bluuebunny/crossref_metadata_2025_split huggingface dataset:
208-LB: Fatty Liver Disease Differentiates Subpopulations with Higher Risk of Incident Type 2 Diabetes Regardless of Their Metabolic Health and Obesity Status: A Nationwide Population-Based Cohort Study
Authors: MI KANG YU , KYUNG CHO YUN , HEE YOO JEE , LEE JIWOO , HAN CHOI JONG , PARK JOONG-YEOL , JE LEE WOO , HEE JUNG CHANG 
Published: June 2019

Objective: We aimed to evaluate the risk of incident type 2 diabetes (T2D) in metabolically healthy, obese (MHO) individuals and the role of fatty liver disease (FLD) in this potentially causal relationship.
Methods: We enrolled 514,866 participants from the Korean National Health Insurance Service-National Health Screening Cohort in 2002-2015. Subjects were categorized into metabolically healthy, non-obese (MHNO), metabolically unhealthy, non-obese (MUNO), MHO, and metabolically unhealthy, obese (MUO) groups. Well-validated FLD indices were used in this study; Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), and Visceral Adiposity Index (VAI).
Results: Over 5.6 years, 67,807 (27.8%) of 244,301 subjects free of T2D and liver disease besides FLD developed T2D. The risk correlated with obesity (HR, 1.35; 95% CI 1.33-1.37) and the number of metabolic risk factors; HRs for 1, 2, 3, and 4 risk factors were 1.43 (95% CI, 1.39-1.47), 1.92 (95% CI, 1.87-1.97), 2.51 (95% CI, 2.44-2.58), and 3.14 (95% CI, 3.02-3.26), respectively. Compared with the MHNO group, the risk of T2D was significantly higher in MUO (multivariate HR, 1.95; 95% CI, 1.91-2.00), MUNO (HR, 1.63; 95% CI, 1.60-1.67), and MHO (HR, 1.28; 95% CI, 1.25-1.30) individuals. Higher FLD scores among MHO individuals also exhibited a strong correlation with the incident T2D, compared with both the MHNO group and the MHO counterpart with lower FLD scores (P &lt; 0.05 for all comparisons). Survival trees analysis based on log-rank test revealed that the best cut-off points to predict incident T2D were 25.1, 33.4, and 1.7 for FLI, HSI, and VAI, respectively.
Conclusion: The number of metabolic risk factors, obesity, and FLD are significant predictors of incident T2D. Higher T2D risk in MHO individuals, with an excess risk related to higher FLD scores, necessitates more intensive monitoring and interventions in these individuals.

Disclosure
Y. Kang: None. Y. Cho: None. J. Yoo: None. J. Lee: None. J. Choi: None. J. Park: None. W. Lee: None. C. Jung: None.
2088-P: Soluble EGFR and Adipsin Are Independent Serum Biomarkers for Insulin Resistance in Mouse and Human
Authors: KYOHARA MAYU , SHIRAKAWA JUN , TERAUCHI YASUO 
Published: June 2019

We identified soluble epidermal growth factor receptor (sEGFR), a hepatokine, and Adipsin, a adipokine, by serum quantitative proteomics as common factors, whose protein levels were significantly reduced across 4, 8, 12, and 24 weeks of ages in obese diabetic db/db mice and were restored by treatment with liraglutide. In this study, we investigated the properties of sEGFR and Adipsin as biomarkers in mouse and human. In mice, the expression of EGFR and Adipsin were abundant in the liver and adipose tissue, respectively, and significantly reduced in db/db mice. The sEGFR and Adipsin were significantly decreased in sera of high-fat diet-fed mice and ob/ob mice. Next, we measured the sEGFR and Adipsin levels in sera from 47 nondiabetes subjects and 106 patients with type 2 diabetes, and analyzed the correlation with clinical parameters by using multiple linear regression analysis. No correlations were observed between sEGFR and Adipsin levels. The sEGFR levels were positively correlated with HbA1c, fasting blood glucose, and HOMA-IR, and the association was remained after adjustment for age and sex (β = 0.357, p &lt; 0.001; β = 0.299, p &lt; 0.001; β = 0.259, p = 0.004). The sEGFR levels were also positively correlated with T-chol, TG, LDL-chol, and AST after adjustment for age and sex (β = 0.378, p &lt; 0.001; β = 0.275, p &lt; 0.001; β = 0.235, p = 0.004; β = 0.202, p = 0.014). The Adipsin levels were positively correlated with BMI, waist circumference, fasting serum insulin, and HOMA-IR, and remained correlation after adjustment for age and sex (β = 0.532, p &lt; 0.001; β = 0.475, p &lt; 0.001; β = 0.383, p &lt; 0.001; β = 0.342, p = 0.003). The Adipsin levels were also positively correlated with FIB-4 index (liver fibrosis index), and negatively correlated with eGFR after adjustment for age and sex (β = 0.264, p = 0.013; β = -0.352, p &lt; 0.001). These findings suggest that sEGFR and Adipsin are independent biomarkers that correlate with factors for insulin resistance, and might reflect liver and fat insulin resistance, respectively.

Disclosure
M. Kyohara: None. J. Shirakawa: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
2091-P: Relationship between Prediabetes (Pre-DM) and the Frequency of Periodontal Disease (PD) in Patients with Severe Obesity—A Retrospective Cohort Study in an Academic Center in Paraguay
Authors: JIMÉNEZ DE PANE VIOLETA M. , BENITEZ ALDO , PALACIOS MAFALDA , BUENO COLMAN ELVIO DARIO , JIMENEZ JORGE T. 
Published: June 2019

Objectives: To determine the relationship between the Pre-DM and the PD frequency in patients with significant obesity and also between the Pre-DM as part of the metabolic syndrome (MS) and the PD in these patients.
Methods: Retrospective cohort study with patients with severe obesity from an unit of multidisciplinary management of obesity. They were distinguished in patients with Pre-DM or normoglycemia. The outcome was the presence and degree of PD with the Modified Periodontal Index of Russell (MPIR).
Results: There were evaluated 62 patients, half of them with Pre-DM. The Pre-DM vs. normoglycemia cohorts had: weight (in kg) 133,3±37,2 vs. 114,7±20,7 (p 0,01) and BMI 49,1±12,9 vs. 43,1±6,3 (p 0,02). According to the MPIR no patient was healthy. In the Pre-DM and normoglycemia cohorts the frequency of gingivitis and periodontitis was equal: 22,5 and 77,4% respectively. The frequency of severe periodontitis (SP) was 51,6% in patients with Pre-DM and 29,03% with normoglycemia (RR 1,77 - p 0,06). The SP was more frequent with higher fasting glucose levels: 29,4, 38,7 and 57,14% for each tertile respectively, as well as with greater BMI: 28,9, 50 and 75% for each tertile. Among patients with Pre-DM and BMI ≥ 45,9 kg/m2, 75% had SP vs. 26,7% of those with lower BMI (RR 2,81 - p 0, 01). Amidst patients with vs. without MS: 44,2 vs. 31,6% had SP (RR 1,39 - p 0,3). The frequency of SP had a fairly linear rise with the increase in the number of elements of the MS: 20, 36, 37, 53 and 43% in the presence of 1 to 5 elements of MS respectively (p &gt; 0,05).
Conclusions: The PD was not more common in patients with Pre-DM. SP was more frequent in those patients with Pre-DM, with a greater and statistically significant difference in those with more severe degrees of obesity. These results show that in the context of severe obesity and MS, even mild hyperglycemia seems to be related to SP and the need to request an evaluation of oral health in this group of patients.

Disclosure
V.M. Jiménez de Pane: None. A. Benitez: None. M. Palacios: None. E. Bueno Colman: None. J.T. Jimenez: None.
2095-P: Association between Markers of Neuro and Systemic Inflammation and Cognitive Function in Obesity
Authors: KHAN ADAM , JOERS JAMES M. , LUCIANA MONICA , RUBIN NATHAN , SIDDIQUI YOUSUF , MANGIA SILVIA , EBERLY LYNN E. , IKRAMUDDIN SAYEED , SEAQUIST ELIZABETH R. , OZ GULIN , MOHEET AMIR 
Published: June 2019

Obesity is associated with alterations in brain structure and cognitive impairment. The mechanisms underlying obesity related decline in cognitive function are not well understood. Obesity related chronic systemic inflammation is postulated to be one of the potential mechanisms leading to cognitive dysfunction. It is unknown whether inflammation impacts brain areas important for higher level cognition such as the anterior cingulate cortex (ACC). Elevated myo-inositol (Ins), as measured by magnetic resonance spectroscopy (MRS), may be a marker of neuroinflammation and reflects activated astrocytes and microglia. We hypothesized that obese subjects (OB) will have higher ACC Ins compared to normal weight controls (CON) and that higher Ins will be associated with elevated blood inflammatory markers and reduced cognitive performance. We examined neurochemical profile from a 24x24x12mm3 voxel over the ACC using 1H MRS at 3 and 7 Tesla (T), in 5 nondiabetic OB (age 33 ± 5 years, BMI 43 ± 6 kg/m2) and 4 CON (age 36 ± 3 years, BMI 23 ± 3 kg/m2). Subjects also underwent cognitive testing and measurement of blood inflammatory markers. MR spectra were quantified using LCModel and the concentrations are expressed as a ratio to total creatine (tCr). There was a strong trend of higher Ins/tCr in ACC in OB compared to CON both at 3T (0.96 ± 0.06 vs. 0.88 ± 0.05, p =0.07) and 7T (0.91 ± 0.07 vs. 0.83 ± 0.08, p =0.17). Pearson correlations were used to test the relationship between Ins/tCr and markers of inflammation among all subjects. Higher blood inflammatory markers were associated with higher Ins/tCr (3T) in ACC (CRP, r=.74, p= 0.04; TNF α, r=.89, p=0.003) and with low levels of crystallized ability as measured by the NIH Toolbox Cognition Battery (CRP, r=-.73, p=0.03). Higher ACC Ins/tCr was also associated with poorer performance on a measure of fine motor coordination (r=.93, p=0.001). These data support the hypothesis that inflammation may contribute to the pathogenesis of brain and cognitive alterations in obesity.

Disclosure
A. Khan: None. J.M. Joers: None. M. Luciana: None. N. Rubin: None. Y. Siddiqui: None. S. Mangia: None. L.E. Eberly: None. S. Ikramuddin: Research Support; Self; Medtronic. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None. A. Moheet: None.

Funding
National Institutes of Health
2098-P: The Accuracy of Meal Test to Diagnose Hypoglycemia after Gastric Bypass
Authors: HONKA HENRI , DEFRONZO RALPH A. , PATTI MARY E. , SALEHI MARZIEH 
Published: June 2019

Gastric bypass (GB) alters postprandial glucose pattern with a higher peak of glucose and lower glucose nadir. Glycemic effects of GB is exaggerated in patients suffering from postprandial hyperinsulinemic hypoglycemia. Diagnosis is complex and requires documentation of concurrent symptoms with low glucose that are relieved by carbohydrate (CHO) intake (Whipple’s triad). Mixed meal tolerance test (MTT) is often used to provoke hypoglycemia but glucose threshold to fulfill Whipple’s triad remains unknown. Here we measured accuracy of 350-kcal MTT (Ensure Plus®, 51 g CHO) to diagnose hypoglycemia in 95 GB subject (43 with prior documented hypoglycemia [H] and 52 asymptomatic [A]). In addition, measured outcomes were compared with those during isovolemic 250-kcal liquid MTT (Ensure®, 40 g CHO) in a separate cohort of 49 GB subjects (31 H vs. 18 A). Time and weight loss since surgery, BMI, and A1c were similar between H and A. The H subjects had lower fasting glucose (80±1 vs. 84±1 mg/dL, P&lt;0.05) and nadir glucose levels (51±2 vs. 67±2 mg/dL, P&lt;0.001). Nadir glucose values were associated with fasting glucose (r=0.6, P&lt;0.001). Plotting true positive rate (sensitivity) against false positive rates (1-specificity) for nadir glucose during MTT yielded an area under the Receiver Operating Characteristics (ROC) curve of 0.80±0.05. A nadir blood glucose cut-off of 53 mg/dL produced the highest sum of sensitivity (65%) and specificity (88%) for detecting hypoglycemia. Lower CHO ingestion (40 g) did not significantly affect the accuracy of MTT to diagnose hypoglycemia (AUC ROC: 0.69±0.08). Our findings indicates that mixed meals containing 40-50 g of CHO have good discriminatory value to diagnose hypoglycemia after GB using blood glucose threshold of &lt;54mg/dL.

Disclosure
H. Honka: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. M.E. Patti: Consultant; Self; Eiger BioPharmaceuticals. Research Support; Self; Dexcom, Inc., Janssen Pharmaceuticals, Inc., MedImmune, Xeris Pharmaceuticals, Inc. M. Salehi: None.

Funding
National Institutes of Health (DK105379, DK083554 to M.S.); National Center for Advancing Translational Sciences (8UL1TR000077); Finnish Cultural Foundation (00180071)
2112-P: Weight Trajectory from Young Adulthood to Midlife and Mortality in U.S. Adults
Authors: CHEN CHEN , PAN XIONG-FEI , PAN AN 
Published: June 2019

Excess adiposity mostly accrues from young adulthood to midlife, however the impact of weight change in early life on mortality risk in later life is unclear.
A total of 26724 individuals aged 40 years and older from the 1988-2010 U.S. National Health and Nutrition Examination Survey (NHANES) recalled their weight at young adulthood (at age of 25 years) and middle adulthood (at ten years before the NHANES survey cycle started). Based on these two weight status, they were categorized into four weight change groups: those who maintained as non-obese (stable non-obese of BMI &lt;30 in both times), those who changed from non-obese to an obese body shape (gaining), those who moved from an obese BMI to a non-obese BMI (losing) and those who remained obese (stable obese). Mortality status was linked with death certificate records from National Death Index up to December 31, 2011. Cox proportional hazard models adjusting for covariates were used for calculating hazard ratios (HRs) and 95% confidence intervals (CI).
During a mean follow-up of 18.9 years, 6732 deaths occurred. Compared with stable non-obese category, those in the gaining group had a 27% (HR 1.27; 95% CI 1.16-1.39) and 40% (1.40; 1.17-1.66) increased risk of total mortality and cardiovascular mortality respectively; those in the stable obese group had significantly higher risk of total mortality (1.87; 1.62-2.15) and cardiovascular mortality (2.40; 1.79-3.22). Weight change was not significantly associated with cancer mortality. Although the weight loss category was associated with a non-significant modest increased risk of total mortality (1.36; 0.96-1.92), the association was mainly driven by non-cardiovascular and non-cancer causes (1.80; 1.13-2.87), rather than cardiovascular mortality (0.82; 0.50-1.33) or cancer mortality (1.18; 0.58-2.42). Analysis in never smokers, different sex and age groups showed similar results.
Maintaining a non-obese body shape from young adulthood to midlife is important for preventing premature death in later life.

Disclosure
C. Chen: None. X. Pan: None. A. Pan: None.

Funding
National Key Research and Development Program of China (2017YFC0907504)
2113-P: Metabolic Effects of Bariatric Surgery in a Group of Patients Aged 65 Years Old or More Compared with a Group of Adults Younger Than 65 Years Old—A Prospective Cohort
Authors: MUSSO CARLA , FERMO GOMEZ FERNANDO AGUSTIN DI , ROSENFARB JOHANNA , BOSIO LUCILA , SANTAMARIA JIMENA , HANSEN MARTIN , GIMENEZ CRISTINA , ERRASTI ANA G. , CARUSO DIEGO , FAINGOLD MARIA CRISTINA 
Published: June 2019

Aim: We compared the anthropometric and metabolic parameters before and after six months of bariatric surgery (BS) between a group of patients aged ≥65 and &lt;65 years old (y/o) with or without comorbidities.
Materials and Methods: We did a prospective study with patients who had undergone BS and followed them for six months from July, 2015 to May, 2018 at Milstein hospital, Argentina and divided them into two cohorts: older and younger than 65 y/o. Outcomes were compared (lost weight [LW], excess weight loss percentage [EWLP], BMI, A1c hemoglobin [HbA1c], HDL, Triglycerides [Tg] and Tg/HDL ratio) and we considered a p &lt;0.05 as statistically significant.
Results: We included 36 patients, 15 were ≥65 y/o and 21 &lt;65 y/o. There were more patients with type 2 diabetes mellitus (DM2) in the oldest group. We found no statistical difference between groups in WL and the EWLP but observed a statistical rise in the levels of HDL (43, RIQ 95% CI: 39-48 vs. 51, RIQ 95% CI: 44-55, p=0.026) and the decrease of the Tg/HDL ratio (1.6 RIQ 95% CI: 1.4-2.1 vs. 3.1 RIQ 95% CI: 2.2-4.6, p=0.02) in the group of ≥65 y/o. The HbA1c levels were significantly higher in the &gt; 65 y/o with DM2 and the decrease was statistically greater after the follow-up. When we compared initial treatment for DM2 after 3 and 6 months of BS, there was a statistically significant decrease in the use of oral antidiabetic drugs and insulin (chi2= 19%, p=0.004 at 3 months, chi2: 27%, p&lt;0.001 at 6 months after surgery). If we analyzed this result by age, there was no difference between both cohorts (chi2=3.73, p=0.15 and chi2=1.46, p=0.4 at 3 and 6 months after surgery respectively).
Conclusion: We found a significant benefit in metabolic effects of BS in the ≥65 y/o cohort, especially by decreasing insulin resistance, even in those patients without diagnosis of DM2. We need more studies and a greater sample size to generalize these results.

Disclosure
C. Musso: None. F.A. Di Fermo Gomez: None. J. Rosenfarb: None. L. Bosio: None. J. Santamaria: None. M. Hansen: None. C. Gimenez: None. A.G. Errasti: None. D. Caruso: Other Relationship; Self; Novartis Pharmaceuticals Corporation. M.C. Faingold: None.
2116-P: A Pipeline to Explore Rare Variation Which Can Contribute to Extreme Obesity in American Indians
Authors: ALTOK CIGDEM KOROGLU , PIAGGI PAOLO , TRAURIG MICHAEL , HANSON ROBERT L. , KNOWLER WILLIAM C. , KIM HYE IN , GOSALIA NEHAL , VAN HOUT CRISTOPHER V. , YE BIN , CENTER REGENERON GENETICS , SHULDINER ALAN R. , BOGARDUS CLIFTON , BAIER LESLIE J. 
Published: June 2019

Identification of high-impact loss-of-function variants for common disease is challenging because these variants are typically rare and thus statistical power is low when sample sizes are limited. In this study, we utilized whole-exome variant detection, variant prediction programs, tissue expression data, and case-control analysis to identify potentially highly penetrant obesity-susceptibility variants for prioritization for functional testing. Whole-exome sequencing was performed on DNA samples collected from a longitudinal, population-based study of American Indians (N=5432; maximum BMI recorded at ≥18 years). Among the 1 million biallelic SNVs detected in this cohort, those that were exonic or splicing, have minor allele frequency (MAF) ≤0.05, predicted to be damaging (CADD score ≥15), and located in genes expressed in hypothalamus were selected for analysis. These selection criteria resulted in 94,444 SNVs, and odds ratios were calculated for them by comparing the group of individuals with BMI in the top 5th percentile for this population (N=271, BMI ≥53.13 kg/m2) vs. those below the median (N=2,717, BMI &lt;35.92 kg/m2). The resulting 19,382 variants with positive OR values were then divided into 4 bins based on MAFs, and those with a OR in the top 1% of the distribution of each bin were prioritized. In the resulting list of 291variants in 266 different genes, a missense variant p.I330V (rs201597085; OR=2.66; CADD=20.3; MAF=0.02) in GNAS was the best candidate, since GNAS was the only gene linked to obesity in humans. GNAS is a highly complex imprinted locus, and the main transcript derived from this locus (Gs-alpha) encodes the alpha subunit of the stimulatory guanine nucleotide-binding protein. The XLas isoform, a large variant of Gs-alpha, is paternally expressed. An association analysis with accountance for parental origin of the alleles is ongoing. Future functional studies would entail examining the effects of this missense variant on G protein-coupled receptor signaling.

Disclosure
C. Koroglu Altok: None. P. Piaggi: None. M. Traurig: None. R.L. Hanson: None. W.C. Knowler: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. N. Gosalia: Employee; Self; Regeneron Pharmaceuticals. C.V. Van Hout: Employee; Self; Regeneron Pharmaceuticals. B. Ye: Employee; Self; Regeneron Pharmaceuticals. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. C. Bogardus: None. L.J. Baier: None.

Funding
National Institutes of Health
212-OR: Factors Associated with Decline of C-Peptide in a Cohort of Young Children Diagnosed with Type 1 Diabetes
Authors: STECK ANDREA , LIU XIANG , KRISCHER JEFFREY , HALLER MICHAEL J. , VEIJOLA RIITTA , AKOLKAR BEENA , TOPPARI JORMA , HAGOPIAN WILLIAM , REWERS MARIAN , ELDING LARSSON HELENA 
Published: June 2019

Preservation of C-peptide after diagnosis of type 1 diabetes (T1D) is associated with lower risk of both hypoglycemia and long-term microvascular complications. The decline of C-peptide after T1D onset is highly variable among subjects. The goal of this study was to evaluate factors associated with the rate of C-peptide decline. TEDDY participants identified at birth with high-risk HLA genotype and followed regularly until T1D diagnosis (n=70) and 60 age-matched children diagnosed with T1D in the community (median age at diagnosis = 6.7 years, IQR 5.1-7.9) were enrolled in a 2-year follow-up with mixed meal tolerance tests at 1, 3, 6, 12 and 24 months. Mixed effects models for repeated measures were used adjusting for age at diagnosis and C-peptide at baseline. In univariate analyses, factors associated with rate of C-peptide loss included sex, age at diagnosis, baseline BMI, AUC C-peptide, HbA1c, IA-2A positivity and ZnT8A positivity. Four of these 7 factors remained significant in multivariate analysis (all p ≤ 0.037, see Table). Younger age at diagnosis, higher HbA1c, IA-2A positivity and ZnT8A positivity were associated with higher rate of C-peptide decline in this young cohort of children diagnosed with T1D.

Disclosure
A. Steck: None. X. Liu: None. J. Krischer: None. M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. R. Veijola: None. B. Akolkar: None. J. Toppari: None. W. Hagopian: Research Support; Self; Novo Nordisk A/S. M. Rewers: None. H. Elding Larsson: None.

Funding
JDRF; National Institutes of Health