Kjøbsted: None. M. Houborg Petersen: None. J.F.P. Wojtaszewski: Consultant; Pfizer Inc. Stock/Shareholder; Pfizer Inc., Novo Nordisk A/S. K. Hojlund: None.
271-OR: Automated Hybrid Closed-Loop (AHCL) Systems for the Treatment of Cystic Fibrosis Related Diabetes (CFRD)
Authors: GRANCINI VALERIA , COGLIATI IRENE , GAGLIO ALESSIA , RESI VERONICA , ORSI EMANUELA 
Published: June 2024

CFRD is the result of a partial to complete insulin deficiency, leading to hyperglycaemia, loss of muscle mass and catabolic state. Insulin is the only recommended therapy and continuous subcutaneous insulin infusion (CSII) systems are gaining evidence to be the best treatment, leading to a better glycemic control and an improvement in muscle mass. Today, data concerning AHCL systems in CFRD are still lacking.
Aim: to evaluate the effects of insulin therapy optimization with AHCL systems on glycemic control in people with CFRD, already insulin treated (CSII or multiple daily injections - MDI) and already trained with a structured educational program for the management of their therapy (training to MDI/CSII and carbohydrates counting)
Methods: 14 patients (7 F/7 M) agreed to participate in the study and switched to AHCL (7 from a CSII system/7 from MDI). All individuals wore a continuous glucose monitoring (CGM) at enrollment. At baseline and after 6 months patients had a blood sample for biochemistry and data were downloaded from their CGM. A mid-term evaluation of data from CGM was performed 4 weeks after baseline.
Results: We demonstrated a substantial improvement in glucose control at end of trial (HbA1c 7.1±0.9 to 6.2±0.6%, p&lt;0.01; glucose 7.9±3.0 to 6.3±2.8 mmol/L, ns; average glucose - AG 8.7±1.7 to 8.4±1.2 mmol/L, ns; Glucose management indicator - GMI 7.5 to 0.9-&gt;6.9±0.5%, p&lt;0.05; time in range - TIR 58.2±22.3-&gt;77.0 to 15.0%, p&lt;0.01; coefficient of variation - CV: 35.5±8.0 to 30.3±4.8, ns). The improvement in the CGM parameters was already relevant at the mid-term analysis (AG 8.7±1.7 to 7.9±1.1 mmol/L, ns; GMI 7.5±0.9 to 6.6±0.5%, p&lt;0.01; TIR 58.2±22.3 to 77.6±11.9%, p&lt;0.01; CV: 35.5±8.0 to 30.4±5.2, ns).
AHCL systems lead to a significative improvement in glycemic control in CFRD and, as for type 1 DM, should be proposed as gold standard therapy, considering the pivotal role of an enhanced glycemic management in body composition and, eventually, long term outcomes in this population

Disclosure
V. Grancini: Speaker's Bureau; Vertex Pharmaceuticals Incorporated. I. Cogliati: None. A. Gaglio: Consultant; Boehringer-Ingelheim. V. Resi: None. E. Orsi: Speaker's Bureau; Sanofi, Lilly Diabetes, AstraZeneca.
287-OR: Traf6 Directs a Noncanonical Role for Innate Immune Signaling in Pancreatic ß-Cells
Authors: LEVI D ANCONA ELENA , ZHU JIE , WALKER EMILY M. , SIDARALA VAIBHAV , SOLEIMANPOUR SCOTT 
Published: June 2024

Innate immune signaling links diverse intracellular pathways in eukaryotic cells, from inflammation to metabolism as well as host defense. In immune cells, mitochondria act as docking sites for innate immune signaling pathways, including those downstream of toll-like receptors (TLRs), whose activation by inflammatory signals contribute to mitochondrial damage. The importance of innate immune signaling in β-cells, however, has been vexing. Deletion of TLRs enhances β-cell mass following diet-induced obesity (DIO), while loss of downstream TLR signaling adaptors impairs β-cell function. Moreover, the regulatory relationships between innate immune signaling and mitochondrial quality control responses to mitochondrial damage are unclear. Here, we observe that the E3 ubiquitin ligase Traf6, which is central to the transmission of TLR-dependent innate immune signals to induce inflammation, surprisingly promotes glucose homeostasis following metainflammatory stress. We generated β-cell specific Traf6 knockout mice (Traf6Δβ), which were euglycemic at baseline, yet developed glucose intolerance and decreased glucose-stimulated insulin secretion following DIO. Islets from HFD-fed Traf6Δβ mice exhibit increased mitochondrial mass, abnormal mitochondrial ultrastructure, and impaired mitochondrial respiration and mitophagy flux. We also observed that Traf6 translocates to the mitochondria during metabolic stress. Interestingly, metabolic defects in Traf6Δβ mice were completely rescued by concomitant deletion of the mitophagy initiator Parkin, indicating a novel and unexpected importance for Traf6 to tune β-cell mitochondrial quality control. Thus, Traf6 links β-cell stress responses with control of mitophagy, revealing a non-canonical role for innate immune signaling in mitochondrial health.

Disclosure
E. Levi D Ancona: None. J. Zhu: None. E.M. Walker: None. V. Sidarala: None. S. Soleimanpour: Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd.

Funding
University of Michigan Research Training in Experimental Immunology T32-AI007413 University of Michigan Career Training in the Biology of Aging T32-AG000114
305-OR: Adipose Tissue Perilipin 1 Insulin Responsiveness in Obesity
Authors: LYTLE KELLI , SONG YILIN , DAMLA KARAKAPLAN NESRIN , JENSEN MICHAEL D. 
Published: June 2024

Adipose tissue (AT) lipolysis is dysregulated in obesity and type 2 diabetes, failing to respond appropriately to the lipolytic suppressive effects of insulin resulting in high free fatty acid (FFA) efflux from AT. Perilipin 1 (PLIN1) is an intracellular adipocyte protein and the primary lipid droplet coat protein. Phosphorylation of PLIN1 is purported to activate and provide access to the lipid droplet surface for lipolytic enzymes. Conversely, dephosphorylation in response to insulin protects the lipid droplet. To test the hypothesis that PLIN1 phosphorylation status is dysregulated in obesity, we recruited 8 lean and 20 volunteers with obesity who underwent a two-step hyperinsulinemic-euglycemic clamp with a [U-13C]-palmitate tracer to quantify FFA kinetics and their AT response to insulin with regards to FFA release (IC50 FFA), we performed abdominal (UBSQ) and thigh subcutaneous adipose tissue biopsies at baseline and at each clamp step. We measured adipocyte cell size, total PLIN1 protein concentrations and phospho-PLIN1-Ser522 in adipose samples. Intra-individual total PLIN1 protein content/1000 adipocytes did not change in either thigh or UBSQ at either baseline or during each clamp step. Total PLIN1/1000 cells was positively correlated with adipocyte size in UBSQ (ρ = 0.85, p &lt;0.001) and thigh (ρ = 0.86, p &lt;0.001). There was a step wise reduction in PLIN Phosphorylation in both depots in response to each insulin clamp step from baseline (UBSQ and thigh, baseline vs. 1st step clamp vs. 2nd step clamp, all p &lt; 0.01) There was no difference between the ratio of phosphorylated PLIN to total PLIN (pPLIN/PLIN) between UBSQ and thigh samples. IC50 FFA was correlated Total PLIN1/1000 cells in UBSQ (ρ = 0.46, p = 0.02), but not in thigh adipose. After correcting for adipocyte size, the relationship between IC50 FFA and Total PLIN1 was no longer significant.
In conclusion, PLIN1 content or responsiveness doesn’t appear to be defective in adults with obesity that have reduced ability of insulin to suppress systemic FFA release.

Disclosure
K. Lytle: None. Y. Song: None. N. Karakaplan: None. M.D. Jensen: Advisory Panel; Biohaven.
306-OR: Diet-Induced Hyperlipidation of Adiponectin Contributes to Adiponectin Dysfunction
Authors: SMITH MAIA , HADLEY JASON , RYU JIYOON , MORALES DESIRAE , DONG LILY Q. 
Published: June 2024

With the noteworthy linear rise in the prevalence of obesity in the United States, adiponectin has swiftly garnered attention as a hormone protein of interest owing to its anti-diabetic, anti-insulin-resistant, and anti-inflammatory properties. Protein S-palmitoylation is a post-translational modification that has been implicated in a wide variety of diseases including cancer, neurodegenerative disorders, and metabolic disorders, supporting its critical role in regulating protein transport, localization, and cell survivability. As serum Adiponectin exists as multimers, the distribution of which differs under disease pathology and by sex, our current study seeks to elucidate the underlying mechanism regulating adiponectin’s cellular localization, function, and stability. Utilizing acyl resin-assisted capture, our current study indicates that Adiponectin undergoes protein S-palmitoylation. Intriguingly, male mice fed a high-fat diet (HFD) exhibited an 18-fold increase in protein S-palmitoylation in their adipose tissue compared to normal chow (NC) diet-fed controls. However, no significant difference was observed in the levels of adiponectin palmitoylation between female mice on HFD compared to NC controls. Similarly, palmitoylation of adiponectin was observed in the adipose tissues of men with a BMI classified as obese and the modification was undetected in lean individuals. Collectively, our findings suggest that adiponectin undergoes protein S-palmitoylation and that this modification is associated with obesity in males. Identifying protein S-palmitoylation of adiponectin as a post-translational modification and a key regulatory mechanism in the expression and function of this beneficial hormone could unveil a novel mechanism contributing to the obesity-induced down-regulation of adiponectin - a causal factor for insulin resistance and related metabolic disorders.

Disclosure
M. Smith: None. J. Hadley: None. J. Ryu: None. D. Morales: None. L.Q. Dong: None.

Funding
National Institutes of Health (R01DK134637-01A1)
316-OR: Interoception Predicts Impaired Awareness of Hypoglycemia (IAH) in Adults with Type 1 Diabetes (T1D)
Authors: MATUS AUSTIN M. , RIEGEL BARBARA , RICKELS MICHAEL R. 
Published: June 2024

Introduction: Recurrent hypoglycemia attenuates hypoglycemia symptoms, making symptom detection more challenging and leading to IAH. However, some with T1D maintain hypoglycemia awareness despite symptom attenuation. Interoception, or the ability to sense, interpret, and integrate internal somatic signals, may contribute to maintenance of hypoglycemia awareness. We sought to assess the association between interoception and IAH in adults with T1D.
Methods: Adults (n = 154, 20% Black, 64% female) with T1D (mean ±SD age: 40 ±16 years, T1D duration: 23 ±14 years) completed the Clarke questionnaire (8-items scored 0-7; ≥ 4 indicates IAH), Gold Score (1 item scored 0-7; ≥ 4 indicates IAH), HypoA-Q Impaired Awareness scale (5-items scored 0-20; ≥ 12 indicates IAH) and Multidimensional Assessment of Interoceptive Awareness Version 2 (MAIA-2; 8 scales measuring 5 dimensions of body awareness; each scale scored 0-5; higher indicates greater interoceptive awareness). IAH was defined as ≥ 2 positive IAH measures. Logistic regression was performed, and odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association between MAIA-2 scales and IAH controlling for disease duration, age, and recurrent severe hypoglycemia.
Results: Seventeen percent of participants (n = 26) screened positive for IAH. Logistic regression revealed significant relationships between IAH and disease duration, recurrent severe hypoglycemia, and 2 MAIA-2 scales (“Attention Regulation” & “Not Worrying”). Each 1-point increase in “Attention Regulation” was associated with 72% decreased odds of IAH (OR: 0.28, CI: 0.12 - 0.66). Each 1-point increase in “Not Worrying” was associated with 87% increased odds of IAH (OR: 1.87, CI: 1.01 - 3.46).
Conclusion: Those with T1D and IAH may have reduced ability to sustain and control attention to body sensations and less worry with sensations of discomfort. Research to better understand the relationship between interoception and IAH is warranted.

Disclosure
A.M. Matus: None. B. Riegel: None. M.R. Rickels: Consultant; Vertex Pharmaceuticals Incorporated, Sernova, Corp. Research Support; Dompé.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK135120)National Institute of Nursing Research (F31NR020137)
330-OR: Narrow Variation of Glucose Inflection Points (IPs) during Progression to Type 1 Diabetes (T1D) Stratified by Demographic and Genetic Differences in Autoantibody-Positive (Ab+) Individuals
Authors: ISMAIL HEBA M. , CUTHBERTSON DAVID D. , JACOBSEN LAURA M. , NATHAN BRANDON M. , SIMS EMILY K. , REDONDO MARIA J. , SOSENKO JAY 
Published: June 2024

Introduction and Objective: Evidence suggests an IP occurs 1 to 2 years before the diagnosis of T1D, after which accelerated metabolic decline occurs. We assessed whether IPs vary when stratified by age, obesity, sex, and presence of both HLA DR3 and DR4 vs. neither.
Methods: TrialNet Pathway to Prevention Ab+ participants (n=596) who had OGTTs between 0.5 years and 3 years before diagnosis were studied. Mixed-effects modeling was used to estimate AUC glucose and AUC C-peptide IPs with 95% confidence intervals (CIs), and to compare IP times before diagnosis. Since AUC C-peptide IPs had wide CIs, only AUC glucose IPs are shown.
Results: The overall AUC glucose IP was 1.39 years before diagnosis. Those older or obese had IPs significantly earlier; however, the difference by age groups was only ~0.2 years and that by obesity 0.1 year (table). The difference between those positive for both DR3 and DR4 was small while males and females did not differ. IPs were consistently within 1.3 and 1.5 years before diagnosis.
Conclusion: Older and more obese individuals have earlier AUC glucose IPs prior to diagnosis. However, the timing of the IPs differs only by a few months between populations that have demographic or genetic differences. This suggests common pathologic progression patterns to T1D despite variations in characteristics.

Disclosure
H.M. Ismail: Consultant; Sanofi, Rise Therapeutics. D.D. Cuthbertson: None. L.M. Jacobsen: Advisory Panel; Insulet Corporation. B.M. Nathan: None. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI. M.J. Redondo: None. J. Sosenko: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
331-OR: Clinical and Immunologic Features Differ in Children at Type 1 Diabetes Onset by Ethnicity
Authors: KARAKUS KAGAN E. , FLEURY THEODORE , BASCHAL ERIN E. , MCDANIEL KRISTEN , CHOI HYELIN , LANGARICA VANESSA , YU LIPING , SIMMONS KIMBER M. , MICHELS AARON W. 
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) incidence continues to increase in children, especially among Hispanic Whites (HW). We investigated the clinical and immunologic characteristics of HW and Non-Hispanic White (NHW) children that presented at T1D diagnosis over the last two decades to the Barbara Davis Center for Diabetes.
Methods: In this single-center, observational study, children who were diagnosed with T1D (&lt;u&gt;&lt;&lt;/u&gt;20 years old) and tested for islet autoantibodies within 1 year of diagnosis were included and divided into two groups by ethnicity.
Results: Of 1256 children, 401 HW children presented with a younger age at T1D onset, and more DKA compared to NHW children (n=855) (Table 1). There was no difference in sex, HbA1c levels, or the number and prevalence of islet autoantibodies between the two cohorts. A subset of our cohort was HLA-DR-DQ typed as specific alleles confer strong genetic risk for T1D (e.g., HLA-DR4 and DQ8). Among 556 HLA-typed children, HW children had a significantly higher prevalence of the DR4-DQ8 haplotype compared to NHW children (75.8% vs. 59.0%, p=0.002). Moreover, DR3-DQ2 was lower in HW compared to NHW T1D children (29.8% vs. 47.1%, p=0.001).
Conclusion: Hispanic White children developing T1D have a strikingly high prevalence of HLA DR4-DQ8, which can be utilized in screening for T1D risk to lessen DKA and potentially prevent diabetes onset.

Disclosure
K.E. Karakus: None. T. Fleury: None. E.E. Baschal: None. K. McDaniel: None. H. Choi: None. V. Langarica: None. L. Yu: None. K.M. Simmons: Advisory Panel; Provention Bio, Inc. Consultant; Provention Bio, Inc. Research Support; Provention Bio, Inc., Novartis AG. Consultant; Medtronic. A.W. Michels: Stock/Shareholder; IM Therapeutics. Advisory Panel; Provention Bio, Inc.
352-OR: Selective Loss of the Spliced Form of Xbp1 Causes Early-Onset Diabetes in Male but Not Female Mice
Authors: FU LING , JANG CHELSEA , PENG YUNQIAN , XIONG QIUTANG , WANG ZHAO V. , DENG YINGFENG 
Published: June 2024

Endoplasmic reticulum (ER) stress is associated with progressive deterioration in pancreatic islet beta cell function, a hallmark of type 2 diabetes. Adaptive unfolded protein response (UPR) is critical for mature beta cells to resolve ER stress due to aging and obesity. X-box binding protein 1 (Xbp1) is an essential, evolutionarily conserved transducer of the UPR. In response to ER stress, the full-length Xbp1 mRNA undergoes noncanonical splicing catalyzed by Ire1, which leads to a frame-shift and the generation of spliced Xbp1 (Xbp1s), a potent transcription factor. Recently, Xbp1 expression was shown to be increased in less mature beta cells from young individuals (&lt;30 y) compared to beta cells from middle-aged adults (30-59 y). The physiological relevance of Xbp1s activation in the early development of the pancreas remains elusive due to the lack of a proper in vivo model; the constitutive Xbp1 KO model is embryonic lethal in rodents, whereas the Cre-loxP-mediated tissue selective Xbp1 KO model ablates both full-length and spliced-form of Xbp1. To fulfill the knowledge gap, we generated a knock-in mutant form of Xbp1 to ablate only the spliced form of Xbp1. We found that homozygous Xbp1s KO mice are born at a rate below the Mendelian ratio, indicating that selective loss of Xbp1s is not developmentally lethal in mammals despite lowering the rate of live births. Strikingly, Xbp1s ablation leads to abnormal islet architecture in both males and females, but only male mice exhibit hyperglycemia and glucose intolerance due to insulin insufficiency. The female Xbp1s KO mice maintain normoglycemia and glucose tolerance due to enhanced insulin sensitivity. Our findings suggest that Xbp1s is essential for the early development of pancreatic islets and beta cell mass, and there are sex-specific mechanisms contributing to adulthood diabetes under Xbp1s deficiency.

Disclosure
L. Fu: None. C. Jang: None. Y. Peng: None. Q. Xiong: None. Z.V. Wang: None. Y. Deng: None.

Funding
American Diabetes Association (1-19-JDF-082)