bluuebunny/crossref_metadata_2025_split huggingface dataset:
1517-P: Rev-Erba as an Intermediate between Regulation of Circadian Rhythm and Skeletal Muscle Insulin Sensitivity
Authors: MUÑOZ VITOR R. , PINTO ANA PAULA S.R. , LINO MARSEL , SILVA ADELINO S.R. , RONALD KAHN C. 
Published: June 2024

Rev-Erbα is a nuclear receptor involved in the control of circadian rhythm and regulates the transcription of many metabolic genes. Skeletal muscle is responsible for &gt;75% of postprandial glucose uptake, and this is significantly reduced in insulin-resistant and type 2 diabetic (T2D) individuals. To determine the potential role of Rev-Erbα in muscle in T2D, we have used human induced pluripotent stem cells (iPSCs) from control and T2D patients differentiated into myoblasts (iMyos) to study its role in insulin action and metabolism in the absence of confounding circulating factors. We find that iMyos from T2D donors have a 25% decrease (p=0.005) in the Rev-Erbα mRNA expression, and this is paralleled by a 35% decrease (p=0.03) in Rev-Erbα protein. This is also accompanied by significant 22-45% reductions in insulin-stimulated phosphorylation of pIRβY1146, pIRS1Y895, pAktS473, pGSK3βS9, and an ~30% decrease in insulin-stimulated glucose uptake. Treatment of T2D iMyos with a Rev-Erbα agonist rescues the impaired glucose uptake in the T2D cells to control levels. CRISPR/Cas9 knockout of Rev-Erbα in murine C2C12 muscle cells results in reduced insulin-stimulated insulin signaling and glucose uptake, paralleling the defects observed in the human T2D iMyos. RNAseq analysis of these knockout cells revealed changes in expression of genes associated with insulin action, including downregulation of Irs2, Gab1, and Shc2. Combining these data with Rev-Erbα ChipSeq data identified 150 genes in the Rev-Erbα-/- cells that are directly targeted and repressed by Rev-Erbα via its binding in the promoter region. These genes are enriched in pathways related to mitochondria physiology and insulin resistance. Taken together, these data demonstrate that Rev-Erbα provides cross-talk between circadian regulation and metabolism by acting as a positive regulator of insulin sensitivity, glucose uptake and mitochondrial function, and this process is attenuated in skeletal muscle in human T2D.

Disclosure
V.R. Muñoz: None. A.S.R. Pinto: None. M. Lino: None. A.S.R. Silva: None. C. Kahn: Consultant; Cellarity. Other Relationship; 1825 Therapeutics. Advisory Panel; TIXiMED, Senseion, ERX.
1549-P: Hyperamylinemia and Its Implications on Brain Function—Amylin Deposition and Cognitive Alterations—A Cross-Sectional Study
Authors: CHOUDHARY BINOD K. , KHAN KAMRAN , KUMAR SANJAY , SHARMA HEM S. 
Published: June 2024

Introduction: Hyperamylinemia, a condition characterized by elevated levels of amylin, may contribute to amyloid deposition in the brain, akin to the amyloid plaques observed in Alzheimer's disease. This cross-sectional study explores the relationship between hyperamylinemia, amylin deposition in the brain, and subsequent effects on brain function.
Methodology: In this cross-sectional study, 120 subjects were divided into normoamylinemic (n=60) and hyperamylinemic (n=60) groups based on serum amylin levels. Participants received clinical evaluations, cognitive tests, and brain imaging. Brain tissues from deceased hyperamylinemic subjects were examined for amylin deposits. Statistical methods, including logistic regression and correlation matrices, analyzed the link between amylin levels, brain deposits, and cognitive function.
Results: The hyperamylinemic group showed 45% more amylin deposition in memory-related brain regions than the normoamylinemic group (p&lt;0.01). Cognitive scores were 30% lower in hyperamylinemics, correlating with their amylin levels (p&lt;0.05). Amylin aggregates were found in 80% of hyperamylinemic subjects. A strong correlation (r=0.78, p&lt;0.001) was observed between hyperamylinemia, amylin brain deposits, and reduced cognitive performance.
Conclusion: Hyperamylinemia is linked to amylin accumulation in the brain and cognitive impairment, suggesting its role as a risk factor for Alzheimer's-like neurodegenerative conditions. Exploring amylin's brain functions may reveal new treatments for these diseases. Future studies are needed to clarify these mechanisms and relationships.

Disclosure
B.K. Choudhary: None. K. Khan: None. S. Kumar: None. H.S. Sharma: None.
1553-P: Estimated Beta-Cell Function and BMI Do Not Explain Racial/Ethnic Differences in Diabetes Incidence in People with Prediabetes
Authors: VAZQUEZ ARREOLA ELSA , HANSON ROBERT L. , KNOWLER WILLIAM C. 
Published: June 2024

Introduction & Objectives: All Diabetes Prevention Program (DPP) participants had prediabetes and received the same interventions (lifestyle, metformin, or placebo), but racial/ethnic differences in diabetes incidence emerged in follow-up, which we try to explain by differences in beta-cell function.
Methods: In 1671 self-identified white (W), 618 black (B), and 487 Hispanic (H) participants in DPP repository data, we analyzed insulin sensitivity index (ISI) and response to oral glucose (30-minute corrected insulin response, CIR) during 17 years of follow-up.
Results: Incidence was 7.5 cases/100 person-years in B, 6.0 in H, and 5.4 in W. B and H had higher rates than W, adjusted for age, sex, and intervention (B: HR=1.35, 95%CI=1.19-1.53; H: HR=1.07, 0.93-1.24) and when further adjusted for BMI, ISI, and CIR (B: HR=1.48, 1.30-1.68; H: HR=1.15, 0.99-1.33). Lower baseline BMI and higher ISI and CIR were protective but did not explain the race/ethnicity effects. Longitudinal relationships of ISI and CIR differed by race/ethnicity (Figure); paradoxically B had the highest CIR which would predict lower diabetes incidence.
Conclusion: Higher diabetes incidence in B was not explained by differences in BMI or beta-cell function. We hypothesize that B with prediabetes compensate for other, unknown, risk factors by increasing CIR which, in many, is insufficient to prevent diabetes.

Disclosure
E. Vazquez Arreola: None. R.L. Hanson: None. W.C. Knowler: None.

Funding
Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases
1560-P: Inflammation in the Exocrine Pancreas Impairs Insulin Secretion
Authors: STEIGER LAURA , MEIER DANIEL T. , RACHID LEILA , MEREAU HELENE , DONATH MARC Y. , DE BAAT AXEL , BOENI-SCHNETZLER MARIANNE 
Published: June 2024

Introduction: In patients with type 2 diabetes, increasing evidence points to pathological changes not only in the endocrine but also in the exocrine pancreas. In particular, the number of immune cells is increased in both compartments. Furthermore, patients with chronic pancreatitis, a form of exocrine inflammation, have an increased risk to develop diabetes. However, the causal relationship between exocrine pathologies and impaired endocrine insulin secretion is unknown.
Methods: We established a mouse model of chronic pancreatitis using caerulein injections, thereby stimulating digestive enzymes secretion in exocrine cells. Over 3 weeks, wild-type mice underwent treatment combined with a high-fat diet to induce insulin resistance. To avoid body weight differences due to the anorexic effect of caerulein, saline-treated control mice were pair-fed. We evaluated insulin secretion and glucose metabolism by in vivo glucose tolerance testing and assessing ex vivo glucose-stimulated insulin secretion in isolated islets. Pancreata were immunohistochemically evaluated and transcriptional changes in islets were studied using RNA sequencing.
Results: Chronic pancreatitis in caerulein-treated mice was confirmed by elevated immune cells in the exocrine pancreas, whereas no increase in immune cells was observed in islets. Functionally, mice with chronic pancreatitis had severely impaired insulin secretion and resulted in hyperglycemia compared to the saline-treated control mice. Islets isolated from caerulein-treated mice showed reduced glucose-stimulated insulin secretion. Surprisingly, despite exocrine tissue destruction and reduced exocrine tissue mass, β-cell mass was not reduced. Further, differentially expressed genes were not associated with β-cell signatures but with extracellular matrix components.
Conclusion: Impaired insulin secretion in chronic pancreatitis may be due to alterations in the extracellular matrix components of the islets rather than to destruction of β-cells.

Disclosure
L. Steiger: None. D.T. Meier: None. L. Rachid: None. H. Mereau: None. M.Y. Donath: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim, Olatec. A. de Baat: None. M. Boeni-Schnetzler: None.

Funding
Swiss National Science Foundation ( 320030_214900)
1607-P: Estimation of Muscle and Hepatic Insulin Sensitivity in Type 1 Diabetes Adults Using Clinical and Research Biomarkers
Authors: JANUSZEWSKI ANDRZEJ S. , SNAITH JENNIFER R. , KOWALSKI GREG M. , BRUCE CLINTON , HOLMES-WALKER JANE , JENKINS ALICIA , GREENFIELD JERRY 
Published: June 2024

Background and Aims: Impaired insulin sensitivity in type 1 diabetes (T1D) is an under-appreciated cardiovascular risk factor yet is challenging to measure. Euglycemic hyperinsulinemic clamps are the “gold standard” for quantifying insulin sensitivity. Adding stable isotope-labeled glucose allows for differentiation of hepatic and muscle insulin sensitivity (assessed by endogenous glucose production [EGP] and glucose infusion rate [GIR] respectively). Non-invasive estimation of both EGP and GIR using biomarkers has not been previously assessed in T1D.
Methods: Two-step clamps were conducted in 40 adults with T1D in the INTIMET trial (INsulin resistance in Type 1 diabetes managed with METformin, ACTRN12619001440112). Subjects were characterized with 33 clinical and research biomarkers. Exhaustive search (XLStat, Lumivero, Denver, CO) was used to derive equations correlating with baseline clamp-quantified EGP and GIR.
Results: Exhaustive search analyses derived a formula predicting unfavorable GIR (dichotomous variable: below median of 60.4 µmol/kgFFM/min) using: total daily insulin dose (TDI), fasting triglycerides (TG), insulin-like growth factor-1 and aspartate aminotransferase (AST) levels, with an AUROC of 0.97, p&lt;0.0001, R2 (Nagelkerke)=0.78, 92.5% accuracy. A model predicting unfavorable EGP level (above median of 6.2 µmol/kgFFM/min) contained four variables: TDI, TG, alkaline phosphatase and uric acid levels, with an AUROC of 0.86, p=0.001, R2 (Nagelkerke) of 0.47, 80% accuracy. Our free online calculator (available at https://bit.ly/EGP-GIR-calculator) enables estimation of GIR and EGP by these binary categories.
Conclusions: Tissue specific estimation of insulin sensitivity is feasible in T1D using clinical and research biomarkers. Incorporating estimates of hepatic and muscle insulin sensitivity in clinical trials may predict response to lifestyle and drug interventions. Validation studies are merited.

Disclosure
A.S. Januszewski: None. J.R. Snaith: None. G.M. Kowalski: None. C. Bruce: None. J. Holmes-Walker: None. A. Jenkins: Research Support; Abbott, Viatris Inc. Advisory Panel; Abbott. Research Support; Medtronic. Board Member; Insulin for Life. Research Support; Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), Jaeb Center for Health Research, National Institutes of Health, National Health and Medical Research Council Australia. J. Greenfield: Other Relationship; Novo Nordisk.
161-OR: Type A Insulin Resistance Can Be Misdiagnosed as Type 1 or Type 2 Diabetes—A Cautionary Tale
Authors: WIRTHWEIN KACI , LOS EVAN A. 
Published: June 2024

We present the case of a 19-year-old male presumed to have type 1 diabetes diagnosed at age 14. He was treated as such until requiring escalating doses of insulin and metformin. He was then lost to follow-up and after self-discontinuing insulin for approximately 1 year, he re-presented with hyperglycemia, the absence of ketonuria or acidosis, and elevated insulin level without use of exogenous insulin. Subsequent genetic testing revealed a mutation in the insulin receptor gene (INSR) consistent with type A insulin resistance. We then contrast the case of his 15-year-old maternal half-brother who has an identical gene mutation. However, this second patient was independently evaluated and diagnosed at age 9 with type 2 diabetes. He presented with significantly elevated BMI, acanthosis nigricans, as well as suboptimal diet and exercise habits. He required escalation of type 2 diabetes treatment to achieve effective glucose control and management of obesity. The case of a half-brother pair with essentially opposite presentations of the same genetic mutation consistent with type A insulin resistance has never been described in the literature.

Disclosure
K. Wirthwein: None. E.A. Los: None.
1611-P: vPIVOT MRI as a Novel Strategy to Assess Vascular Function in COVID and Type 2 Diabetes
Authors: ENGLUND ERIN , BARKER ALEX J. , MEDRANO GABRIEL I. , CREE-GREEN MELANIE , MAICKI RICHARD , DOUGLAS IVOR S. , REUSCH JANE E.B. 
Published: June 2024

Introduction & Objective: Diabetes and SARS-CoV-2 target the endothelium, causing microvascular dysfunction. We present a novel test to measure recovery dynamics of blood flow post-isometric exercise in the leg. We hypothesized that T2D related microvascular injury would augment perfusion abnormalities in people with COVID-19.
Methods: 14 hospitalized adults with COVID-19 and acute hypoxemia (7 with DM) underwent vPIVOT MRI on a 3T scanner 1 month post hospitalization. Scans were compared to 4 healthy controls (no DM or severe COVID-19). vPIVOT is an MRI sequence that simultaneously measures micro- and macrovascular blood flow and oxygenation, enabling quantification of integrated peripheral vascular responses to hyperemic stimuli, such as exercise. Here, the perfusion response following a 90s isometric plantar flexion contraction at 70% maximum effort was analyzed.
Results: Quantitative analysis of the MRI data was performed as shown (Figure). Significant between group differences of area under the curve (AUC, p=0.021) and time to recovery (TTR, p=0.024) were observed by ANOVA. Post-hoc comparisons did not detect any significant differences in COVID-19 participants with or without T2DM in this limited sample.
Conclusion: We demonstrate a novel MRI exam can elucidate total perfusion after exercise, and preliminary results show that it is reduced in time and in magnitude for people post severe COVID-19 infection.

Disclosure
E. Englund: None. A.J. Barker: None. G.I. Medrano: None. M. Cree-Green: Consultant; Pollie, Inc. Research Support; Amino Co. R. Maicki: None. I.S. Douglas: None. J.E.B. Reusch: Advisory Panel; Medtronic.

Funding
NIH (R01 DK130351); NIH/NCATS Colorado CTSA (KL2TR002534); American Heart Association (853697)
1621-P: Lower Osteocalcin Levels Are Associated with Abnormal Adipose Tissue Distribution and Higher Cardiovascular Risk in People with Autoimmune Diabetes
Authors: RISI RENATA , AMENDOLARA ROCCO , BALENA ANGELA , MASI DAVIDE , D'ONOFRIO LUCA , WATANABE MIKIKO , GNESSI LUCIO , MADDALONI ERNESTO , BUZZETTI RAFFAELLA 
Published: June 2024

Introduction & Objective: Osteocalcin (OCN) plays a role on adipose tissue (AT) and cardiovascular risk (CVR) in subjects with diabetes. Aim: to evaluate the relation between OCN, AT and CVR in autoimmune diabetes (AD).
Methods: In this cross-sectional study, body composition was evaluated with DXA-scan in subjects with AD. Adipokines (vaspin, leptin, adiponectin) and OCN were measured. CVR was assessed by the Steno T1 risk engine score (ST1RES). Logistic regression was used to determine predictors of medium/high CVR.
Results: Sixty-two patients (median age 49.4 [23-79] years, HbA1c 7.9 [5.7-10.7]%, BMI 25.8[17.2-46.8] Kg/m2) were enrolled. OCN was negatively associated with upper body fat deposition index (UBDFI, p .002 β -.4) and vaspin (p .01, β -.3), positively with adiponectin (p .01 β .3). Patients with lower OCN levels showed higher CVR risk (fig1). A logistic binary regression for including UBFDI, OCN, vaspin, adiponectin as independent variables showed that UBFDI and adiponectin were significant predictors of CVR in AD (R square .356).
Conclusion: The association between OCN and adiposity markers suggests its involvement in AT regulation. Nonetheless, patients with lower OCN levels showed higher CVR, suggesting that OCN might be involved in CVR in AD by regulating AT.

Disclosure
R. Risi: None. R. Amendolara: None. A. Balena: None. D. Masi: None. L. D'Onofrio: None. M. Watanabe: None. L. Gnessi: Consultant; Novo Nordisk. E. Maddaloni: Advisory Panel; Novo Nordisk, Merck Sharp & Dohme Corp. Speaker's Bureau; Abbott, Eli Lilly and Company. Consultant; PikDare. Speaker's Bureau; MTD. R. Buzzetti: Consultant; Abbott, Eli Lilly and Company, Sanofi, Novo Nordisk, AstraZeneca, Boehringer-Ingelheim.

Funding
D3 4 Health—Digital Driven Diagnostics, Prognostics and Therapeutics for Sustainable Health Care (PNC0000001)
1625-P: GS-4571, an Oral Small Molecule GLP-1R Agonist, Improves Glucose Tolerance and Suppresses Food Intake in Obese Diabetic Cynomolgus Monkeys
Authors: VOGEL JEN , SEUNG MINJI , MARCHAND BRUNO , BHANGRE NEERAJA , MUKHERJEE JIT , AMMANN STEPHEN E. , ARMSTRONG MEGAN , BRIZGYS GEDIMINAS , CHIN ELBERT , CHOU CHIEN-HUNG , COTTELL JEROMY , SCHROEDER SCOTT D. , THOMAS-TRAN RHIANNON , YANG ZHENG-YU , PETERS MICHAEL , BUDAS GRANT , MITCHELL MICHAEL L. , CHOJNACKA MAJA , JERMAIN SCOTT , HUNG JOEY , KULKARNI SUPRIYA , YUE QIN , LIN DAVID W. , MIRANDA DIEGO A. 
Published: June 2024

The Glucagon-like peptide 1 receptor (GLP-1R) is a class B1 G-protein-coupled receptor (GPCR) that is widely expressed and helps mediate insulin secretion, gastric emptying, and satiety. Currently, GLP-1R peptide agonists are used as standard of care for the treatment of T2DM and more recently for obesity. These GLP-1R peptide agonists require frequent subcutaneous injections or strict dosing guidelines thus increasing the need to develop an oral small-molecule GLP-1R agonist. Here we describe the identification of a novel small molecule GLP-1R agonist (GS-4571) which stimulated a potent cAMP response in pancreatic β-cells (EndoC-BH1) and selective agonism against human and monkey GLP-1R versus other class B GPCRs. In an intraperitoneal glucose tolerance test (IPGTT) it demonstrated improved glucose tolerance in humanized GLP-1R mice. Further studies, in obese cynomolgus monkeys, GS-4571 demonstrated similar improvements in glucose tolerance after a single dose treatment. Once-daily oral administration of GS-4571 in obese diabetic cynomolgus monkeys not only showed improved glycemic control but also showed a reduction in energy intake which led to an increase in weight loss over 36 days. Together these data support the continued development of GS-4571 into the clinic as a novel orally bioavailable GLP-1R small molecule agonist.

Disclosure
J. Vogel: None. M. Seung: None. B. Marchand: Employee; Gilead Sciences, Inc. Stock/Shareholder; Gilead Sciences, Inc., Pfizer Inc., Arrowhead Pharmaceuticals, Inc., Kronos Bio, Inc., Allogene Therapeutics, Inc., AbCellera Biologics Inc., Arbutus Biopharma Corporation. N. Bhangre: Employee; Gilead Sciences, Inc. Research Support; Gilead Sciences, Inc. Stock/Shareholder; Gilead Sciences, Inc. J. Mukherjee: None. S.E. Ammann: Employee; Gilead Sciences, Inc. M. Armstrong: Employee; Gilead Sciences, Inc. G. Brizgys: Employee; Gilead Sciences, Inc. E. Chin: Employee; Gilead Sciences, Inc. C. Chou: None. J. Cottell: Employee; Gilead Sciences, Inc. S.D. Schroeder: Employee; Gilead Sciences, Inc. R. Thomas-Tran: Employee; Gilead Sciences, Inc. Z. Yang: None. M. Peters: Employee; Gilead Sciences, Inc. G. Budas: Employee; Gilead Sciences, Inc. M.L. Mitchell: Employee; Gilead Sciences, Inc. M. Chojnacka: None. S. Jermain: None. J. Hung: Employee; Gilead Sciences, Inc. S. Kulkarni: None. Q. Yue: None. D.W. Lin: Employee; Gilead Sciences, Inc. D.A. Miranda: None.
163-OR: RNAseq Analysis Reveals Temporal Dynamics of Colonic Immune Response to High-Fat Diet in Mice
Authors: KELLER LENA , BOSCH ANGELA J. , LOW ANDY J.Y. , CAVELTI-WEDER CLAUDIA 
Published: June 2024

Introduction & Objective: We previously showed that 1 week of high-fat diet (HFD) increases pro-inflammatory colonic macrophages (Mϕ) and that their depletion was associated with improved glycemic control. The current study aimed to elucidate the temporal changes of gene expression of intestinal immune cells in mice fed a HFD compared to chow.
Methods: Male C57BL/6N mice were fed either a HFD or chow for 1 week or 3 months. GTTs assessed the metabolic status. Colon CD45+ cells were isolated, subjected to single-cell RNA sequencing (analyzed by the Bioinformatics Core Facility), and used for flow cytometry analysis. Rectal inhibition of the cGAS-STING pathway was performed using H-151 (STING inhibitor). To compare chow with HFD, an unpaired Mann-Whitney U test with a two-sided distribution was done.
Results: After 1 week of HFD, glucose tolerance was impaired, and pro-inflammatory Mϕ of the colon increased, which were no longer elevated after 3 months of HFD. ScRNA-seq revealed an early increase in T-cells, which remained after 3 months, while B cells were only increased and activated after 3 months of HFD. Enrichment analysis showed an increased IFN-γ and IFN-α response in monocytes (Mono) and Mϕ after 1 week of HFD, while after 3 months EMT and ROS pathways were downregulated. Pseudo-bulk RNA-seq unveiled an upregulation of the cGAS-STING pathway within Mono and Mϕ after 1 week of HFD, which was no longer present after 3 months. Local STING inhibition for 1 week led to improved glucose tolerance and downregulation of IFN-α gene expression in the colon but did not protect against the increase of inflammatory Mϕ upon HFD.
Conclusion: 1 week of HFD resulted in profound changes in the immune cell landscape of the colon with an early innate and late adaptive immune response upon HFD feeding. The cGAS-STING pathway was upregulated early after initiation of the HFD, suggesting its initiating role in the disease. Indeed, interfering with the cGAS-STING pathway led to improved glycemia in HFD-fed mice.

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

Funding
The Swiss National Science Foundation (SNSF) Grant number 32003B_204937 / 2