bluuebunny/crossref_metadata_2025_split huggingface dataset:
1349-P: Bariatric Surgery Causes an Early Improvement in the Lipidomic Profile and a Decrease in Plasma Ceramides and Diacylglycerols in Patients with Type 2 Diabetes and NAFLD
Authors: KALAVALAPALLI SRILAXMI , BARB DIANA , DILLARD RACHEL E. , GODINEZ EDDISON , FRIEDMAN JEFFREY , FANOUS NADA , WARREN CURTIS O. , BRIL FERNANDO , LOMONACO ROMINA , ZARRINPAR ALI , CUSI KENNETH 
Published: May 2022

Bariatric surgery (BarS) is known to improve insulin resistance (IR) , atherogenic dyslipidemia and steatohepatitis in patients (pts) with type 2 diabetes (T2D) . Total ceramides (Cer) and diacylglycerols (DAGs) have been implicated in the development of IR and nonalcoholic fatty liver disease (NAFLD) , but the impact of BarS on their plasma concentration remains unclear. The aim of this study was to assess early changes in the plasma lipidome, before and 3-6 months post BarS. To this end, we recruited 17 pts with NAFLD who underwent BarS (age 47±3, BMI 46±2 kg/m2, 76% with T2D) , and 6 controls without T2D (baseline data only, age 47±6, BMI 31.2±2.1 kg/m2) . Global lipidomic profiling was performed on orbitrap mass spectrometer with UHPLC. Data was analysed using LipidMatch software. Plasma levels of total lipids (TL) (34%; p=0.01) , Cer (20%; p=0.31) , DAGs (50%; p=0.03) and total triglycerides (TG) (79%; p=0.01) were higher in pts with NAFLD compared to controls. Bariatric surgery reduced plasma TL (-26%) , Cer (-31%) , DAGs (-34%) and TG (-43%) levels (all p&lt;0.01) . In pts with vs. without T2D, plasma TL were higher (28%; p=0.01) . There was a reduction in TL (-29%; p&lt;0.01) , Cer (-22%; 0.27) , DAGs (-41%; p=0.02) and TG (-52%; p&lt;0.01) post BarS and a similar pattern was observed across the lipidomic profile (cholesterol esters, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol) . Reduction in weight after BarS correlated with lower DAGs (r=0.81; p=0.03) and TG (r=0.66; p=0.07) . Reduction in Cer correlated with improved HOMA-IR (r= 0.71; p=0.04) and Adipo-IR (r= 0.63; p=0.09) .
In conclusion, pts with NAFLD and T2D have a significantly worse lipidomic profile compared to pts without T2D. The unfavorable lipidomic profile was normalized after BarS, in particular Cer and DAG levels, known to be linked to IR. Assessment of the lipidomic profile may provide further insights into insulin sensitivity changes after BarS.

Disclosure
S.Kalavalapalli: None. A.Zarrinpar: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. D.Barb: None. R.E.Dillard: None. E.Godinez: None. J.Friedman: n/a. N.Fanous: None. C.O.Warren: None. F.Bril: None. R.Lomonaco: None.
1350-P: Elucidation of Terminal Fatty Acid–Derived Acetyl-CoA Preference for Ketogenic Flux
Authors: MCLEOD MARC , RAGAVAN MUKUNDAN , RUSHIN ANNA , MERRITT MATTHEW , GIACALONE ANTHONY G. 
Published: May 2022

Insulin resistance is a major contributor to nonalcoholic fatty liver disease (NAFLD) . NAFLD is a progressive disease that leads to impaired hepatic function and liver cirrhosis. Increased ketogenesis has been correlated with a protective phenotype in mice and humans. During our study we identified differences in acetyl-CoA partitioning between the oxidative tricarboxylic acid cycle (TCA) , and ketogenesis. 8 week old C57Bl6 mice were fed a high fat or low fat (60% or 10% fat by calories respectively) diet for 16 weeks before performing liver perfusion in 12-14 hours fasted mice with 1 mM [D15]-octanoate fatty acid tracer. The effluent perfusate was collected and GC-MS analysis was performed to identify the distribution of deuterium label. Enrichments were greater in ketones (˜70%) than the TCA cycle (˜20%) with the unexpected determination that terminal acetyl-CoA units derived from fatty acids were preferentially used for ketogenesis as compared to internal acetyl-CoA units (Figure 1) . These changes were confirmed with fractional enrichment analysis and metabolic modeling of the ketogenic pathway and TCA cycle. This finding elucidates differential handling of acetyl-CoA that could be exploited for therapeutic benefit to NAFLD.

Disclosure
M.Mcleod: None. M.Ragavan: None. A.Rushin: None. M.Merritt: None. A.G.Giacalone: None.
1352-P: Differential Metabolomics and Lipidomics Profiles in Low-Birth-Weight Men Unmasked by Four-Weeks High-Carbohydrate Overfeeding
Authors: VILLUMSEN SOFIE O. , JUSTESEN LOUISE , ELINGAARD-LARSEN LINE OHRT , THUESEN ANNE CATHRINE B. , KIM MIN , LEGIDO-QUIGLEY CRISTINA , DANIELSEN ELSE R. , HANSEN TORBEN , BRØNS CHARLOTTE , VAAG ALLAN A. 
Published: May 2022

Background: We hypothesized that low birth weight (LBW) subjects with a known increased risk of type 2 diabetes exhibit increased sensitivity towards the deleterious metabolic effects of 4-weeks high carbohydrate overfeeding (HCOF) compared with normal birth weight (NBW) controls.
Methods: Untargeted serum metabolomics and lipidomics were measured before and after 4-weeks HCOF (+25% energy) in 26 non-obese men with LBW (2789±174 g) and 21 normal birth weight (NBW) men/controls (3804±172 g) matched for BMI and age. Data were analyzed using a combination of advanced statistical and bioinformatical tools.
Results: Among 65 identified metabolites, 8 metabolites were affected differentially by HCOF between the two groups (p&lt;0.05) . In response to HCOF, ingenuity pathway analysis (IPA) revealed increased accumulation and peroxidation of lipids in LBW subjects. In contrast, NBW controls increased albumin synthesis after HCOF. Changes in upstream regulators such as nicotinamide nucleotide transhydrogenase (NNT) , uncoupling protein 1 (UCP1) , and carbonic anhydrase 9 (CA9) were observed in both groups in response to HCOF. NBW controls displayed increased NNT and UCP1 activation, whereas LBW subjects responded with paradoxically decreased NNT and UCP1 activation. CA9 expression was decreased in both groups. Network correlation analysis revealed an upregulation of fatty acids in LBW subjects, contrasting a downregulation among NBW controls. Among 279 lipids identified, the LBW subjects exhibited a significantly higher number of lipids to be increased in response to HCOF (n=26) compared to NBW subjects (n=6) (PFisher=0.0004) , and IPA analysis revealed an activation of the PPARG pathway in NBW as opposed to a paradoxical inhibition in LBW subjects.
Conclusion: The results document severe differential perturbations of lipid metabolism in LBW men exposed to HCOF. Public health initiatives promoting low carbohydrate diets in LBW subjects are warranted.

Disclosure
S.O.Villumsen: None. A.A.Vaag: Stock/Shareholder; AstraZeneca. L.Justesen: None. L.Elingaard-larsen: None. A.B.Thuesen: None. M.Kim: None. C.Legido-quigley: None. E.R.Danielsen: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk.
1355-P: Carbohydrate Overfeeding Unmasks Severe Dysmetabolic Traits in Low-Birth-Weight Men
Authors: BRØNS CHARLOTTE , THUESEN ANNE CATHRINE B. , JUSTESEN LOUISE , ELINGAARD-LARSEN LINE OHRT , STØRLING JOACHIM , DANIELSEN ELSE R. , HANSEN TORBEN , VAAG ALLAN A. 
Published: May 2022

Background: Low birth weight (LBW) individuals are at increased risk of developing Type 2 diabetes (T2D) , especially when exposed to an affluent dietary pattern. Impaired subcutaneous adipose tissue expandability and ectopic fat storage may represent key features explaining the link between LBW and risk of T2D. We hypothesized that a 4-week simple carbohydrate overfeeding challenge (+25% energy) (COF) would adversely influence dysmetabolic traits including hepatic fat content in LBW compared to normal birth weight (NBW) men.
Methods: Twenty-two non-obese LBW and 21 age- and BMI-matched NBW men with a mean age of 37.6 years were included. Body composition, hepatic fat (MR spectroscopy) , glucose and insulin metabolism, hepatic glucose production (HGP; deuterium glucose) , energy metabolism (indirect calorimetry) and selected plasma biomarkers (multiplex ELISA) were measured before and after 4 weeks COF.
Results: Fasting plasma glucose and C-peptide levels, as well as energy expenditure (EE) and fat oxidation (FOX) rates increased significantly more in response to COF among the LBW compared to NBW subjects (all P&lt;0.05) . However, despite significantly increased baseline hepatic fat content, COF resulted in similar body weight and hepatic fat content increments in LBW compared to NBW subjects. HGP and hepatic insulin resistance were unaffected by COF in both groups. Fasting plasma adiponectin levels were significantly reduced in LBW versus NBW subjects before and after COF, whereas plasma leptin and FGF21 levels were increased (both P&lt;0.005) after COF in LBW men only.
Conclusion: LBW compared to NBW subjects respond to COF with differential increments in plasma glucose, C-peptide, leptin and FGF21 levels, as well as increased EE and FOX rates. The results underscore the importance of LBW individuals avoiding simple carbohydrate overfeeding. Further studies are needed to understand the role of increased hepatic fat and insulin resistance as key mechanisms linking LBW with increased risk of T2D.

Disclosure
C.Brøns: Stock/Shareholder; Novo Nordisk. A.B.Thuesen: None. L.Justesen: None. L.Elingaard-larsen: None. J.Størling: None. E.R.Danielsen: None. T.Hansen: None. A.A.Vaag: Stock/Shareholder; AstraZeneca.

Funding
Novo Nordisk Foundation (NNF15OC0016692) , Aase and Ejnar Danielsens Fond, Augustinus Foundation, Simon Spies Fonden, TrygFonden.
1360-P: Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency
Authors: HU LILI , XIA XINYI , GU YUNJIE , YIN JUN 
Published: May 2022

Backgrounds: It's well known that calorie restriction (CR) brings striking benefits in metabolic improvement with complex and unclear mechanism. In this study, we aimed to investigate the specific manifestation and possible mechanisms of metabolism in CR mice.
Methods: B6 mice were randomly assigned to three groups: (1) chow diet (control) , (2) chow diet with 40% calorie restriction (CR) , (3) high-fat diet (HFD) . The metabolism status and related examination were performed after 12 weeks of feeding.
Results: In this study, we found that CR increased fasting blood glucose and plasma insulin, as well as reduced insulin sensitivity reflected by insulin tolerance test. Comparing to the control mice, the decrease of phosphorylation levels of IRS-1 including serine307 and tyrosine632 residues, and AKT (threonine308) after insulin rejection further confirmed that CR induced insulin resistance. Different from insulin resistance induced by HFD, CR improved glucose tolerance and reduced gluconeogenesis. Meanwhile, CR led to absolute lipid reduction, manifested in decreased plasma lipid, liver lipid deposition and fat mass. In contrast, liver glycogen increased dramatically. Fasting glycogen was twice as much as that of HFD group and 20 times as that of control group. Furthermore, the CR increased p-PYGL, p-GSK3β and decreased p-GS notably indicating active glycogen synthesis and decomposition. Subsequently, we found that CR increased plasma corticosterone and decreased plasma c-reactive protein (CRP) compared with control and HFD groups, while plasma corticosterone and CRP in HFD were higher than those in control group. Additionally, CR lowered levels of orexigenic neuropeptides and elevated levels of anorexigenic neuropeptides.
Conclusions: Our study suggested that CR induced lipid insufficiency and stress from starvation, resulting in physiological insulin resistance and enhanced glycogen metabolism, including increased glycogen synthesis, glycogenolysis and glycogen content.

Disclosure
L.Hu: None. X.Xia: None. Y.Gu: None. J.Yin: None.

Funding
National Natural Science Foundation of China (No. 82070885) ,Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (No. 20172025)
1368-P: Skeletal Muscle Mitochondrial Dysfunction Contributes to Increased GDF15 Levels in Aged Mice with Insulin Resistance and Sarcopenia
Authors: CHEN JEFFREY , BELLO FIONA , KASTROLL JAKE , VANDEVENDER AMBER , PANGBURN MARTHA , SILVA AGUSTIN A. GIL , SIPULA IAN J. , ALDER JONATHAN , JURCZAK MICHAEL J. 
Published: May 2022

Growth differentiation factor 15 (GDF15) is a secreted protein whose cellular expression increases in response to a variety of stimuli, including mitochondrial dysfunction. Plasma GDF15 levels increase with advanced age and positively associate with sarcopenia. The prevalence of type 2 diabetes (T2D) increases with age and the incidence of sarcopenia is elevated in patients with T2D. Despite these established associations, the relationship between skeletal muscle mitochondrial function and changes in GDF15 expression, as well as how they may contribute to sarcopenia and T2D in the context of aging, remain poorly defined. We hypothesized that mitochondrial dysfunction in skeletal muscle would be positively associated with increased GDF15 expression and plasma levels in aged mice, and that muscle function and insulin sensitivity would be impaired also. Lean mass as a percentage of body weight was significantly reduced in aged (52 months) male C57BL6 compared with young (4 months) mice. Skeletal muscle function and mobility, assessed as peak and max sustained speeds achieved during voluntary wheel running, were significantly impaired in aged mice. Hyperinsulinemic euglycemic clamps demonstrated impaired insulin sensitivity in skeletal muscle, adipose and liver of aged mice. High-resolution respirometry studies using permeabilized muscle fibers detected significant reductions in the respiratory control ratio (RCR) in aged mice that was due to increased state 4 or leak respiration. Muscle GDF15 gene expression was significantly elevated in old mice, as were plasma levels of circulating GDF15. Our data suggests that skeletal muscle is a significant contributor to increased plasma GDF15 levels seen during aging, and that changes in mitochondrial function may contribute to increased skeletal muscle GDF15 expression. Elevated GDF15 may therefore serve as a strong predictor of mitochondrial pathology and subsequent risk of T2D in aging.

Disclosure
J.Chen: None. F.Bello: None. J.Kastroll: None. A.Vandevender: None. M.Pangburn: None. A.A.Gil silva: None. I.J.Sipula: None. J.Alder: None. M.J.Jurczak: None.
1370-P: Effects of Concomitant High-Intensity Interval Training or Resistance Exercise Training on Muscle Protein Synthesis, Body Composition, and Metabolic Markers following 6-Week VLCD among Healthy Overweight/Obese Men
Authors: AZIZ MUHAMMAD HARIZ ABDUL , RAMZAN IMRAN , GHARAHDAGHI NIMA , BROOK MATTHEW , WILKINSON DANIEL J. , PHILLIPS BETHAN E. , SMITH KEN , ATHERTON PHILIP J. , IDRIS ISKANDAR R. 
Published: May 2022

Background: Very Low-Calorie Diet (VLCD) is effective for rapid weight loss but is associated with lean mass (LM) loss. Resistance exercise training (RET) and high-intensity interval training (HIIT) are known to promote muscle hypertrophy or improvements in cardiopulmonary fitness (CPF) . We therefore explored the effects of VLCD with or without RET or HIIT on body composition, metabolic markers, and CPF.
Methods: Participants were randomly allocated into VCLD only (n=10; 46±8y; 104±12kg; BMI 32±4, mean±SD) , VLCD+RET (n= 8; 40±8y;99k±10kg; BMI 32±2) or VLCD+HIIT (n=8; 46±11y; 101±12kg; BMI 33±3) . All groups had six weeks of VLCD. Exercise groups had supervised training three times/week. Pre- and post-interventions assessment included DXA scan, lipid profiles, insulin sensitivities, blood pressure, cardiopulmonary exercise test and biopsy of vastus lateralis muscle for muscle protein synthesis (MPS) using deuterium oxide technique.
Results: Significant reduction in body weight (-11.1±3 kg, -10.8±4kg, -11.7±4kg) , fat mass (-6.8±2kg, -6.9±2kg, -7.7±3kg, and LM (-4.3±2kg, -3.9±2kg, -4±1kg) were seen for VLCD only, VLCD+RET and VLCD+HIIT respectively (P&lt;0.0001) , with no between-groups difference. MPS rate following interventions were 0.8%±0.2d-1, 0.9%±0.2d-1 and 1.2%±0.2d-1 (statistically higher in VLCD+HIIT compared to VLCD only; P=0.004) . Significant improvements were seen in metabolic markers (insulin sensitivities, lipid profiles and blood pressure) in all groups, with no inter-group difference. No intra- and inter-groups differences were seen for VO2max or anaerobic threshold.
Conclusion: VLCD with or without exercise induced marked weight loss, improved insulin sensitivities, and metabolic markers despite LM loss. HIIT was associated with significant improvement in MPS and may be used as an adjunct to preserve VLCD induced LM loss.

Disclosure
M.Abdul aziz: None. I.Ramzan: None. N.Gharahdaghi: None. M.Brook: None. D.J.Wilkinson: None. B.E.Phillips: None. K.Smith: None. P.J.Atherton: None. I.R.Idris: None.
1372-P: Hyperglycemia Impacts Mouse Skeletal Muscle in a Sex-Specific Manner
Authors: KNAUB LESLIE , POTT GREGORY , HULETT NICHOLAS A. , HULL SARA , SCALZO REBECCA L. , REUSCH JANE 
Published: May 2022

Functional Exercise Capacity (FEC) , a universal predictor of cardiovascular and all-cause mortality, is lower in adults and youth with diabetes for reasons that are poorly understood. Skeletal muscle is key determinant of FEC. We hypothesized that skeletal muscle capillary and mitochondrial density are lower with hyperglycemia and respond to exercise training. To test this hypothesis we generated a model of short-term hyperglycemia (HG) with inducible beta cell deletion of glucokinase (GKlox/lox;PdxCreER) . Male (M) and female (F) HG mice and euglycemic littermate controls (EG) completed 3 weeks of treadmill training (Ex) or remained sedentary (Sed) . The gastrocnemius was collected 24 hours after the final exercise bout. Expression of COX1 (mitochondrial marker) , Dystrophin (muscle fiber sarcolemma boundary marker) , and CD31 (capillary marker) was detected by immunofluorescence. Sirtuin 3 (SIRT3) , an NAD+ dependent deacetylase (mitochondrial homeostasis) was measured using the JESS system. (Fig 1) Mitochondrial density (mitochondria per fiber as quantified by fluorescence intensity units per fiber [FIU/fiber]) was significantly lower in HG vs. EG (p&lt;0.0001) and differed by sex (p=0.0048 sex x glycemia interaction) . Ex resulted in greater mitochondrial density (p=0.0265) independent of sex and glycemia. Capillary density and SIRT3 were unchanged. Sex-differences in muscle response to HG warrant further investigation.

Disclosure
L.Knaub: None. G.Pott: None. N.A.Hulett: None. S.Hull: None. R.L.Scalzo: None. J.Reusch: Advisory Panel; Medtronic.

Funding
VA Merit (BX002046)
138-LB: Improving Type 2 Diabetes Medication Prescribing
Authors: RIOLES NICOLE , DESIMONE MARISA , HESS EMILIE J. , IWUMMADU CHINONSO V. , OSPELT EMMA L. , ROMPICHERLA SAKETH , GREENFIELD MARGARET , TSAI SANDRA 
Published: May 2022

Background: For people with type 2 diabetes, implementing best practice guidelines for diabetes and cardiovascular comorbidities is important to reduce the risks of complications. Two adult medical clinics used population health EMR data reports to increase medication prescribing for statins, ACE & ARB, SGLT2 & GLP-1.
Methods: The clinics tracked measures and used data analytics to identify a cohort population and medication needs for 6241 patients. Table 1 reflects data from a one-year pilot. Patients with a diagnosis of type 2 diabetes, duration of disease for at least one year, ages 18-75, with at least one in-person or telehealth visit were included.
Results: Three medication prescribing baselines were tracked to improve type 2 diabetes and heart disease management. Prescribing rates of SGLT2 and GLP1 increased by 2%, ACE-I and ARB use increased by 1% and statins rates remained at 73%.
Conclusion: The clinics used data to identify the cohort and prescribe necessary medications. Partnering with clinical pharmacists helped to support patients, educate providers, and standardize medication prescribing workflows. Planning care so that the teams consistently identified appropriate medications for diabetes and cardiovascular disease management were clinical priorities. While the goal rate of medication prescribing has not been achieved yet, new reporting workflows are now incorporated, setting up the clinics for continued improvement.

Disclosure
N. Rioles: None. M. Desimone: None. E. J. Hess: None. C. V. Iwummadu: None. E. L. Ospelt: None. S. Rompicherla: None. M. Greenfield: None. S. Tsai: None.

Funding
Helmsley Charitable Trust
138-OR: Earlier Onset of Type 2 Diabetes Increases Genetic Risk of Cardiovascular Complication
Authors: LEE HYUNSUK , CHOI JAE WON , KIM NA YEON , LEE SEUNGGEUN , PARK KYONG SOO , KWAK SOO HEON 
Published: May 2022

Earlier age at diagnosis of type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD) . However, genetic risk factors associated with accelerated CVD in people with early onset T2D remain elusive. We aimed to investigate if the impact of polygenic risk for developing CVD differs according to age at diagnosis of T2D.
Using prospective cohorts of UK Biobank (T2D, N=15,915) and Seoul National University Hospital (SNUH) T2D cohort (N=1,228) , we compared the incidence of newly developed CVD among four groups based on age at diagnosis of T2D (30-39, 40-49, 50-59, and 60-69 years of age) using time to event analysis. Polygenic risk scores (PRSs) for T2D and coronary artery disease (CAD) were calculated by PRS-CS, Bayesian regression using continuous shrinkage priors, using 1.1 million SNPs each from summary statistics of DIAGRAM and CARDIoGRAMplusC4D Consortium.
In UK Biobank, people diagnosed as T2D between age 30-39 had 5.8 (95% CI 4.04-8.42) fold increased risk of CVD compared to those who developed T2D between 60-69. Higher T2D PRS was associated with earlier onset of T2D but not with risk of myocardial infarction (MI) . On the other hand, higher CAD PRS was associated with increased risk of MI but not with earlier age at diagnosis of T2D. The effect of CAD PRS on MI was largest in people diagnosed between age 30-39 and its effect size decreased as the age at diagnosis increased: HR 2.34 (1.47-3.71) for age 30-39, 1.42 (1.20-1.68) for 40-49, 1.39 (1.25-1.54) for 50-59, and 1.28 (1.11-1.48) for 60-69. Interaction analysis between age at diagnosis and CAD PRS showed additional 10% increase in risk of MI for year earlier onset of T2D (P=0.0056) . These findings were replicated in the SNUH T2D cohort, which is a hospital based cohort of East Asians.
In summary, people with earlier onset T2D had higher risks for CVD, and the impact of CAD PRS for incident MI increased as age at diagnosis decreased. Genetic information in people with early onset T2D could be used to identify those with increased risk of CVD.

Disclosure
H.Lee: None. J.Choi: None. N.Kim: None. S.Lee: None. K.Park: None. S.Kwak: None.