bluuebunny/crossref_metadata_2025_split huggingface dataset:
180-OR: Empagliflozin Does Not Affect Pancreatic Fat Content and Insulin Secretion in Humans with Prediabetes
Authors: HUMMEL JULIA , MACHANN JÜRGEN , DANNECKER CORINNA , KULLMANN STEPHANIE , BIRKENFELD ANDREAS L. , HÄRING HANS-ULRICH , PETER ANDREAS , FRITSCHE ANDREAS , WAGNER ROBERT , HENI MARTIN 
Published: May 2022

Introduction: Pancreatic fat accumulation is a potential pathogenic factor in type 2 diabetes. Evidence from hypocaloric diet indicates that reduction of pancreatic fat could contribute to an improvement in ß-cell function. There is no established pharmacological approach to reduce pancreatic steatosis. We now tested the ability of empagliflozin to reduce pancreatic fat content in overweight and obese persons with prediabetes.
Methods: In this double-blind, placebo-controlled randomized trial (NCT03227484) , 40 participants were 1:1 randomized to receive 25 mg empagliflozin qd or placebo for 8 weeks. Pancreatic fat was quantified by magnetic resonance imaging (6-point Dixon technique) . Insulin sensitivity and insulin secretion was estimated from 75g oral glucose tolerance test. The study was adequately powered to detect effects on pancreatic fat previously reported from the DiRECT trial.
Results: There was no significant change in pancreatic fat content in either treatment group (empagliflozin group -0.88 % ± 2.71 %, placebo group 0.22 % ± 3.02 % [mean±SD], both p≥0.2) and the course of pancreatic fat content was comparable between treatments (p=0.2) . Insulin secretion, as assessed by Disposition Index and AUC-C-peptide0-30/AUC-glucose0-30 (adjusted for insulin sensitivity) did not differ between treatments (p=0.3 and p=0.7, respectively) .
Discussion: This randomized, controlled trial did not detect effects of empagliflozin on pancreatic fat content and insulin secretion in persons with prediabetes. This implicates that the beneficial effects of empagliflozin on liver fat and systemic glucose metabolism do not rely on alterations in pancreatic fat. Consequently, further options for pancreatic fat reduction need to be evaluated.

Disclosure
J.Hummel: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. J.Machann: None. C.Dannecker: None. S.Kullmann: Other Relationship; Novo Nordisk. A.L.Birkenfeld: None. H.Häring: None. A.Peter: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH.

Funding
This study was supported by Boehringer Ingelheim through an Independent Research Grant. Boehringer Ingelheim had role in the study design, in the collection, analysis or interpretation of data, or in writing of this abstract.
19-LB: The Impact of Diabetes on 30-Day Readmission, In-Hospital Mortality, and Medical Cost in ST-Segment Elevation Myocardial Infarction after Primary Percutaneous Coronary Intervention—A Nationwide Readmissions Database Analysis
Authors: KANG YU MI , JANG SUN-JOO 
Published: May 2022

Background: ST-elevation myocardial infarction (STEMI) poses significant morbidity, mortality and economic burden in people with diabetes. We sought to determine the impact of diabetes on the short-term outcome and hospital costs post-percutaneous coronary intervention (PCI) for STEMI.
Methods: STEMI hospitalizations were selected in the Nationwide Readmissions Database from 2010 to 2014. From the patients who underwent PCI, we examined the 30-day readmission, in-hospital mortality, and total cost according to the presence of diabetes, prior stroke, and prior MI. All statistical analyses were performed using R statistical software version 4.1.2.
Results: Among 539,171 index STEMI hospitalizations for primary PCI, 10.1% were readmitted within 30 days and 4.6% died in hospital. The readmission rates were 10.2%, 12.9%, 14.4%, 17.5%, and 18.4% in the reference (i.e., no diabetes, prior MI or stroke) , diabetes-only, diabetes and MI, diabetes and stroke, diabetes, MI, and stroke groups, respectively (P&lt;0.001) . The corresponding adjusted hazard ratios for 30-day readmission were 1.14 (95% CI 1.10-1.18) , 1.23 (1.12-1.35) , 1.24 (1.10-1.39) , and 1.29 (0.99-1.68) . In-hospital mortality rates during index hospitalization were 4.3%, 5.3%, 5.5%, 7.2%, and 7.4% in the reference, diabetes-only, diabetes and MI, diabetes and stroke, diabetes, MI, and stroke groups, respectively (P&lt;0.001) . The corresponding adjusted odds ratios for mortality were 1.24 (95% CI 1.15-1.33) , 1.55 (1.28-1.87) , 1.51 (1.22-1.87) , and 2.03 (1.27-3.25) . The median overall cost increased by 4.5% and 11.8% in the diabetes-only group and diabetes, MI, and stroke group, respectively, compared with the reference group (P&lt;0.001) .
Conclusion: Within 30 days of PCI for STEMI, diabetes increases readmission rate, in-hospital mortality, and financial burden with and without prior CVD. These findings underscore the importance of aggressive optimization in STEMI patients with diabetes.

Disclosure
Y. Kang: None. S. Jang: None.
19-OR: KidneyIntelX Association with Clinical Outcomes in Diabetic Kidney Disease
Authors: NADKARNI GIRISH N. , TAKALE DIPTI , NEAL BRUCE , MAHAFFEY KENNETH W. , YAVIN YSHAI , HANSEN MICHAEL K. , FLEMING FERGUS , HEERSPINK HIDDO L. , COCA STEVEN 
Published: May 2022

Individuals with diabetic kidney disease (DKD) are at risk for progression, heart failure, and death. We assessed the association of KidneyIntelX, a bioprognostictest validated for DKD progression, with a composite time-to-event endpoint of 57% eGFR decline, kidney failure, heart failure hospitalization (HFH) , or death in a posthoc analysis of a subgroup of CANVAS participants with DKD. sTNFR-1, sTNFR-2, and KIM-1 were measured via proprietary assays, and KidneyIntelX scores were calculated using the existing algorithm. Hazard ratios for high vs. low-risk strata for the composite outcome were adjusted for age, sex, race, treatment arm, baseline CVD, HbA1c, SBP, DBP, LDL, BMI) . During 5.6 years follow-up, 282 (22%) of the 1278 CANVAS participants with DKD experienced the outcome (57% decline in eGFR/ESKD 3%, HFH 6%, death 16%) . The adjusted HR for the composite outcome in KidneyIntelX high-risk group was 2.7 (95% CI 1.9 to 3.8) vs. the low-risk group. Canagliflozin reduced the risk for the composite event vs. placebo, with larger absolute risk reductions for the high-risk stratum (11%) , compared to intermediate (6%) or low-risk strata (4%) (p&lt;0.01) .
In conclusion, KidneyIntelX successfully risk-stratified adults with DKD for clinical outcomes. Absolute risk reductions with canagliflozin were greatest in the high-risk stratum, thereby potentially allowing its use to identify patients most likely to benefit from treatment.

Disclosure
G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; AstraZeneca, Reata Pharmaceuticals, Inc., Renalytix, Siemens, Other Relationship; Renalytix, Stock/Shareholder; Renalytix. D.Takale: None. B.Neal: Other Relationship; Janssen Research & Development, LLC. K.W.Mahaffey: Consultant; Novo Nordisk. Y.Yavin: Employee; Janssen Research & Development, LLC. M.K.Hansen: Employee; Janssen Research & Development, LLC. F.Fleming: Employee; Renalytix. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Coca: Advisory Panel; 3ive Labs, Nuwellis, Reprieve Cardiovascular, Consultant; Axon Therapies, Bayer AG, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Stock/Shareholder; pulseData, Renalytix.

Funding
Renalytix
194-LB: Tacrolimus-Induced Hyperglycemic Emergencies in Posttransplant Patients—A Case Series
Authors: GUPTA SHAVETA , LOVRE DRAGANA , GALAGAN ROBERT 
Published: May 2022

Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits calcineurin and prevents T cell activation. Post-transplantation diabetes mellitus (PTDM) is a well-established adverse effect of tacrolimus. We report the rare occurrences of DKA and hyperosmolar hyperglycemia syndrome respectively in 2 patients on tacrolimus after renal transplants.
Description Case 1: A 25 year old obese (BMI 37.7 kg/m2) black female with no history of DM received a live donor kidney transplant. She was on mycophenolate 720 mg po bid, tacrolimus 7 mg po bid, and prednisone 5 mg daily. Eleven weeks after transplant she presented with polyuria and polydipsia and was admitted for DKA. Labs revealed glucose 1000 mg/dL (74-106) , HCO3 7.0 meq/L (21-32) , beta-hydroxybutyric acid 8.4 mg/dL (0.2 - 2.8) , tacrolimus trough levels 19.6 ng/mL (4.1 - 10.7) . Her A1c was 10.6% compared to 5.3% pre-transplant. Case 2: A 50 year old obese (BMI 35.6 kg/m2) black female with no prior history of DM received a cadaveric kidney transplant due to ESRD. Patient was on mycophenolate 360 mg bid, and tacrolimus 8 mg bid. She was admitted to hospital for HHS 9 weeks later. Labs revealed a glucose 940 mg/dL, serum osmolality 341 msom/kg (275-295) , HCO3 22 mmol/L, tacrolimus trough levels 12.1 ng/mL. Her A1c was 8.7% compared to 5.3% pre-transplant.
Discussion: Our 2 patients with no history of DM developed hyperglycemic emergencies within 3 months of receiving kidney transplants and initiating tacrolimus. Both responded well to IV fluids and insulin and were transitioned to SQ insulin by discharge. Risk factors for post-transplant de novo DKA and HHS common to both patients were African American ethnicity, high BMI, and tacrolimus treatment with elevated trough levels. Tacrolimus inhibits insulin secretion and is linked to increased rates of PTDM, which is often reversible with tacrolimus dosage reduction. Both of our patients were prescribed tacrolimus at reduced dosage and were scheduled for outpatient Endocrine clinic evaluation to determine whether they should continue insulin treatment.

Disclosure
S. Gupta: None. D. Lovre: Other Relationship; AstraZeneca, Bayer AG, Novo Nordisk. R. Galagan: None.
197-LB: Adipocyte ZAG Improves Obesity-Triggered Insulin Resistance by Reshaping Macrophages Populations in Adipose Tissue
Authors: XIAO XINHUA , LIAO ZHEZHEN , WANG YA-DI , QI XIAO-YAN 
Published: May 2022

Adipose tissues macrophages (ATMs) serve as critical effectors in the mediating occurrence of metabolic inflammation to impact whole-body insulin sensitivity in obesity. Discovering the key adipokines mediating crosstalk of adipocyte-macrophage and understanding the molecular mechanism of ATMs polarization and function have become hot topic issues in the immunometabolism fields. Zinc-α2-glycoprotein (ZAG) as an anti-inflammatory adipokines plays important roles in obesity-related metabolic diseases. We attempt to explore the precise role of adipose ZAG in metabolic inflammation and obesity-associated insulin resistance. Here we showed that Omental ZAG was positively associated with insulin sensitivity and M2 macrophages markers. ZAG-specific ablation in adipocyte aggravated insulin resistance and adipose tissues inflammation as evidenced by enhanced M1 macrophages proportion and inhibited AKT signaling pathway in mice fed with a high-fat diet. ZAG overexpression attenuated insulin resistance and accumulation of pro-inflammatory macrophages. Exogenous ZAG inhibits PA-induced M1 macrophage polarization via β3-AR/PKA/STAT3 signaling in RAW264.7 macrophages. These findings suggest that adipocyte ZAG maintains insulin sensitivity via the cross talk with adipose-resident macrophages.
Keywords: ZAG; inflammation; insulin resistance; obesity; adipose tissue macrophages

Disclosure
X. Xiao: None. Z. Liao: None. Y. Wang: None. X. Qi: None.

Funding
National Natural Science Foundation of China (82070873, 82000813) , Natural Science Foundation of Hunan province (2020JJ8097, 2021JJ40496) and Major special projects of Hunan provincial health and family planning commission (A2017011)
198-LB: The Loss of the Lysine Acetyltransferase KAT8 in Adipocytes Confers Lipodystrophy and Metabolic Dysfunction in Male and Female Mice
Authors: RICHARD ALLISON J. , MENDOZA TAMRA M. , STEPHENS JACQUELINE M. 
Published: May 2022

KAT8, also known as MOF or MYST1, is a lysine acetyltransferase with both histone and non-histone substrates. While KAT8 is the major H4K16 acetyltransferase in Drosophila and mammals and is essential for embryonic development, its role in specific cell types is not well understood. Moreover, studies within the past decade have demonstrated lineage-, differentiation state-, or stress-dependent roles of KAT8. Our recent efforts have shown that KAT8 is necessary for in vitro adipogenesis prior to or during the proliferative phase. Notably, several, independent genetic studies reveal that single nucleotide polymorphisms (SNPs) within or near the KAT8 gene are associated with body mass index and/or waist circumference. To investigate the role of KAT8 in differentiated adipocytes and to understand the contribution of KAT8-deficient adipocytes to whole-body glucose and lipid metabolism, we generated both congenital and doxycycline-inducible adipocyte-specific knockout mice, in which Kat8 gene deletion occurs only in adiponectin-expressing cells. Adult mice lacking adipocyte KAT8 exhibited significant fat mass loss with no change in lean mass. While the size of inguinal and brown adipose tissue was significantly reduced in both sexes fed either chow or high-fat, high-sucrose (HFHS) diet, male mice also had decreased gonadal, retroperitoneal, and mesenteric depots. Histological assessments revealed substantial remodeling within adipose tissue depots, and these mice demonstrated reduced insulin sensitivity and increased lipid accumulation in the liver when fed HFHS diet. Although further investigation is necessary to identify KAT8 targets that confer lipodystrophy, these studies are the first to show the impact of the loss of adipocyte KAT8 in vivo.

Disclosure
A. J. Richard: n/a. T. M. Mendoza: None. J. M. Stephens: None.

Funding
National Institutes of Health COBRE P&F grant (P30 GM118430)
199-OR: Exercise Decreases Mouse and Human Islet Senescence through Glucagon-Mediated AMPK Activation
Authors: CARAPETO PRISCILA , KAHNG JIHO , WAGNER ANA BARBARA T. ALVES , MIDDELBEEK ROELAND , HIRSHMAN MICHAEL F. , GOODYEAR LAURIE J. , AGUAYO-MAZZUCATO CRISTINA 
Published: May 2022

Aging is a major risk factor for type 2 diabetes (T2D) and cellular senescence plays a critical role in β-cell dysfunction leading to T2D. Exercise is a central component in the treatment of T2D and has been shown to attenuate many of the biochemical changes that occur with aging including senescence, but nothing is known about the effects of exercise on β-cells and their aging process. To test the hypothesis that exercise decreases β-cell senescence we used two mouse models of insulin resistance: high-fat diet (HFD, 60% kcal from fat, 6 wks) and insulin receptor antagonist S961 (40nM/wk for 2 wks) . Exercise (treadmill, 1 h/day, 5 times/wk for 2 wks at 17 cm/s and 5% incline) prevented entrance of β-cells into senescence and reversed established senescence in both males and females across the lifespan (started at 1.5-9m or 14m old mice) as seen by a decrease in one or several of the following markers: βGal, p21Cip1 and p16Ink4a. This decrease in senescence was accompanied by improved glucose stimulated insulin secretion characterized by recovery of glucose responsiveness in islets from HFD and S961 exercised animals. Islets cultured with serum from trained animals showed decreased p21Cip1 mRNA, indicating a circulatory factor (s) was responsible for these effects. Exercise increased serum glucagon expression, identified as such factor. Incubation of human and mouse islets with glucagon (1nM) decreased p21Cip1 mRNA, and using AMPK agonist (1uM C99) and antagonist (5uM Compound C) , we found that AMPK mediates the glucagon-stimulated decrease in p21Cip1. Human cadaveric donor islets treated with serum obtained before and after 10-weeks of exercise-training in people with T2D demonstrated that training decreased senescence markers through AMPK activation.
In conclusion, exercise has anti-aging effects on mouse and human pancreatic islets by decreasing senescence and improving function. This is a novel mechanism of the effects of exercise on β-cell aging with implications for the treatment of T2D.

Disclosure
P.Carapeto: None. J.Kahng: None. A.T.Alves wagner: None. R.Middelbeek: Research Support; Novo Nordisk. M.F.Hirshman: Stock/Shareholder; Abbott, AbbVie Inc., Amgen Inc., Colgate-Palmolive, Eli Lilly and Company, Medtronic. L.J.Goodyear: None. C.Aguayo-mazzucato: Consultant; eGenesis.

Funding
American Diabetes Association (1-17-PMF-009) ; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001; Short-Term Research Experience for Underrepresented Persons (1R25DK113652) ; NIDDK grant (K23-DK114550) ; NIH grant (R01DK099511) and the Joslin Diabetes Center DRC (P30 DK36836) .
201-LB: Overexpression of GOT1 in Brown Adipose Tissue Enhances Thermogenesis and Glucose Metabolism by Activating the Malate-Aspartate Shuttle
Authors: PARK CHUL-HONG , CHENG HELIA , LEE SANG R. , EILERTSEN KENNETH , SUK CHANG JI 
Published: May 2022

Brown adipose tissue (BAT) is characterized by thermogenic and glucose-consuming properties. BAT takes up large amounts of circulating glucose during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) , but glucose oxidation in mitochondria only modestly contributes as a fuel source for thermogenesis. How glucose metabolism supports thermogenesis is incompletely understood. Here, we identify a novel role of the malate-aspartate shuttle (MAS) in enhancing thermogenesis, glucose uptake and glycolysis in brown adipose tissue. We found that glutamic-oxaloacetic transaminase 1 (GOT1) , a key enzyme of the MAS, exists at very low levels in BAT but is markedly induced by cold or β3AR agonists, while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Enforced expression of Got1 in BAT increased energy expenditure in mice and further enhanced thermogenesis upon cold exposure or β3-adrenergic stimulation. Moreover, mice overexpressing Got1 in BAT exhibited enhanced glucose tolerance. Mechanistically, Got1 overexpression stimulated mitochondrial uncoupled respiration. MAS-driven thermogenesis in turn led to AMPK activation, which likely explains enhanced glucose uptake and glycolysis. Collectively, our data demonstrate a novel GOT1-MAS-AMPK axis that regulates thermogenesis and glucose metabolism in cold-activated BAT.

Disclosure
C. Park: None. H. Cheng: None. S. R. Lee: None. K. Eilertsen: None. J. Chang: None.

Funding
NIH (DK104748, 1P30GM118430, P30DK072476)
201-OR: Evaluation of the Effects of Harmine on ß-Cell Function and Proliferation in Standardized Human Islets Using 3D High-Content Confocal Imaging and Automated Analysis
Authors: TITLE ALEXANDRA C. , KARSAI MARIA , MIR-COLL JOAN , GRINING OZLEM YAVAS , RUFER CHANTAL , SONNTAG SEBASTIAN , FORSCHLER FELIX , JAWUREK SAYRO , KLEIN THOMAS , YESILDAG BURCAK 
Published: May 2022

Restoration of β-cell mass by inducing proliferation of residual β-cells represents an attractive therapeutic approach for diabetes treatment. Native and dispersed primary human islets undergo rapid loss of viability and function ex vivo, complicating their use in proliferation studies. Here, we establish a novel method for evaluating compound effects on β-cell proliferation and count using reaggregated primary human islet microtissues (MTs) , of homogeneous size and architecture and that maintain stable viability and function for 4 weeks in culture. We utilized this platform to evaluate the effects of short- and long-term harmine treatment on β-cell proliferation and function in a dose-dependent manner. Following harmine treatment and EdU incorporation, islet MTs were stained in 3D for DAPI (nuclear marker) , NKX6.1 (β-cell marker) , and EdU (proliferation marker) , imaged on a high-content confocal microscope, and subjected to automated 3D analysis of numbers of total cells, β-cells, and proliferating β- and non-β-cells per islet MT. In parallel, assessment of insulin secretion, intracellular insulin and ATP contents, and Caspase 3/7 activity was performed for a comprehensive overview of islet MT function and viability. We observed that 4 days of harmine treatment increased β- and non-β-cell proliferation, NKX6.1 expression, and basal and stimulated insulin secretion in a dose-dependent manner, whereas fold-stimulation of secretion peaked at intermediate doses. Interestingly, 15-day harmine treatment led to a general reduction in proliferative effects as well as altered dose-dependent trends. The methodology presented here thus constitutes a unique tool for in vitro high-throughput evaluation of short- and long-term changes in human β-cell proliferation, count and fraction in parallel with a variety of functional parameters, in a representative and standardized 3D human islet microtissue model.

Disclosure
A.C.Title: None. B.Yesildag: None. M.Karsai: None. J.Mir-coll: None. O.Yavas grining: None. C.Rufer: None. S.Sonntag: None. F.Forschler: None. S.Jawurek: None. T.Klein: Employee; Boehringer Ingelheim International GmbH.
203-LB: The Role of the Exocyst Trafficking Complex in CD36 Fatty Acid Translocase Trafficking in Skeletal Muscle Cells
Authors: NAKAMURA NICOLE K. , TOKUNAGA DARCY S. , HA HERENA Y.J. , POLGAR NOEMI 
Published: May 2022

Skeletal muscle free fatty acid (FFA) uptake correlates with the amount of fatty acid translocase CD36 on the cell surface. In obesity, chronic membrane-localization of CD36, but not other FFA transporters, augments FFA uptake and intracellular lipid accumulation. This ectopic lipid accumulation then causes insulin resistance (IR) by inhibiting GLUT4 glucose transporter trafficking and glucose uptake in response to insulin. GLUT4 and CD36 cell-surface delivery is stimulated by insulin and contraction signaling, sharing conserved downstream effectors. The eight-protein exocyst complex is responsible for the targeted docking of membrane-bound vesicles, a process underlying cell-surface delivery of fuel transporters. The exocyst indeed regulates insulin-induced glucose uptake via GLUT4 trafficking to the membrane in adipocytes and skeletal muscle. In addition, it controls lipid uptake in adipocytes, but we do not know which of the FFA-transporting proteins the exocyst targets during this process. Based on the high degree of conservation of the fuel transporter trafficking mechanisms in adipose and skeletal muscle tissue, we hypothesized that the exocyst contributes to lipid uptake in skeletal muscle via the targeted trafficking of CD36. Our data shows that the exocyst plays a role in FFA uptake in skeletal muscle cells. Using an L6 GLUT4myc myoblast model we demonstrate that the exocyst is recruited to CD36 vesicles upon insulin and contraction signaling. We also show that disrupted exocyst activity leads to an impaired CD36 surface delivery and decreased FFA uptake in skeletal myoblasts. We are the first to demonstrate that the exocyst is necessary for insulin- and contraction-induced CD36 membrane trafficking and FFA metabolism in muscle cells. Further studies will continue to investigate the mechanism of exocyst-regulated FFA uptake and lipid metabolism in skeletal muscle to help our understanding of ectopic lipid accumulation leading to IR.

Disclosure
N. K. Nakamura: None. D. S. Tokunaga: None. H. Y. J. Ha: None. N. Polgar: None.