bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obesity and Liver Function in a Group of Children Visiting a Pediatric Clinic in South Texas
Authors: QUINTANA FERNANDO G. , CADENA JULIA A. , CERVANTES-GONZALEZ FRANCISCO J. 
Published: June 2018

It has been determined that there is a relationship between obesity and liver function. Purpose: the aim of this study is to analyze the relationship between obesity and liver function in a group of children.
Methods: the study was based on data obtained from 692 boys and 675 girls aged 0 to 15 years that visited the clinic in South Texas from 2000 to 2003. Children were classified according with the CDC BMI-for-age growth charts. Patients were classified also by age as stay home (SH) 0.5 to 3.99 years, elementary school (ES) 4 to to 11.99 years, Middle school (MS) 12 to 14.99 years and High school (HS) more than 15 years. Liver function was measured with the following enzymes alanine amino transferase (ALT), serum aspartate amino transferase (AST), and alkaline phosphatase (ALP). Analysis of variance was used for the analysis.
Results: there was a difference between obese and normal children for ALT (n = 45.18±0.83 IU/L vs. 38.87±1.09 IU/L, p&lt;0.05). There were no differences for ALP or AST between obese and normal children. AST levels were higher in boys when compared with girls (n=691, 30.84±0.479 IU/L vs. n=675, 27.91±0.49 IU/L, p&lt;0.05). ALT levels were higher in boys when compared with girls (n=691, 45.29± IU/L, n= 675, 39.30±0.66 IU/L, P&lt;0.05). There was no difference for levels of ALP between boys and girls. There was a decrease of ALP levels with age when children are classified as SH, ES, MS, and HS (n = 288, 327.29±27.16 IU/L; n=791, 291.36±2.69 IU/L; n=151, 261.27±9.17 IU/L; n=134, 139.73±6.30 IU/L; p&lt;0.05). There was a decrease of AST levels with age when children are classified as SH, ES, MS, and HS (n=288, 35.66±0.53 IU/L; n=791, 29.25±0.45 IU/L; n=151, 25.40±1.23 IU/L, n=134, 29.91±0.87, p&lt;0.05).
Conclusions: obesity represents an important factor that affects ALT levels. ALT is directly related with BMI percentile. Boys have higher levels of liver enzymes than girls. As children attend school and leave home ALP and AST levels decrease.
The research was approved by TAMIU IRB with ID number #2012-01-13.

Disclosure
F.G. Quintana: None. J.A. Cadena: None. F.J. Cervantes-Gonzalez: None.
Assessment and Expansion of Models for 13C-Metabolic Flux Analysis (MFA) In Vivo
Authors: HASENOUR CLINTON , RAHIM MOHSIN , YOUNG JAMEY 
Published: June 2018

Isotope-based MFA is a valuable tool to determine rates of biochemical reactions in vivo, which cannot be assessed by other approaches. Its application in biomedicine may help to uncover metabolic disease determinants in diabetes and obesity. However, various simplifying assumptions have been applied to constrain models used for in vivo MFA studies. These constraints are approximate, and their validity may change with varying experimental conditions. Here we used our flexible flux modeling platform (INCA) to test and eliminate several assumptions imposed on prior estimates of liver gluconeogenesis, anaplerosis, and citric acid cycle (CAC) fluxes in overnight fasted, conscious mice. Male C57Bl/6J mice were given a primed, continuous infusion (160µmol/kg and 40µmol/kg/minutes) of [13C3]lactate intravenously for ∼2 hour. 13C-enrichment of plasma and liver metabolites obtained at the end of the study were measured by GC-MS and used to regress liver metabolic fluxes using several different models of in vivo metabolism. In particular, we developed models to assess (1) the extent of reversibility of 4C reactions of the CAC, (2) the impact of pyruvate-decarboxylation, and (3) the influence of secondary isotope recycling on liver flux estimates. Confidence intervals were computed a posteriori to assess uncertainties of individual flux estimates. Glucose production originated largely from PEP. Cataplerosis (PEPCK flux) was ∼3.9-4.5 fold higher than citrate synthase, with ∼56-67% recycling back to the CAC through pyruvate. The modeling of pyruvate decarboxylation increased the relative ratio of gluconeogenesis to citrate synthase flux by ∼18-32% but also reduced the precision of flux estimates. Interestingly, Cori cycling reduced pyruvate kinase flux ∼16% relative to cataplerosis. Thus, interorgan crosstalk with the liver can be estimated with fewer assumptions in vivo, providing a potential path for understanding metabolic disease with greater consideration of whole-body physiology.

Disclosure
C. Hasenour: None. M. Rahim: None. J. Young: None.
Changes in Carbohydrate Metabolism are Related to Gut Microbiota Modification after H. Pylori Eradication
Authors: CORNEJO-PAREJA ISABEL , MARTIN-NUÑEZ GRACIA MARÍA , MAR ROCA-RODRIGUEZ M. , MORENO-INDIAS ISABEL , VINUELA LAURA , COIN-ARANGÜEZ LETICIA , MANCHA-DOBLAS ISABEL , TINAHONES FRANCISCO 
Published: June 2018

Introduction: Antibiotic treatments cause changes in gut microbiota. Dysbiosis of gut microbiota has been linked to metabolic diseases such as type 2 diabetes mellitus (T2DM). Objective: To evaluate whether changes in gut microbiota due to antibiotic treatment in patients colonized by H. pylori, could be related to improvements in carbohydrate metabolism.
Material and Method: A prospective case-control study were performed. Clinical data, carbohydrate metabolism, and microbiota composition in feces (determined by 16S rRNA gene (V3-V4) sequencing using the Illumina Miseq) before and 2 months after eradication treatment were analyzed.
Results: We studied 40 cases and 20 controls (60% women, respectively). Average age was 47.0 ± 2 vs. 43.6 ± 2.7 years old. 70% vs. 60% had family history of digestive disorders and 42.5% vs. 40% clinical history of gastrointestinal disease. After antibiotics, we found significant changes in gut microbiota profile at phylum, family, genus and species levels. The Chao and Shannon indices showed a decreased in bacterial richness and diversity in patients (pre and post H. pylori eradication) compared to controls. We observed an improvement in glucose homeostasis in cases 2 month after H. pylori eradication treatment, with decrease in HbA1c (p=0.014), 60’ (p=0.018) and 120’ (p=0.019) glucose post OGTT. Changes in Rikenellaceae, Butyricimonas, E. biforme, B. fragilis, and Megamonas were inversely associated with changes in glucose level and Hb1Ac in patients which got H. pylori eradication.
Conclusion: H. pylori eradication treatment causes alteration in human gut microbiota. The glucose homeostasis improvement found after antibiotic treatment was related to changes in microbial community, particularly in Megamonas and Butyricimonas genus, Rikenellaceae family and E. biforme and B. fragilis species. SCFA-producing and glucose remover bacterias could play an important role in these associations.

Disclosure
I. Cornejo-Pareja: None. G. Martin-Nuñez: None. M. Roca-Rodriguez: None. I. Moreno-Indias: None. L. Vinuela: None. L. Coin-Arangüez: None. I. Mancha-Doblas: None. F. Tinahones: None.
Clinical Utility of the T1D Genetic Risk Score—Examples from the U.S. Monogenic Diabetes Registry
Authors: SANYOURA MAY , LETOURNEAU LISA R. , NAYLOR ROCHELLE N. , PHILIPSON LOUIS H. , WEEDON MICHAEL N. , ORAM RICHARD A. , GREELEY SIRI ATMA W. 
Published: June 2018

Monogenic forms of diabetes are often difficult to distinguish from type 1 (T1D) and type 2 diabetes due to overlapping clinical features. As a result, a growing majority of patients remain misdiagnosed and often inappropriately treated. We used a T1D genetic risk score (T1D-GRS), generated from 10 T1D-associated common genetic variants, to help identify patients with a low T1D-GRS, and thus a potential monogenic etiology. We genotyped 798 probands from the U.S. Monogenic Diabetes Registry: 37% (n=293) had a known monogenic cause and 63% (n=505) had an unknown cause or were not exhaustively sequenced. To improve the discriminatory power of the T1D-GRS, participants were categorized using a T1D-GRS equivalent to the 5th, 25th, 50th, 75th, and 95th centile of the UK T1D cohort. 45% (132) of the registry participants with a confirmed monogenic cause had a T1D-GRS below the 5th percentile, 35% (103) had a T1D-GRS between the 5-25th percentile, 12% (35) between the 25-50th percentile, 5% (15) between the 50-75th percentile, and 2% (7) between the 75-95th percentile. Of the participants with an unknown cause, 24% (n=108) had a T1D-GRS below the 5th percentile, 30% (n=137) had a T1D-GRS between the 5-25th percentile, 16% (72) between the 25-50th percentile, 15% (67) between the 50-75th percentile, and 15% (69) between the 75-95th percentile. We sequenced a total of 124 participants with a T1D-GRS below the 25th percentile using a targeted next-generation sequencing library that includes more than 140 genes known to be associated with diabetes. 21% (n=24) were found to have a pathogenic variant in a known diabetes gene. Further tests are ongoing. Our results show that the T1D-GRS is a useful discriminatory tool between diabetes types and a strong predictor of whether a monogenic cause is likely. More importantly, patients with a low T1D-GRS and negative for all known monogenic subtypes should be prioritized for exome or whole genome sequencing to maximize the chance of novel gene discoveries.

Disclosure
M. Sanyoura: None. L.R. Letourneau: Other Relationship; Self; Novo Nordisk Inc.. R.N. Naylor: None. L.H. Philipson: Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; JAEB Center For Health Research, JDRF, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc.. M.N. Weedon: None. R.A. Oram: Other Relationship; Self; Randox. S.W. Greeley: Research Support; Self; Novo Nordisk Inc..
A Nonsynonymous Variant in GLP-1R Is Associated with Decreased Risk of Type 2 Diabetes in Koreans
Authors: KWAK SOO HEON , CHAE JEESOO , YOON JIWON , CHOI SUNGHEE , LIM SOO , MOON MIN KYONG , CHO YOUNG MIN , JANG HAK CHUL , JANG YOON SHIN , KANG HYUN MIN , KIM JONG-IL , PARK KYONG SOO 
Published: June 2018

Type 2 diabetes (T2D) is a common complex disorder with strong genetic predisposition. Although different ethnic groups share most of the common variants of T2D, there might be nonsynonymous variants that are specific to an ethnic group. In this study, we used whole exome sequencing (N=917) and exome genotyping array (N=3,026) to identify nonsynonymous variants in Korean T2D cases and controls (stage 1) and validated the findings in an independent set of 15,095 T2D cases and controls (stage 2). Whole exome capture was prepared using Agilent SureSelect version 4+UTR and sequencing was performed by Illumina HiSeq 2000. Nonsynonymous variants were incorporated into customized Axiom Biobank Plus Genotyping array. Genotype imputation was performed with 1,000 Genomes Project phase 3 reference. In silico data look-up was done for stage 2 analyses. EPACTS software was used for association testing and METAL was used for meta-analysis of stage 1 and 2 results. We identified 728,838 variants using whole exome sequencing, which include 258,463 novel variants. A nonsynonymous variant in GLP-1R (rs3765467, R131Q) was associated with decreased risk of T2D in genome-wide significance (OR = 0.85, P = 3.01x10-8). This variant was associated with lower fasting glucose concentration (P = 0.00020) and lower HbA1c level (P = 0.0085) in nondiabetic controls. The minor allele frequency of this variant was 21.1% in Koreans but it was monomorphic in Europeans. We also validated the previous association between PAX4 nonsynonymous variant (rs2233580, R192H) and increased risk of T2D (OR = 1.52, P = 6.41x10-15). This variant was associated with lower age at diagnosis and decreased C-peptide level in T2D cases (P &lt; 0.05). Gene-wise analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 0.00010) by Madsen and Browning method.
In summary, we have identified East Asian specific nonsynonymous variants in GLP-1R and PAX4 to be associated with T2D in genome-wide significance.

Disclosure
S. Kwak: None. J. Chae: None. J. Yoon: None. S. Choi: None. S. Lim: None. M. Moon: None. Y. Cho: None. H. Jang: None. Y. Cho: None. H. Kang: None. J. Kim: None. K. Park: None.
The Induction of TRIB3 Causing Glucose Toxicity in Muscle Requires the O-GlcNAcylation of SP1
Authors: LIU XIAOBING , KANG MINSUNG , TIMOTHY GARVEY W. 
Published: June 2018

Background: Glucose-induced insulin resistance is mediated by induction of the pseudokinase TRIB3, which requires glucose metabolism via the hexosamine biosynthetic pathway (HBP). We have also shown that the SP1 binding site in the TRIB3 promoter region is essential for glucose’s ability to induce TRIB3 in skeletal muscle. However, the mechanism by which glucose regulates TRIB3 gene expression remains unknown.
Hypothesis: Since the HBP provides the substrate for O-GlcNAcylation, we hypothesize that glucose results in O-GlcNAcylation of SP1 and this modulates induction of TRIB3 causing insulin resistance.
Results: When treated with 5mM or 25mM glucose, the induction of TRIB3 gene expression (P&lt;0.01) in L6 myotubes is accompanied by upregulation of SP1 expression (P&lt;0.01). When fully differentiated L6 myotubes are transiently transfected with SP1 siRNA, knockdown of SP1 produced a corresponding suppression of TRIB3 both in the high and low glucose (P&lt;0.05). To identify whether O-GlcNAcylation is involved, we cultured L6 myotubes in either 5mM or 25mM glucose medium with or without OSMI-1, an inhibitor of rate-limiting O-GlcNAc transferase (OGT). OSMI-1 did not affect glucose’s ability to augment SP1 2-fold (p&lt;0.01), but effectively blocked induction of TRIB3. At the same time, OSMI-1 downregulated O-GlcNAcylation of SP1 and other O-GlcNAc modified proteins.
Conclusion: (1) Increased TRIB3 mRNA expression parallels with upregulated SP1 expression; (2) Glucose induction of TRIB3 mRNA and protein is eliminated when HBP flux and O-GlcNAcylation is disrupted by the inhibition of OGT; (3) SP1 sites are critical in the regulatory action of glucose on the TRIB3 promoter and can be modulated by SP1 O-GlcNAcylation. While further studies are underway, these data provide new insights regarding mechanisms causing glucose-induced insulin resistance, and TRIB3 and TRIB3 promoter regulation are attractive targets for prevention of glucose toxicity in diabetes.

Disclosure
X. Liu: None. M. Kang: None. W. Garvey: Advisory Panel; Self; Novo Nordisk Inc., Merck & Co., Inc.. Research Support; Self; Sanofi, Pfizer Inc., Novo Nordisk Inc., AstraZeneca, Merck & Co., Inc., Elcelyx Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Eisai Inc..
Serum Anti-Phospholipidase A2 Receptor Antibody Differentiating Membranous Nephropathy from Diabetes Kidney Disease in a Large Population of Type 2 Diabetes Mellitus Patients
Authors: WANG QIAN , DONG ZHEYI , CHEN XIANGMEI 
Published: June 2018

Background: With the increase of diabetes, diabetes kidney disease (DKD) was increasing year by year. The pathological types of DKD were various, among which, membranous nephropathy (MN) accounts for a large proportion of nondiabetic renal diseases (NDRD). Recently, serum anti-phospholipidase A2 receptor antibody(sPLA2R-Ab) was used for the diagnosis of MN, the diagnostic efficacy of sPLA2R-Ab for MN in DKD population need to be further verified.
Methods: Screened on patients with type 2 diabetes mellitus (T2DM) who underwent a renal biopsy and have a valid sPLA2R-Ab test results, hospitalized in the general hospital of the people’s liberation army of China between May 1st, 2016 and January 30th, 2018. Eligible patients were divided into two groups according to the pathological results: MN group and non-MN group. Patients’ clinical and laboratory datas were collected. Statistical analysis was performed with SPSS20.0, and P&lt;0.05 was considered statistically significant.
Results: The study included 252 patients: 59 (23.4%) in the MN group and 193 (76.6%) in the non-MN group. MN accounts for 38% of NDRD. The sPLA2R-Ab test results of 35 patients were positive, all of them belonged to MN group. The positive rate of sPLA2R-Ab was 59.3% in MN group and 0 in non-MN group. Patients in the MN group had a higher fasting plasma glucose, age and lower estimated glomerular filtration rate, creatinine and blood pressure as well as a shorter duration of DM than patients in the non-MN group.sPLA2R-Ab achieved a good diagnostic efficiency with a sensitivity of 59.3%, specificity of 100%, negative predictive value of 88.9% and accuracy of 90.5% for MN in DKD.
Conclusion: If the sPLA2R-Ab result of DKD patients is positive, the patient must be MN, and if the result is negative, further renal biopsy should be done. The high accuracy of sPLA2R-Ab may be substituted for renal biopsy partially in the diagnosis of MN in DKD population.

Disclosure
Q. Wang: None. Z. Dong: None. X. Chen: None.
NFIA Colocalizes with PPARgamma and Activates the Cell-Type–Specific Enhancers to Control the Brown Fat Gene Program
Authors: HIRAIKE YUTA , WAKI HIRONORI , TSUTSUMI SHUICHI , ABURATANI HIROYUKI , YAMAUCHI TOSHIMASA , KADOWAKI TAKASHI 
Published: June 2018

Brown fat dissipates energy as heat by means of the uncoupling protein-1 (UCP1) on the mitochondrial inner membrane. Brown fat activity is inversely correlated with body mass index in humans, and pilot studies have shown that interventions such as chronic cold exposure successfully recruit human brown fat and increase systemic energy expenditure. Therefore, stimulating development and/or function of brown fat would be a novel strategy for the treatment of obesity and its complications. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of the brown-fat-specific open chromatin regions. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. In human brown fat, expression of NFIA and the brown-fat-specific genes including UCP1 is positively correlated. Mechanistically, NFIA co-localizes with the master transcriptional regulator of adipogenesis, PPARgamma, selectively at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, leading to increased chromatin accessibility and active transcription. Most recently, we performed mass spectrometry analysis of NFIA protein complex to identify and characterize the crucial partner of NFIA-dependent brown-fat-specific chromatin regulation. Collectively, these results indicate that NFIA is a key transcription factor that activates the cell-type-specific enhancers and facilitates the binding of PPARgamma for controlling the brown fat gene program.

Disclosure
Y. Hiraike: Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S, Mitsubishi Tanabe Pharma Corporation. H. Waki: Research Support; Self; MSD K.K., Novartis Pharma K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda PHarmaceutical Co., Ltd.. S. Tsutsumi: None. H. Aburatani: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
Fasting-Induced Changes in Glucagon Secretion Are Dysregulated in Obesity
Authors: STERN JENNIFER H. , SMITH GORDON I. , UNGER ROGER H. , KLEIN SAMUEL , SCHERER PHILIPP E. 
Published: June 2018

Hyperglucagonemia is a hallmark in obesity and type 2 diabetes (T2DM). Suppression of glucagon signaling improves glycemic control in T2DM. We evaluated glucagon homeostasis in lean and obese mice and people. Discordant with the canonical rise in glucagon with fasting, our studies show that fasting (4, 8, 16 and 24 h) caused a progressive decrease in serum glucagon in diet-induced obese, hyperglucagonemic mice (P&lt;0.01), yet a progressive increase in serum glucagon in lean mice (P&lt;0.01). Serum insulin decreased with fasting in both lean and obese mice (P&lt;0.01). Accordingly, fasting increased the glucagon:insulin ratio in the lean mouse (P&lt;0.01), but did not affect the glucagon:insulin ratio in the obese mouse. Two hours of re-feeding restored hyperglucagonemia in obese mice (P&lt;0.01). Pancreatic perfusion studies in obese, hyperglucagonemic mice confirm that 16 h of fasting decreases pancreatic glucagon secretion (P&lt;0.01). Consistent with our findings in the mouse, fasting decreased (P&lt;0.05) serum glucagon in obese participants. In contrast, fasting increased serum glucagon concentrations in lean participants (P&lt;0.05). As expected, fasting decreased serum insulin in both lean and obese participants (P&lt;0.05 for both). As a result, fasting induced a more robust rise in the glucagon:insulin ratio in lean compared to obese participants (P&lt;0.01). In addition, mixed meal feeding increased serum glucagon in people with obesity. These findings suggest that the metabolic pathophysiology of obesity may be driven by inappropriate meal-induced regulation of glucagon, resulting in a relatively static glucagon:insulin ratio.

Disclosure
J.H. Stern: None. G.I. Smith: None. R.H. Unger: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics. P.E. Scherer: None.