bluuebunny/crossref_metadata_2025_split huggingface dataset:
1624-P: Changes in Childhood Adiposity and Adolescent Testosterone in the EPOCH (Exploring Perinatal Outcomes among Children) Study
Authors: KIM CATHERINE , HARRALL KYLIE K. , GLUECK DEBORAH H. , DABELEA DANA 
Published: June 2019

Whether changes in visceral adipose tissue (VAT) in childhood predict adolescent androgens is not known. We examined the longitudinal relationship between MRI-assessed visceral adipose tissue (VAT) in childhood and future testosterone (T) among 418 EPOCH participants (209 girls and 209 boys) who were, on average 10.5 years at visit 1 and 16.7 years at visit 2. We used reverse Cox proportional hazards models in which hazard ratios less than 1 indicate greater risk for low (undetectable) sex hormones consistent with pre-puberty. Models explored the associations of baseline VAT, and change in VAT from visit 1 to visit 2, with risk of low sex hormone levels at visit 2, adjusted for covariates selected through backwards regression (race, self-reported Tanner stage, maternal income, insulin and leptin levels). All analyses were stratified by sex. In addition, due to different patterns of fat deposition in white and non-white adults, we tested for effect modification by race. In boys, the association between VAT at visit 1 and T at visit 2 differed by race; more VAT at visit 1 was associated with lower risk of low T at visit 2 among non-white boys (HR 1.02, 95% CI 1.007, 1.04) but not white boys (HR 1.00, 95% CI 0.98, 1.01). In contrast, greater fat accumulation between visits was associated with higher risk of low T at visit 2 (HR 0.90, 95% CI 0.83, 0.96), independent of race and other covariates. Among girls, neither baseline VAT levels, nor VAT accumulation between visits predicted risk of later low T concentrations. We conclude that greater VAT accumulation in childhood is associated with increased risk for low T levels, suggesting delayed puberty, in boys. These associations suggest that fat deposition may influence sex hormone profiles even in early childhood.

Disclosure
C. Kim: None. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None.

Funding
National Institutes of Health
1632-P: Trends in Obesity and Medical Expenditure among Women with Diabetes, 2008-2016: Differences by Race/Ethnicity
Authors: WILLIAMS JONI S. , NAGAVALLY SNEHA , EGEDE LEONARD E. 
Published: June 2019

Background: Obesity results in significant morbidity, preventable mortality, and increased medical expenditures among women with diabetes. The aim of this study was to examine racial/ethnic differences in obesity trends and medical expenditures among a nationally representative sample of women with diabetes.
Methods: Nine years of data (2008-2016) from the Medical Expenditure Panel Survey (MEPS) Full Year Consolidated File were used for the analyses. Cochran-Armitage tests were used to determine statistical significance of trends in obesity and mean expenditure for women with diabetes. Two-part statistical modeling with a combination of binomial and positive distributions was used to evaluate differences in medical expenditure. Data were clustered to 3 time points: 2008-2010, 2011-2013, 2014-2016. BMI levels were classified as underweight (&lt;18.5), normal (≥18.5 - 24.9, overweight (≥25.0 - 29.9), and obese (≥30.0 - 134.7). Analyses were weighted for the U.S. population.
Results: Cochran-Armitage tests showed trends in obesity from 2008 to 2016 differed significantly between Hispanic and Non-Hispanic white (NHW) women with diabetes (p=0.01). Among obese women, trends in mean medical expenditures differed significantly between Hispanic (p&lt;0.001), non-Hispanic black (NHB) (p&lt;0.001), and other (p&lt;0.001) women with diabetes compared to NHW women with diabetes. Two-part modeling showed obese Hispanic (-0.66 (-0.87, -0.42)) and NHB (-0.33 (-059, -0.01)) women with diabetes were significantly less likely to spend on healthcare compared to NHW women with diabetes; however, among those with expenditure, Hispanic women spent 30% less ($4520.81) and NHB women spent 17% less ($2555.72) compared to NHW women with diabetes.
Conclusions: These findings suggest further understanding of the factors associated with differences in trends for obesity between Hispanic and NHW women with diabetes and medical expenditures among obese minority and NHW women with diabetes.

Disclosure
J.S. Williams: None. S. Nagavally: None. L.E. Egede: Consultant; Self; Novo Nordisk Inc. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases.

Funding
National Institutes of Health
1646-P: The Impact of a Diabetes Codiagnosis on Hospitalisation and Mortality in Patients with Malignancy
Authors: KIBURG KATERINA V. , WARD GLENN , STEELE KATHLEEN M. , MULROONEY ELIZABETH M. , LOH MARGARET M. , MCLACHLAN SUE-ANNE , SUNDARARAJAN VIJAYA , MACISAAC RICHARD 
Published: June 2019

Objective: To document the characteristics and outcomes for patients with malignancies with or without diabetes at a tertiary referral hospital.
Research Design and Methods: Emergency department and hospital discharge data between 1 Jan 2015 and 31 Dec 2017 were used to identify patients with a diagnosis of a malignancy and diabetes. Multivariate Cox-regression models were used to estimate the effect of diabetes on all-cause mortality. A truncated negative binomial regression model was used to assess the impact of diabetes on length of hospital inpatient stay. Prentice, Williams and Peterson Total Time (PWP-TT) models were used to assess the effect of diabetes on number of Emergency Department presentations and inpatient admissions. Results are presented as incidence-rate ratios (IRR) or hazard ratios (HR). These models were adjusted for age, gender, type of malignancy and Charlson comorbidities.
Results: For 7,058 patients identified with malignancies, 1,230(17.4%) were also diagnosed with diabetes. During the three-year study period a diagnosis of diabetes was associated with an increased number of inpatient admissions (adjusted Hazard Ratio (adjHR): 1.14, 95% CI: 1.04, 1.25), increased number of emergency department presentations (adjHR: 1.19, 95% CI: 1.11, 1.28) and length of stay for patients with diabetes (adjIRR: 1.16, 95% C.I: 1.06, 1.28). A co-diagnosis of diabetes was also associated with a 48% increased risk of all-cause mortality (adjHR 1.48, 95% CI: 1.23-1.77).
Conclusions: Patients with diabetes had significantly higher numbers of emergency department presentations, inpatient admissions, length of hospital stay and higher rates of all-cause mortality compared to cancer patients without diabetes. This adverse link between diabetes and health outcomes in patients with malignancies requires further exploration.

Disclosure
K.V. Kiburg: None. G. Ward: None. K.M. Steele: None. E.M. Mulrooney: None. M.M. Loh: None. S. McLachlan: None. V. Sundararajan: None. R. MacIsaac: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. Other Relationship; Self; AstraZeneca, Novo Nordisk Inc.

Funding
Australian Government Research Training Program (to K.V.K.)
165-LB: The SGLT2 Inhibitor Canagliflozin Prevents Increased Lipid Oxidation in the Heart following High-Fat Feeding
Authors: FLORES ITZEL , SHANNON CHRIS , FOURCAUDOT MARCEL , BAKEWELL TERRY , NORTON LUKE 
Published: June 2019

Patients with type 2 diabetes (T2DM) are at increased risk for developing cardiovascular disease (CVD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are antidiabetic agents that significantly reduce the risk of acute myocardial infarction, stroke and CV death in patients with T2DM. However, the physiologic, metabolic and molecular mechanism of this cardioprotective effect are unclear. Given our preliminary and published findings, we hypothesized that SGLT2i may regulate mitochondrial function in the heart to improve cardiac function in the context of obesity and T2DM. We treated high-fat diet (HFD)-fed mice with canagliflozin (CANA; 10 mg/kg/day) for 1-week, and examined mitochondrial function in the heart, as well as in skeletal muscle, kidney and liver. Glucose tolerance tests were performed before and after treatment, and blood was collected at the end of the study to quantitate plasma lipids and ketones. Isolated mitochondria were provided with either pyruvate/malate (P/M) or palmitoylcarnitine/malate (PC/M) in the absence or presence of ADP to analyze basal and state III respiration. The CANA treatment prevented HFD-induced glucose intolerance independent of changes in body weight or free fatty acids (FFA), but significantly increased plasma ketones. The HFD markedly increased ATP-linked oxidation of PC/M in cardiac mitochondria, which was completely prevented by short-term CANA treatment. Canagliflozin did not affect pyruvate oxidation in the heart and had no effect on mitochondrial function in the other tissues tested. These data suggest that SGT2i may improve cardiovascular health through primary effects on mitochondrial metabolism. Further studies are needed to relate these metabolic effects of SGLT2i to improved cardiac function in vivo.

Disclosure
I. Flores: None. C. Shannon: None. M. Fourcaudot: None. T. Bakewell: None. L. Norton: None.
1671-P: Comorbid Autoimmune Disease in Participants at Risk for Type 1 Diabetes
Authors: SIMMONS KIMBER , GEYER SUSAN , WHERRETT DIANE K. , ISMAIL HEBA M. , LUNDGREN MARKUS , BOCCHINO LAURA E. , SOSENKO JAY M. , GREENBAUM CARLA , STECK ANDREA 
Published: June 2019

People with type 1 diabetes (T1D) are at increased risk for comorbid autoimmune disease (CAID). The TrialNet Pathway to Prevention (PTP) Study screens relatives of people with T1D for islet autoantibodies (Ab) to determine T1D risk. PTP Ab+ participants self-reported (Y vs. N) whether or not they had CAIDs at the start of monitoring. Outside of celiac disease, CAID has not been examined in Ab+ participants. Of the 5,740 Ab+ participants, 586 (10.2%; 95% CI: 9.4 - 11.0%) reported having a CAID. Of those with a single confirmed Ab+, GADA+ participants had a higher prevalence of CAID (230/1709=13.5%) vs. those who were IA-2A+ (8/88=9.1%) or mIAA+ (40/592=6.8%; p&lt;0.0001). Across all Ab+ participants, the number of Abs was inversely associated with prevalence of CAID at baseline, where a higher number of Abs corresponded to a lower likelihood of CAID (1 Ab+: 278/2393=11.6%; 2 Ab+: 165/1388=11.9%; 3 Ab+: 73/891=8.2%; 4 Ab+: 44/687=6.4%; 5 Ab+: 26/381=6.8%; p&lt;0.0001). The most prevalent CAID reported was thyroid disease (5.7%) with celiac disease reported in 1.3%. The influence of HLA status on CAID prevalence was mixed; celiac disease was more prevalent in those with DR3 (OR=2.79, p&lt;0.0001) while thyroid disease was less prevalent in those with DR4/DQ8 (OR=0.61, p&lt;0.0001). Although being single confirmed Ab+ at screening was associated with a higher likelihood of having CAID in the univariate setting, it was significantly protective (OR=0.77; p=0.007) when adjusting for age, sex and HLA status. In multivariable logistic regression models, the prevalence of CAID at baseline was associated with older age, being female and HLA DR4/DQ8 negative.
In conclusion, the reported prevalence rates of CAID is high in Ab+ relatives of people with T1D, inversely correlated with the number of Ab present, and related to DR3 and DR4/DQ8 haplotypes. The change in the direction of association of CAID with Ab number after an adjustment for HLA status suggests that DR3 and DR4/DQ8 could contribute to both CAID and Ab development.

Disclosure
K. Simmons: None. S. Geyer: None. D.K. Wherrett: None. H.M. Ismail: None. M. Lundgren: None. L.E. Bocchino: None. J.M. Sosenko: None. C. Greenbaum: Research Support; Self; Janssen Research & Development. A. Steck: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK0855095, K12DK094712-08)
1674-P: Age of Onset Is Associated with Insulin Resistance in Patients with Type 1 Diabetes Mellitus
Authors: YANG DAIZHI , WEI XUEYING , WANG CHAOFAN , ZHENG XUEYING , LUO SIHUI , LIN QIONGYAN , YAN JINHUA , WENG JIANPING 
Published: June 2019

Objective: Data are limited on insulin resistance (IR) status in patients with type 1 diabetes (T1D). This study aimed to assess the IR status and the effect of onset age on IR in patients with T1D.
Methods: Through the Guangdong T1D registry study, we identified adult patients (aged≥18 years) with a diabetes duration≥1 year. Clinical data were collected. A previously established model based on euglycemic-hyperinsulinemic clamp were used to calculate the estimated glucose disposal rate (eGDR) via clinical parameters. Participants were categorized into groups based on age of onset: childhood-onset group (cT1D, age of onset&lt;12 years); adolescent-onset group (pT1D, age of onset 12-17 years); and adult-onset group (aT1D, age at onset ≥18 years). Spearman correlation was used to analyze the correlation between IR and age of onset. ANOVA and Chi square test were used for comparisons of IR status and clinical parameters among the three groups.
Results: This analysis included 872 adults with T1D (58.3% female). The mean (SD) eGDR was 8.98 (3.34) mg/kg/min. There was a negative correlation between the level of IR status and the onset age (r=-0.093, p=0.003). The IR status assessed by eGDR decreased alongside an increase in age of onset (p=0.018). Compared with participants with older age of onset, patients in cT1D group had a higher level of A1c, lower proportion of participants with A1c less than 7%, higher daily insulin dose and higher frequency of hypoglycemic events (all p&lt;0.05).
Conclusions: Age of onset was significantly and negatively correlated with IR status. Childhood-onset patients with T1D are more likely to benefit from treatment of IR condition.

Disclosure
D. Yang: None. C. Wang: None. X. Zheng: None. S. Luo: None. Q. Lin: None. J. Yan: None. J. Weng: None.
1675-P: Does Intensification of Insulin Therapy Lead to Increased Body Fat among Youth and Young Adults with Type 1 Diabetes (T1D)?
Authors: MAYER-DAVIS ELIZABETH , REBOUSSIN BETH A. , PIHOKER CATHERINE , KAHKOSKA ANNA R. , DABELEA DANA , DOLAN LAWRENCE M. , JENSEN ELIZABETH T. , IGUDESMAN DARIA , LAWRENCE JEAN M. , SAYDAH SHARON , WADWA R. PAUL ,   FOR THE SEARCH FOR DIABETES IN YOUTH STUDY GROUP
Published: June 2019

Intensive insulin therapy may have the unintended consequence of increased adiposity, contributing to the high prevalence of overweight and obesity in people with T1D.
We examined the longitudinal association of insulin intensification with estimated body fat percentage (eBFP) among 746 individuals with T1D (age 10-21 years at initial visit) in the SEARCH for Diabetes in Youth study.
eBFP was calculated using validated, published sex and race/ethnic specific formulae incorporating age and anthropometrics. Insulin intensification was defined as more intense, less intense or no change, in which “more intense” was an increased number of injections or addition of long-acting insulin, or a change from injections to an insulin pump. Sex-specific, linear mixed effects models used continuous eBFP at each available visit (baseline, and 1-4 follow-up visits; median T1D duration at the last visit, 8 years). Interaction terms between time and insulin intensification relative to change in eBFP tested the study hypothesis.
Mean diagnosis age was 12.7 years ± 2.5, 47% were female, 80% non-Hispanic white. At baseline, mean BMIz score was 0.51 ± 0.93, with 32% overweight or with obesity. Although BMIz and weight status did not differ by sex, eBFP was significantly higher in females compared to males (32.4% ± 5.3 and 25.3% ± 5.9 respectively; p&lt;0.0001). After adjustment for age at diagnosis, study site, and sociodemographic factors, there was a statistically significant increase in eBFP over time for females (4.8% over the median duration of 8 years) and a statistically significant decrease for males (1.6% over the median duration of 8 years). For females, this increase was 2.2% greater over the median duration of 8 years for more intense compared to less intense therapy (p=0.0009). Rates of change in eBFP did not depend on insulin intensification for males (p=0.09). Further work may determine metabolic and behavioral drivers of this unintended increase in eBFP, particularly among females with T1D.

Disclosure
E. Mayer-Davis: None. B.A. Reboussin: None. C. Pihoker: None. A.R. Kahkoska: None. D. Dabelea: None. L.M. Dolan: None. E.T. Jensen: None. D. Igudesman: None. J.M. Lawrence: None. S. Saydah: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Beta Bionics, MannKind Corporation, Novo Nordisk Inc., Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Other Relationship; Self; Dexcom, Inc.

Funding
Centers for Disease Control and Prevention; National Institutes of Health
1696-P: PBMC of Recent-Onset Patients with Type 1 Diabetes Present a Differential Gene Expression Profile
Authors: SANTOS ARITANIA , CHEVILLARD CHRISTOPHE , GONFINETTI NELSON , BERTONHA FERNANDA , MOREIRA-FILHO CARLOS , KALIL JORGE , CUNHA-NETO EDECIO , SILVA MARIA ELIZABETH 
Published: June 2019

Introduction: Type 1 diabetes is characterized by the autoimmune destruction of insulin-secreting β-cells, mediated by T auto reactive infiltrating cells, inflammatory cytokines and immunological mechanisms. However, little is known about the expression of genes and pathways dysregulated in peripheral blood mononuclear cells of patients with T1D.
Objective: to investigate the gene expression profiles of circulating PBMC in recent-onset T1D patients (up to 6 months of diagnosis) in comparison with controls in the context of putative disease-related pathobiological processes and pathways.
Methods: expression of mRNA from PBMC of 20 T1D patients, 15.8±8.6 years and age-matched 20 healthy controls, 14.7±6.7 years, (p&gt;0.05) was evaluated with the Whole Human Genome Microarray Agilent and analyzed by GeneSpring with a fold change cutoff of 1.5 and adjusted P value &lt;0.05; pathways analysis was performed with the software IPA.
Results: 326 genes were differentially expressed between T1D patients and controls, being 204 (63%) upregulated, and 122 (37%) downregulated in T1D. Interactions between the differentially expressed genes evidenced expression patterns of 24 networks. The most significantly enriched canonical pathways were namely ErbB (erythroblastic leukemia viral oncogene) signaling, micropinocytosis signaling, savage pathways of pyrimidine ribonucleotides and hepathocyte growth factor in descending order of significance. The up-regulated protein targets within these signaling pathways were NEK2, PLK1, ATM, PRKCD, CCND1, NRG2 and those down regulated were AREG, CDC42 and CDADC1.
Conclusion: The majority of upregulated genes of patients with T1D was related to cell cycle control, mitotic progression, proliferation and DNA repair, probably related to changes in PBMC metabolism and function due to DNA damage associated with hyperglycemia. The lower expression of AREG and CDC42 can be related to reduce immunosuppressive activity of regulatory T cells and B cell functions.

Disclosure
A. Santos: None. C. Chevillard: None. N. Gonfinetti: None. F. Bertonha: None. C. Moreira-Filho: None. J. Kalil: None. E. Cunha-Neto: None. M. Silva: None.

Funding
European Foundation for the Study of Diabetes; São Paulo Research Foundation
1698-P: Integrative Genomics Analysis Reveals Tissue-Specific Pathways and Gene Networks for Type 1 Diabetes
Authors: BLENCOWE MONTGOMERY , SALEEM ZARA , YANG XIA 
Published: June 2019

Type 1 diabetes (T1D) is a complex disease involving genetic predisposition that interacts with environmental triggers, leading to the loss of insulin producing beta cells. However, the molecular cascades underlying T1D are poorly understood. We hypothesize that genetic risk factors of T1D perturb tissue-specific biological pathways and gene networks, ultimately leading to the pathogenic end point in beta cells. We sought to identify the gene networks and key regulators for T1D by conducting a comprehensive, data-driven multi-omics analysis that integrates human genome-wide association studies (GWAS) of T1D, tissue-specific genetic regulation of gene expression in the form of expression quantitative trait loci (eQTLs), and tissue-specific gene network models using a computational pipeline Mergeomics. Our analysis revealed immune pathways such as adaptive immune system, cytokines and inflammatory response, primary immunodeficiency and immunoregulatory interactions between a Lymphoid and non-Lymphoid cell, across various tissues as well as tissue-specific signals such as regulation of complement cascade, class B/2 (Secretin family receptors) and neuroactive ligand-receptor interaction. Our integrative genomics approach offers comprehensive insights into the tissue-specific molecular networks and regulators underlying T1D.

Disclosure
M. Blencowe: None. Z. Saleem: None. X. Yang: None.

Funding
National Institutes of Health (R01DK104363)
17-LB: Prognostic Value of Gamma-Glutamyl Transferase Variability in Individuals with Diabetes: A Nationwide Population-Based Study
Authors: LEE DA YOUNG , YU JI HEE , HAN KYUNGDO , SEO JI A , KIM NAN HEE 
Published: June 2019

Objective: We investigated whether gamma-glutamyltransferase (GGT) variability can predict the risk of stroke, myocardial infarction (MI), and all-cause mortality in individuals with diabetes.
Methods: The study subjects were Koreans with diabetes who had undergone health examinations provided by the Korean National Health Insurance Corporation more than once during 2009-2012 (baseline). After excluding subjects aged &lt;40 years and those with histories of stroke, MI, chronic liver disease, or drinking ≥30g/day of alcohol, a total 698937 individuals were included. As a parameter of variability, we calculated the average successive variability (ASV) of GGT values measured during the five years before the baseline exam. We estimated the risk of stroke, MI, all-cause mortality according to GGT ASV quartiles using multivariate-adjusted Cox analyses, until December 31, 2016. Stroke and MI was defined using ICD-10 codes (I63-I64 and I21-I22) and admission record.
Results: During follow-up period, 26119 cases of stroke, 15103 cases of MI, and 39982 cases of death were identified. GGT ASV quartile showed significantly higher risk of stroke and all-cause mortality compared with quartile 1, even after adjustment for age, sex, renal function, obesity, drinking, smoking, exercise, presence of hypertension and dyslipidemia, hemoglobin, income status, glucose and GGT level, duration of diabetes, the number of histories of oral antidiabetic medication, prescription history of insulin, presence of diabetic retinopathy and peripheral artery disease. The fully adjusted HRs (95% CIs) of GGT ASV quartiles 4 were 1.06 (1.03-1.10) and 1.23 (1.20-1.27), respectively. This significance was maintained regardless of baseline GGT quartile in all-cause mortality.
Conclusions: GGT variability was associated with the risk of all-cause mortality and stroke. This tendency is most pronounced in all-cause mortality, regardless of baseline GGT levels.

Disclosure
D. Lee: None. J. Yu: None. K. Han: None. J. Seo: None. N. Kim: None.

Funding
National Research Foundation of Korea