bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gamma Glutamyltransferase and Risk of Dementia in Normal, Prediabetes, and Diabetes Populations—A Nationwide Cohort Study with 6.5 Million People
Authors: HAN EUGENE , LEE MINYOUNG , CHO YONGIN , LEE BYUNG-WAN , AHN CHUL WOO , CHA BONG-SOO , LEE YONG-HO 
Published: June 2018

Diabetes is associated with cognitive impairment and increases risk of dementia, but until now the role of gamma-glutamyltransferase (γ-GT) in dementia has not been studied. We thus investigated the impacts of γ-GT and glycemic status on incident dementia in a nationwide cohort study. We determined incident dementia including Alzheimer’s disease and vascular dementia, analyzing data from participants aged 40 years or older in the National Health Insurance Database, collected by the National Health Insurance Service in Korea, from January 2009 to December 2015. During a median follow-up of 7.6 years, 272,657 participants (5.4%) were diagnosed as having dementia at a mean age of 76.5 years. Higher serum γ-GT was associated with increased risk of dementia (HR=1.22, 95% CI=1.20-1.24), and had a strong positive association with early onset dementia (HR=1.32, 95% CI=1.24-1.40). An additive impact of higher γ-GT on dementia was observed regardless of glycemic status, and prevalent diabetes with the highest γ-GT quartile had a 1.8-fold increased dementia risk (HR=1.82, 95% CI=1.78-1.85). This effect of γ-GT concentration in diabetes was more prominent in individuals with vascular dementia (HR=1.94, 95% CI=1.84-2.04). In subgroup analysis, young age, male sex, and relatively healthy subjects with a higher γ-GT quartile had more increased dementia risk.
In conclusion, γ-GT concentration as well as glycemic status could be a future risk factor for dementia in the general population.

Disclosure
E. Han: None. M. Lee: None. Y. Cho: None. B. Lee: None. C. Ahn: None. B. Cha: None. Y. Lee: None.
Socioeconomic Relationship Trends between Diabetes and Postcodes in NSW, Australia
Authors: BURNS KHARIS , HNG TIEN-MING , CHEUNG NGAI WAH 
Published: June 2018

Diabetes prevalence is increasing in Australia. The Ausdiab Study 2001 found diabetes affected 7.4% of adults &gt;25y with 0.7% of Australians diagnosed yearly. The distribution of diabetes and standard of care however is not nationally uniform. Health disparities may be due to social disadvantage, ethnicity, age distribution and services access. We examined the distribution of diabetes and level of control based on postcode in NSW at two time periods, to determine if the relationship between the level of care (defined by HbA1c) and geographical distribution had changed with time. Data was sourced from a pathology company performing the bulk of testing, capturing the majority of subjects with diabetes. Subjects were identified by HbA1c measurement. Two periods were examined, 20and 2013. For each subject who had an HbA1c collected, data was extracted for gender, age, postcode, eGFR, lipids and urine microalbumin. Mann Whitney U tests compared differences in parameter medians between the two periods. Spearman correlations and linear regression assessed relationships between socioeconomic disadvantage scale based on postcode (SEIFA), and diabetes control. Data was available for 119018 subjects in 20and 185954 subjects in 2013. During both years, the number of diabetes cases was higher in areas of greater disadvantage and HbA1c was correlated with higher disadvantage score (p&lt;0.01). Control significantly improved over time (Mdn HbA1c 6.5% vs. 6.3%) and the proportion of patients with poor control (HbA1c &gt;7.0%) also improved (36.5% vs. 31.7%) (p&lt;0.01). SEIFA significantly predicted diabetes control in both 20(F (1,119016) =907.4 p&lt;0.01, r2=0.01) and 2013 (F (1,185952)=1940.3 p&lt;0.01, r2=0.01). Control improved within 9/10 SEIFA categories over time (p&lt;0.05) though the gap between socioeconomic tiers remained. Health inequalities in diabetes control parallel socioeconomic disadvantage levels in NSW. Despite an 8 year interim disparities in HbA1c between socioeconomic tiers have not changed.

Disclosure
K. Burns: None. T. Hng: None. N. Cheung: None.
Inverse Associations between Circulating SFRP5 and Adiposity among African-Caribbean Men
Authors: ALI HIRA , ZMUDA JOSEPH M. , CVEJKUS RYAN , KERSHAW ERIN E. , KUIPERS ALLISON L. , BUNKER CLAREANN H. , MILJKOVIC IVA 
Published: June 2018

Background: African ancestry populations are at the epicenter of the obesity and diabetes epidemic. Secreted frizzled-related protein 5 (SFRP5) is a novel adipokine and Wnt pathway modulator which is thought to be inversely related with adiposity and diabetes risk, however data in humans is conflicting. Therefore, we examined the association of SFRP5 with parameters of obesity and insulin resistance among an African ancestry population.
Methods: We measured fasting serum SFRP5 in a pilot study of 139 elderly Afro-Caribbean men (mean age 71.7years, mean BMI 27.6 kg/m2). These men represented a random subset of a population-based study comprising ∼3000 African ancestry men with anthropometrics, DXA measured adiposity, and fasting morning blood collections for biomarker analysis. SFRP5 was measured in duplicate in previously unthawed serum with ELISA.
Results: Using Pearson correlations, we found SFRP5 level to be positively associated with age (R = 0.18, p = 0.03) and negatively associated with BMI (R = - 0.14, p = 0.09), waist circumference (R = - 0.18, p = 0.02) and DXA trunk fat (R = - 0.24, p = 0.003), independent of age. Among nondiabetics (N=87), SFRP5 was inversely associated with fasting insulin levels (R = - 0.21, p= 0.04) and to some extent with HOMA-IR (R = -0.20, p = 0.06), independent of age and BMI. However, after adjustment for age and waist circumference, the associations between SFRP5 and fasting serum insulin and HOMA-IR were no longer significant.
Conclusion: Our findings suggest that among African ancestry men, SFRP5 might have a beneficial role against general and central obesity. Our findings also suggest that the link between SFRP5 and diabetes risk in African Ancestry men may be explained by its correlation with central adiposity. Additional larger studies among African ancestry populations are needed to explore this novel biomarker along with its temporal relationship with clinically relevant metabolic outcomes.

Disclosure
H. Ali: None. J.M. Zmuda: None. R. Cvejkus: None. E.E. Kershaw: Consultant; Self; Regeneron Pharmaceuticals, Inc.. A.L. Kuipers: None. C.H. Bunker: None. I. Miljkovic: None.
Overweight Individuals with Type 1 Diabetes Are Less Likely to Present with Diabetic Ketoacidosis—Data from the After Diabetes Diagnosis Research Support System (ADDRESS-2) Cohort
Authors: MISRA SHIVANI , KAUR AKAAL , GODSLAND IAN F. , WALKEY HELEN C. , JOHNSTON DESMOND G. , OLIVER NICK 
Published: June 2018

Introduction: Insulin resistance has been proposed to accelerate progression to type 1 diabetes (T1D) in antibody positive relatives of affected individuals. We hypothesised that overweight individuals with confirmed T1D would be less likely to present with diabetic ketoacidosis (DKA), signifying an earlier onset of T1D, due to concomitant insulin resistance.
Methods: The ADDRESS-2 study recruits incident clinician-assigned T1D cases within 6-months of diagnosis and systematically assesses pancreatic autoimmunity by GAD-65, IA-2 and ZnT8 antibodies. People with at least two positive antibodies were selected to confirm diagnosis of T1D and categorised for adiposity according to BMI (adults) or Z-scores (children). Odds ratios (OR) for presentation with DKA were compared, adjusted for potential confounders and sub-analysed by whether adult or child at recruitment.
Results: 31% (969/ 3132) were positive for two or more pancreatic antibodies. Of these 44% (424/969) presented with DKA. The proportions with DKA varied significantly by adiposity: 59% underweight (16/27), 47% normal (280/601), 39% overweight (103/263), 30% obese (19/63) and 40% severely obese (6/15) (p=0.02). When adjusted for age, being overweight or obese was associated with lower risk of DKA in adults (OR 0.58, p=0.006; 0.44, p=0.03, respectively) not children (OR 0.9, p=0.81; 0.51, p=0.12, respectively). Higher adiposity category was associated with higher daily insulin-requirements independent of age, with obesity associated with a 4 unit/day increase (p=0.03) and severe obesity, 11 units/day increase (p=0.008).
Conclusion: Adults with T1D are less likely to present with DKA if overweight or obese. Despite smaller proportions of DKA, insulin requirements are higher. These data suggest that, in adults, T1D presentation is unmasked by the insulin resistance of obesity prior to absolute insulin deficiency and ketoacidosis.

Disclosure
S. Misra: None. A. Kaur: None. I.F. Godsland: None. H.C. Walkey: None. D.G. Johnston: None. N. Oliver: Advisory Panel; Self; Dexcom, Inc., Roche Diabetes Care Health and Digital Solutions, Medtronic. Research Support; Self; Dexcom, Inc., Roche Diabetes Care Health and Digital Solutions. Other Relationship; Self; Novo Nordisk A/S, Takeda Development Centre Europe Ltd..
The First Genome-Wide Association Study (GWAS) for Type 2 Diabetes in Youth from the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration
Authors: SRINIVASAN SHYLAJA , TODD JENNIFER , CHEN LING , DIVERS JASMIN , GIDDING SAM , CHERNAUSEK STEVEN , GUBITOSI-KLUG ROSE , KELSEY MEGAN M. , SHAH RACHANA , BLACK MARY HELEN , WAGENKNECHT LYNNE E. , MERCADER JOSE M. , MANNING ALISA , FLANNICK JASON , DABELEA DANA , FLOREZ JOSE C. 
Published: June 2018

The prevalence of type 2 diabetes is increasing in youth, particularly in certain ethnic groups, and studies have highlighted differences between youth- and adult-onset disease. However, its genetic determinants remain largely unexplored.
To identify genetic variants predisposing to type 2 diabetes in youth, we formed ProDiGY, a multi-ethnic collaboration of the TODAY, SEARCH for Diabetes in Youth, and T2D-GENES studies, with 30young cases (mean age= 15.1 y ±2.8, 63% female, 22% white, 36% African American, 42% Hispanic) and 6061 diabetes-free adult controls (mean age = 54.2 y ±12.4; 57% female, 24% white, 18% African American, 58% Hispanic).
After stratifying by self-reported and principal component-clustered ethnicity, we performed association analyses on 206,928 directly genotyped variants using a generalized linear mixed model using a genetic relationship matrix to account for population structure.
We identified 5 genome-wide significant loci, including the novel locus rs13130484 in GNPDA2 (P= 1.4 ×10-8, odds ratio [OR]= 1.24), which has nominal association with type 2 diabetes in adults. Known loci identified in our analysis include rs4132670 in the well-known type 2 diabetes locus TCF7L2 (P= 4.2×10-13, OR 1.35) in high linkage disequilibrium with causal SNP rs7903146 (R2=0.83), rs11662368 near the obesity locus MC4R (P= 3.9×10-9, OR =1.31), rs11257655 in RN7SL232P (P= 5.7×10-12, OR= 1.33), and rs7075724 in CDC123 (P= 8.3×10-11, OR= 1.29); effect sizes are greater for these latter three loci than those found in adults (Pdiff= 8.2×10-5, 2.4×10-5, and 1.7×10-6, respectively). Secondary analysis with 856 diabetes-free youth controls demonstrated consistent direction of effect but no additional loci.
In conclusion, we identified known and novel genetic loci predisposing to type 2 diabetes in youth. Our future analysis of ∼10 million variants holds the potential to uncover additional new type 2 diabetes susceptibility loci.

Disclosure
S. Srinivasan: None. J. Todd: None. L. Chen: None. J. Divers: None. S. Gidding: None. S. Chernausek: Advisory Panel; Self; Novo Nordisk Inc.. R. Gubitosi-Klug: None. M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp.. R. Shah: None. M. Black: None. L.E. Wagenknecht: None. J.M. Mercader: None. A. Manning: None. J. Flannick: None. D. Dabelea: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen.
A High Resolution Capture-C Promoter "Interactome" Implicates Causal Genes at Type 2 Diabetes GWAS Loci
Authors: MANDUCHI ELISABETTA , JOHNSON MATTHEW , LEONARD MICHELLE , LU SUMEI , HODGE KENYAITA M. , CHESI ALESSANDRA , WELLS ANDREW D. , GRANT STRUAN F.A. 
Published: June 2018

GWAS has revealed many loci for type 2 diabetes (T2D). However, GWAS just reports genomic signals and not necessarily the precise localization of effector genes, with eQTLs making inferences to only a subset of such loci. Chromatin conformation capture-based techniques that detect contacts between distant regions of the genome offer an opportunity to understand GWAS signals that principally reside in non-coding regions, thus likely influencing regulatory elements. To move beyond analyzing one locus at a time and to improve on the low resolution of available Hi-C data, we developed a high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters in any cell type. We applied this to the immortalized human β-cell line, EndoC-βH1, a model relevant to T2D. We designed a custom Agilent SureSelect library targeting both ends of DpnII restriction fragments that overlap promoters of protein-coding, plus noncoding, transcripts, totaling 36,691 RNA baited fragments. Following sequencing, we investigated significant interactions at varying resolutions depending on how the fragments were leveraged and/or collapsed. In parallel, we generated ATAC-seq open chromatin maps to filter for informative proxy SNPs (r2&gt;0.8) to each of the 104 T2D independent sentinels reported to date, yielding overall 150 (harbored in 94 DpnII fragments) for 50 of these loci. By filtering our promoter ’interactome’ results at 4 DpnII fragment resolution (median distance between interacting regions ∼115kb, median region size =1,440bp) based on these proxies and openness of the regions they interact with, we observed contacts relevant to 17 of the original loci. Some ’nearest’ genes were supported e.g., GIPR and ZFAND3, while at other loci more distant genes were implicated e.g., OGFOD2 at ’MPHOSPH9’ and MESP2 at ’AP3S2’.
In conclusion, we observed informative contacts at putative effector genes for 16% of T2D GWAS loci in this particular cellular context.

Disclosure
E. Manduchi: None. M. Johnson: None. M. Leonard: None. S. Lu: None. K.M. Hodge: None. A. Chesi: None. A.D. Wells: None. S.F.A. Grant: None.
Genetics of Circulating HbA1c Long-Term Change over Time in Nondiabetic Subjects—The Long Life Family Study
Authors: AN PING , LENZINI PETRA , THYAGARAJAN BHARAT , LEE JOSEPH H. , ZMUDA JOSEPH M. , VARDARAJAN BADRI N. , MILJKOVIC IVA , YASHIN ANATOLIY I. , CHRISTENSEN KAARE , PERLS TOM , PROVINCE MICHAEL 
Published: June 2018

HbA1c is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank T2D. Trajectories of repeated HbA1c measurements over years are also associated with aging, cognitive performance and mortality. To identify genomic regions and loci for long term change in HbA1c, we conducted genome-wide linkage (GWLS) and association (GWAS) studies in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the U.S. and Denmark. We performed GWLS/GWAS in 1902 non-T2D participants of European ancestry who had complete data from two exams collected 7 years apart. HbA1c change over time was derived using growth curve modeling, and was adjusted for age, sex, BMI, smoking, centers and PCs, and blom-transformed to approximate normality. SNPs imputed using the HRC all-Caucasian reference panel were analyzed. LOKI/SOLAR were used for GWLS. EPACTS with make-kin and emmax options for familial clustering assuming additive genetic effects were used for GWAS. Lods &gt; 3 for GWLS and p &lt; 5e-8 for GWAS were used to declare significance. Heritability for HbA1c change over time reached 38% (p = 8e-10). GWLS yielded a significant region on 17p12 (Lods 3.5, 13 Mb). Two previous reports highlighted this region for fasting glucose and metabolic syndrome. From the GWAS, one SNP on 10q22.1 was significant (HK1-rs16926246, p = 4e-8, MAF = 0.14, β = -0.26). HK1 encodes hexokinase 1, which phosphorylates glucose to produce G6P, the first step in glycolysis. HK1-rs16926246 is a SNP previously associated with baseline HbA1c, erythrocyte traits, hematocrit and hemoglobin. Together, we identified 17p12 and HK1-rs16926246 as candidate loci for longitudinal change in HbA1c among non-T2D subjects in the LLFS. This analysis yields new information about the genetic regulation of HbA1c among nondiabetic individuals selected for exceptional survival and healthy aging. Replication in the external datasets is underway.

Disclosure
P. An: None. P. Lenzini: None. B. Thyagarajan: None. J.H. Lee: None. J.M. Zmuda: None. B.N. Vardarajan: None. I. Miljkovic: None. A.I. Yashin: None. K. Christensen: None. T. Perls: None. M. Province: None.
Low Vitamin B12 Levels in Early Pregnancy Are Associated with Fasting Glycemia—A Prospective Cohort Study
Authors: SUKUMAR NITHYA , ANTONYSUNIL ADAIKALA , GHEBREMICHAEL-WELDESELASS YONAS , GOLJAN ILONA , BAGIAS CHRISTOS , SARAVANAN PONNUSAMY 
Published: June 2018

Background: The pathogenesis of gestational diabetes mellitus (GDM) is not fully understood and combining novel biomarkers with established risk factors could improve early prediction of GDM. Low vitamin B12 (B12) levels have been linked to obesity, insulin resistance and GDM but its predictive ability in early pregnancy as a risk factor for later GDM has not been proven.
Methods: Micronutrients in Pregnancy as a Risk factor for gestational diabetes and Effects on mother and baby (PRiDE) is a cohort study of pregnant women at high risk of developing GDM (n=4751 recruited). GDM was diagnosed by a 2-hour 75g OGTT according to UK NICE criteria (fasting blood glucose, FBG ≥5.6mmol/l or 2-hour BG ≥7.8mmol/l). B12 and folate were measured by electrochemiluminescence and deficiency defined as ≤200pg/ml and ≤3ng/ml respectively. Multiple linear and logistic regression models were done with covariates including age, BMI, ethnicity, parity, smoking status, gestational weight gain and folate levels.
Results: The data from the first 3412 women with complete B12/folate and OGTT results were analysed (median (range) gestational age 12+5(4+3, 16+0) and 26+4 (15+0, 32+1) weeks respectively). Mean (±SD) age was 30.7±5.2 years, BMI 30.8±7.3 kg/m2 and 56.0% were obese. 11.5% had GDM and B12 and folate deficiency rates were 10.2% and 0% respectively (p&gt;0.05 in GDM vs. no-GDM). GDM women had similar B12 and folate values to no-GDM (346±151 vs. 357 ± 155 pg/ml and 19.8±12.6 vs. 18.8±12.1 ng/ml respectively, adjusted p&gt;0.05). B12 was negatively correlated with BMI (Pearson’s r=-0.24, p&lt;0.001) and inversely related to FBG, after adjustment for covariates including BMI (β=-0.03, p=0.003). There was no association with 2-hour BG. Low B12 values were more predictive of GDM among obese women (mean 314±119 vs. 328±134 pg/ml, adjusted p=0.06).
Conclusions: Early pregnancy B12 values were predictive of high FBG in late gestation. Low B12 levels may be an independent risk factor for GDM, particularly in obese women.

Disclosure
N. Sukumar: None. A. Antonysunil: None. Y. Ghebremichael-Weldeselass: None. I. Goljan: None. C. Bagias: None.
Hepatic Transcriptomic Signature of High-Sucrose Diet in Nonobese Model of Metabolic Syndrome and Prediabetes
Authors: MARKOVÁ IRENA , HÜTTL MARTINA , MALINSKA HANA , SEDA ONDREJ , KAZDOVA LUDMILA 
Published: June 2018

Both genetic predisposition and nutrition factors, such as high sucrose diet (HSD), are involved in the development of metabolic syndrome and insulin resistance. HSD can cause glucose intolerance and liver steatosis and exert hypertriglyceridemic effect. The aim of this study was to investigate the liver transcriptome profile under standard diet or HSD (70 kcal% as sucrose) in two strains of rats. We used Wistar rats and a strain of hereditary hypertriglyceridemic rats (HHTg) as a polygenic model of metabolic syndrome and insulin resistance. HSD feeding in 2 weeks did not affect body weight, but fasting glucose and AUC were increased (P diet&lt;0.01, P strain&lt;0.05). HSD feeding in both strains led to marked accumulation of hepatic triglycerides (P diet&lt;0.01). However, cholesterol concentrations in the liver were reduced after HSD (P diet&lt;0.01) in both strains. Comparative transcriptomic analyses in the liver identified (FDR&lt;0.05) sets of differentially expressed genes in response to HSD common to both strains (n=959 transcripts) as well as HHTg (n=687) and Wistar (n=1531) specific sets. Network analysis revealed overrepresentation of genes involved in transport, synthesis or regulation of lipid metabolism (SREBF, PPARA, PPARG, SCD), mitochondrial dysfunction, excessive oxidative stress response (NRF2-mediated) and endoplasmic reticulum stress. Expression of genes related to sterol biosynthesis and oxidative phosphorylation was down-regulated, whereas genes involved in fatty acid synthesis (FAS, ACC), oxidative or endoplasmic reticulum stress were up-regulated after HSD. Our results support that HSD induced alterations in the liver transcriptome in both strains, which precede the development and progression of liver steatosis. The top regulated gene networks included lipid metabolism and mitochondrial dysfunction. Most of the major expression shifts due to HSD were similar in direction in both strains but differed in magnitude of expression change.

Disclosure
I. Marková: None. M. Hüttl: None. H. Malinska: None. O. Seda: None. L. Kazdova: None.
Central Obesity in Early Pregnancy Increased Risk for Gestational Diabetes
Authors: ZHU YEYI , HEDDERSON MONIQUE , QUESENBERRY CHARLES , FENG JUANRAN , FERRARA ASSIAMIRA 
Published: June 2018

Central obesity has been linked to type 2 diabetes but prospective data are limited among pregnant women. We examined the associations of central obesity measures, waist-to-hip ratio (WHR) and waist circumference (WC), in early pregnancy with subsequent gestational diabetes (GDM) risk; and evaluated the potential for insulin resistance markers to mediate the central obesity and GDM association. Within the Pregnancy Environment and Lifestyle Study prospective cohort of 1,750 women, waist and hip circumferences were measured at 10-13 weeks of gestation. In a nested case-control study within the cohort, 115 GDM cases ascertained by Carpenter-Coustan criteria and 230 non-GDM controls had fasting serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and adiponectin measurements at weeks 16-19. Multivariable Poisson and conditional logistic regression models were used, adjusting for established risk factors including age ≥35 years, minority race/ethnicity, pre-pregnancy overweight/obesity, family history of diabetes, previous GDM, and preexisting hypertension. Compared to women with WHR &lt;0.85 and no established risk factors, women with WHR ≥0.85 and no risk factors had a 3.74-fold (95% CI 1.92-7.27) increased risk of GDM, and women with WHR ≥0.85 and at least one risk factor had a 6.63-fold (3.48-12.63) increased risk. In the receiver-operating-characteristic curve analysis, WHR significantly improved GDM risk prediction beyond established risk factors (C-statistics 0.796 vs. 0.744, P-for-difference &lt;0.0001). Similar but attenuated results were observed for WC ≥88cm. Insulin, HOMA-IR, and adiponectin levels mediated the WHR-GDM association by 9.0%, 9.6%, and 11.1%, respectively; corresponding mediation proportions for WC-GDM were 40.0%, 41.1%, and 35.4% (all P-values &lt;0.04). Our findings suggest that central obesity in early pregnancy represented a high-risk phenotype for GDM and may help identify at-risk women for early screening, prevention, and treatment.

Disclosure
Y. Zhu: None. M. Hedderson: None. C. Quesenberry: None. J. Feng: None. A. Ferrara: None.