bluuebunny/crossref_metadata_2025_split huggingface dataset:
2442-PUB: Religion and Religiosity Are Associated with Hyperglycemia in Adults without Diabetes in Northern Israel
Authors: BASHKIN AMIR , SHEHADEH MONA , YAACOVY RONIT , NODELMAN MARINA , ZUR ANITA , BARHOUM MASAD 
Published: June 2019

Background: Northern Israel is characterized by a multi-ethnic population. We looked for differences in the risk factors for hyperglycemia in Jews, Muslims and Druze without diabetes.
Methods: Adult visitors to our Medical Center without known diabetes were included in the study. A point-of-care (POC) capillary blood glucose level with institutional glucometer and a seated blood pressure were measured and additional data were collected from an interview. We excluded people with hypoglycemic drug usage, acute disease, glucocorticoid usage, pregnancy and capillary blood glucose in the diabetes range. The blood glucose levels were divided according to last caloric intake to postprandial (4 hours or less) or pre-prandial (more than 4 hours). Hyperglycemia was defined as pre-prandial blood glucose level ≥100 mg/dl or postprandial glucose level ≥140 mg/dl. High systolic blood pressure was defined as ≥140 mm Hg. Backward stepwise logistic regression was used to identify the factors independently associated with hyperglycemia.
Results: A total of 1062 Jews, 419 Muslims and 341 Druze were included in the analysis. 57% of Muslims, 44% of Jews and 34% of Druze reported that they are religious. Compare to Jews, Muslims had increased risk for hyperglycemia (OR 1.73, 95% CI 1.22-2.43, p=0.002) and Druze had no significant difference. After adjusting for sex, high systolic blood pressure and fewer than 12 years of education, age was a significant risk factor for hyperglycemia in all three religions and obesity was an independent risk factor for Druze (OR 2.45, 95% CI 1.28-4.69, p=0.07) and Muslims (OR 2.25, 95% CI 1.31-3.86). Only religious Muslims had an independently lower risk for hyperglycemia than non-religious Muslims (OR 0.5, 95% CI 0.29-0.86, p=0.012).
Conclusion: Religion and religiosity are independently associated with hyperglycemia in people without diabetes. Muslims in north Israel have increased risk for hyperglycemia compared to Jews but this risk is lower in religious people.

Disclosure
A. Bashkin: None. M. Shehadeh: None. R. Yaacovy: None. M. Nodelman: None. A. Zur: None. M. Barhoum: None.
2449-PUB: Sex-Specific Associations between Diabetic Status and Cognitive Performance
Authors: VISARIA AAYUSH , AMOROSA LOUIS F. 
Published: June 2019

Background: We studied cognitive performance in prediabetes (PD) and diabetes mellitus (DM) in males and females.
Methods: A population of 1,895 males and 2,249 non-pregnant females aged 20-59 with data on the Symbol Digit Substitution Test (SDST) and DM status and no history of stroke, depression, or recreational drug use were included in this secondary analysis of NHANES III (1988-1994). Diabetic status, as determined by FPG, in mg/dl, was categorized into Normal (70-99), PD (100-125), and DM (≥126 or HbA1c &gt; 6.5% or medication use). Cognitive performance was measured using a computer-based SDST, commonly used to assess frontal lobe-related functions. Multivariate linear regression models were run using an inverse transformed SDST score (digits/90 sec) and adjusted for confounders and study design in 3 additive models listed in Table 1.
Results: The mean (SE) SDST score (in digits/90 sec) was 36.9 (0.3) for females and 35.2 (0.3) for males. DM males matched, on average, 4.02 fewer digits than normals. This association did not hold after adjustment in Model 2 and 3. PD males, however, significantly matched 1.16 fewer digits than normals even after adjustment. Although PD and DM females also had lower SDST scores compared to normals, the difference lost significance after adjustment.
Conclusion: PD and DM did poorer on SDST than normals. Males seem to be more affected cognitively by impaired glucose tolerance than females.

Disclosure
A. Visaria: None. L.F. Amorosa: None.
2452-PUB: Use of Controlled Transient Elastography (VCTETM) Evaluation in a Clinical Research Clinic to Assess Degree of Liver Fibrosis and Steatosis in a Largely Hispanic Population
Authors: MORA PABLO F. , CAMACHO ALLISON S. , ADAMS-HUET BEVERLEY 
Published: June 2019

The aim of this study was to describe a population referred as potential research study candidates for diabetes, obesity and nonalcoholic Fatty Liver Disease (NAFLD). NAFLD is now the leading cause of cirrhosis, ahead of viral hepatitis and alcohol-related liver disease and is associated with type 2 diabetes, dyslipidemia and obesity. The clinical challenge is how to screen these subjects to determine the degree of fibrosis and steatosis, ideally with a non-invasive procedure and to complement it with the traditional clinical and biochemical markers for NAFLD. We utilized Controlled Transient Elastography (VCTETM) measurements performed with a Fibroscan® (Echosens) to produce a minimum of ten acquired measurements with a median liver stiffness (fibrosis) measured in kPa with IQR/Median percentage and a CAP ultrasound attenuation rate (steatosis) value measured in dB/m. Patients were evaluated from December 2017 to December 2018 with a consent form obtained prior to the examination and IRB approval for the analysis of the data. A total of 198 individuals had a complete, valid Fibroscan® report, median age 52. 54% were females with a majority of them (67%)identified as of Hispanic ethnicity. The median (IQR) kPa score was 5.8 (4.5-7.9), QR/Mean percentage 11.9% (7.8-16.9)and CAP attenuation rate of 320 (282-352) dB/m. The percentage of individuals who had an elevated kPa over 7.5 (identified as F2) was 27% and CAP attenuation score over 290 was 71%, with 24% of them had both an elevated kPa and CAP scores identifying the presence of both fibrosis and steatosis. We conclude that in a population of primarily Hispanic individuals, we detected a high rate of clinically significant fibrosis and steatosis suggesting a high prevalence of NAFLD in these high-risk group and emphasize the role of non-invasive testing of individuals with T2DM, obesity and metabolic syndrome.

Disclosure
P.F. Mora: Consultant; Self; Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., MannKind Corporation, Merck & Co., Inc., Novo Nordisk Inc., Valeritas, Inc. A.S. Camacho: None. B. Adams-Huet: None.
246-LB: Rare Noncoding Intronic HNF1A Sequence Variants Cause Aberrant mRNA Processing in MODY
Authors: SOLHEIM MARIE H. , KHAKIANI MOJDEH NASROLLAHZADEH , MOLNES JANNE , AUKRUST INGVILD , NJøLSTAD PåL RASMUS , JOHANSSON STEFAN 
Published: June 2019

The transcription factor Hepatocyte nuclear factor-1α (HNF1A) is important for normal pancreas development and function. Some HNF1A genetic variants are associated with type 2 diabetes, others can cause Maturity-Onset Diabetes of the Young (MODY3). Since variations in the HNF1A gene give different clinical consequences, novel sequence variants require thorough clinical and functional analysis. Here we investigate, in vitro, the consequence of rare non-coding intronic sequence variants of HNF1A from the Norwegian MODY registry. To evaluate the effect of four potential splice site mutations, fragments of intron/exon/intron genomic DNA from patient blood was amplified and cloned between two exons in a pCAS2 splicing minigene vector. Total RNA was isolated from HeLa and HepG2 cells transfected with minigene plasmids (wt or mutant) and analyzed by RT-PCR followed by agarose gels and sanger sequencing. All selected variants showed alternative mRNA splicing compared to wt by the minigene assay. The major splicing event of mutant c.526+1G&gt;A showed the activation of a cryptic donor site, causing loss of the last 31 nucleotides of exon 2. In mutant c.714-1G&gt;A, the major splicing event showed loss of 38 nucleotides in exon 4, due to activation of a novel cryptic acceptor site. In the event of c.956-2A&gt;G, sequencing showed a complete skipping of the subsequent exon 5. The c.1502-6G&gt;A variant causes activation of a cryptic acceptor site in intron 7 which leads to a four-nucleotide retention of the intronic sequence. The consequences of all variants were additionally evaluated using in silico splice site predictions by the integrated software tool Alamut v.2.6. Predictions of cryptic sites and the in vitro nucleotide changes observed were fully in agreement. These four intronic HNF1A variants likely cause MODY3 due to abnormally spliced mRNAs. By combining in silico predictions and the pCAS2 minigene expression system, we here provide further evidence of the variants role as pathogenic MODY3 mutations.

Disclosure
M.H. Solheim: None. M. Nasrollahzadeh Khakiani: None. J. Molnes: None. I. Aukrust: None. P. Njølstad: None. S. Johansson: None.
2470-PUB: Standardized Glucose, Insulin, and ß-Cell Response to Glucose Reveal Important Details of the Pre-DM Trajectories Not Shown in Retrospective or Prospective Epidemiological Analyses
Authors: HANSEN BARBARA C. , NEWCOMB JENNIFER D. , LIN PAUL K. , CATHERINE JEN K-L. 
Published: June 2019

Over the past 30 years, in prospective longitudinal studies of the development of T2DM and its risk factors, within-subject individual variable trajectories (as characterized in nonhuman primates (NHPs) have shown very different individual profiles compared to data synchronized retrospectively on the time point of DM diagnosis (DM DX) (e.g., Whitehall II or ARIC studies). About 30% of unrelated NHPs naturally and spontaneously develop T2DM at an average age of 19.2 ± 5.4 years (equivalent to ∼60 years in humans). New trajectory analyses of the standardized fasting glucose (FPG), fasting insulin (FPI) and β- cell function of those monkeys that became DM while under longitudinal study indicate that the functional β-cell changes in the pre-DM period, applying the usual epidemiological analytical approach used in humans, is likely to be highly misleading. The NHP DM progression data of 24 adult monkeys studied for an average of 8 years, with pre-DM data obtained up to 18 years pre-DM DX show that these trajectories must be analyzed individually and then standardized for rate of progression, timing of progression and amplitude of changes in order to establish the valid naturally-occurring patterns of the pre-DM progression seen below.

Disclosure
B.C. Hansen: None. J.D. Newcomb: None. P.K. Lin: None. K. Jen: None.

Funding
National Institutes of Health
2471-PUB: Evaluation of Model-Based Indices of Glucose Metabolism in Morbidly Obese Subjects
Authors: BRIX JOHANNA , KRZIZEK EVA-CHRISTINA , TURA ANDREA , PACINI GIOVANNI , LUDVIK BERNHARD 
Published: June 2019

Patients with MO are insulin resistant and the degree of insulin resistance (IR) further depends on glycemic status. To determine IR, model-based indices use fasting and/or post-challenge glucose and insulin levels. In this study, we examined the validity of indices of GM in a large cohort of patients with MO and varying degrees of glucose tolerance. We included 1337 patients with MO without known diabetes (mean age 40±12 years, mean±SD, BMI 45.0± 6.6kg/m²). All patients underwent a 75g oGTT, glucose and insulin levels were repeatedly measured for the calculation of IR and Insulin Sensitivity indices (Table) and analysis for the respective glucose tolerance categories. Diabetes mellitus (DM) was detected in 120 (9%) patients, 348 (26%) had impaired glucose tolerance or impaired fasting glucose (IGT/IFG), 869 (65%) patients had normal glucose tolerance (NGT). Patients with DM were older (p&lt;0.001) and had a lower BMI (p= 0.014) compared to NGT. GM indices are depicted in the Table. and show that all indices except for Matsuda and AUC insulin show differences between the glucose tolerance categories. In patients with MO, GM indices using basal glucose and insulin levels can be used to routinely measure insulin resistance without need of more elaborate testing. In particular, they can be used in patients with diabetes when an OGTT would be inappropriate.

Disclosure
J. Brix: None. E. Krzizek: None. A. Tura: None. G. Pacini: None. B. Ludvik: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Takeda Development Centre Europe Ltd. Research Support; Self; Akebia Therapeutics, Eli Lilly and Company, Novartis AG, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.
2473-PUB: Differential Effects of High-Fat Diet and Niacin on Nonalcoholic Fatty Liver Disease in C57BL/6J and B6129SF2/J Mice: A Metabolomic Analysis
Authors: FANG HAN , LI ZHUOYUE , GRAFF EMILY , MCCAFFERTY KAYLEEN J. , JUDD ROBERT L. 
Published: June 2019

Recent studies have demonstrated significant metabolic changes in different strains of mice fed a high-fat diet (HFD). Pharmacological doses of niacin can improve nonalcoholic fatty liver disease (NAFLD) in HFD-fed rodents. However, previous study from our lab demonstrated that niacin increases the hepatic triglyceride content and histological score in HFD-fed B6129SF2/J (B6129) mice but has no effect in C57BL/6J (B6) mice. Therefore, the aim of this study was to identify the mechanism responsible for niacin-induced fatty liver in B6129 mice using targeted liver metabolomic analysis. Livers were collected from B6 and B6129 mice, which were fed either a chow (10% fat) or HFD (60% fat) for 20 weeks with niacin (360 mg/kg/day) or vehicle supplementation from week 5 to week 20. Two hundred polar metabolites were identified in these livers. A total of 21 and 26 metabolites identified as different between chow and HFD group in B6 and B6129 mice, respectively. In B6 mice, only 6 metabolites were identified as different with niacin treatment and no specific pathways appeared to be impacted. In contrast to B6 mice, 16 metabolites and 5 pathways were impacted by niacin in HFD-fed B6129 mice. Of the metabolites that were changed in these pathways, only hydroxyphenylpyruvate (also known as 4-Hydroxyphenylpyruvate, 4-HPP) did not change with HFD feeding but significantly decreased with niacin treatment. 4-HPP is an intermediate in the metabolism of phenylalanine/tyrosine and improves mitochondrial oxidation in rats subjected to hemorrhagic shock. Therefore, decreased 4-HPP by niacin may lead to decreased beta-oxidation in the liver and subsequent lipid accumulation and liver damage in B6129 mice. Further lipidomic analysis suggested different hepatic lipid profiles with HFD and niacin treatment in B6129 mice, which may explain the increased NAFLD development in these mice with niacin treatment.

Disclosure
H. Fang: None. Z. Li: None. E. Graff: Research Support; Self; Elanco Animal Health. K.J. McCafferty: None. R.L. Judd: None.

Funding
Boshell Diabetes and Metabolic Diseases Research Program
249-LB: Identification of Hybrid Insulin Peptides through Mass Spectrometric Analyses
Authors: DELONG THOMAS 
Published: June 2019

Hybrid insulin peptides (HIPs) form if peptide fragments of (pro)insulin bind through peptide bonds to fragments of other proteins. We previously demonstrated that HIPs can be detected in human and murine islets by mass spectrometry, are targeted by diabetes-triggering CD4 T cell clones from non-obese diabetic mice, and are recognized by CD4 T cells isolated from the residual islets of pancreatic organ donors with type 1 diabetes (T1D). HIPs may be key antigens in the development of T1D as they contain non-genomically encoded amino acid sequences. Since the initial discovery of HIPs, we have established a set of rigorous criteria that allow us to identify various new HIPs in pancreatic islets with high confidence. The formation of HIPs involves the chemical activation of the C-terminal carboxylic acid groups of (pro)insulin peptides. These activated peptides can react with N-terminal amines of other peptides, leading to the formation of HIPs. The identification of such activated peptides is of great interest as it will help us understand which peptides contribute to hybrid peptide formation. We developed a new technique, which allows us to identify such chemically activated peptides by mass spectrometry. This technique may lead to the identification of activated peptides that are not derived from (pro)insulin and could provide valuable information needed for the identification of new hybrid peptides that may play a role in the development of type 1 diabetes and other autoimmune diseases.

Disclosure
T. Delong: None.

Funding
American Diabetes Association (1-15-ACE-14); National Institutes of Health; JDRF
2491-PUB: Proinsulin C-Peptide Attenuates Vascular Dysfunctions by Activating Nrf2
Authors: LAN FAN , LIN YAN , GAO ZHENFENG , ZHAO PAN , ZHANG XINGYU , SHIRAISHI YASUNAGA , IDO YASUO 
Published: June 2019

We and others demonstrated that insulin C-peptide has biological activities and may prevent tissue damages by diabetes. Our research using STZ diabetic rats and other models suggested that diabetic vascular dysfunctions, e.g., increased vascular permeability and blood flows are caused by oxidative and nitrosative stress initiated from increased NADH redox (reductive stress). However, C-peptide prevented dysfunctions without normalizing redox state and worked in nondiabetic rats. In this study, we further examined modes of actions and investigated its mechanisms. Male Wistar rats were used in animal study. Human de-differentiated adipocytes (DFAT cells) were used for cell culture study. Lentivirus vector expressing LC3-GFP was created to assess autophagy. Regional blood flow was assessed using microsphere. Acute hyperglycemia induced by glucose infusion for 5 hours resulted in increased regional blood flows in retina, sciatic nerve and kidney. Simultaneous infusion of C-peptide up to 16 mg/kg did not prevent the increases, while twice daily subcutaneous injection of 400 µg/kg for 2-days prior to infusion prevented completely. One-day injection was only slightly effective. Bolus i.v. injection of L-lactate 1 mol/kg but not NaCl caused reductive stress and blood flow increase, and this was also prevented by twice daily 2-days injection of C-peptide. Thus, C-peptide appeared to induce some factors counteracting oxidative stress during 2 days. In DFAT cells, LC3-GFP puncta was increased 3-fold by one time 100 nM C-peptide treatment in 1 hour. This was followed by nuclear localization of Nrf2 transcription factor at 2 hours. At 4 hour, 4-fold increase in Nrf2 target genes, IDH and SRXN1, expression were observed (p&lt;0.05). Similar 35-62% increase in Nrf2 target genes (Idh, Srxn1, Pgd and Hmox) were observed in rat aorta after twice daily 2-days injection of C-peptide. These results suggest that injections of pharmacological dose of C-peptide increase Nrf2 antioxidants expression through activating autophagy.

Disclosure
F. Lan: None. Y. Lin: None. Z. Gao: None. P. Zhao: None. X. Zhang: None. Y. Shiraishi: None. Y. Ido: None.

Funding
Japan Society for the Promotion of Science
2493-PUB: Distinct 5-Methylcytosine Profiles in Ribo-Minus RNA from Mouse Brown Adipose Tissue
Authors: ZHANG CHUANHAI , YIN RUILI , WANG JINGJING , QUANWEI WEI 
Published: June 2019

Methylation of DNA and RNA has become a research hotspot because of its diverse regulation of biological function and processes. In particular, posttranscriptional modifications in RNA, including methylation of the N6 positions in adenine (m6A), N1 positions in adenine (m1A) and methylation of carbon 5 in cytosine (m5C). However, information about the transcriptome-wide distribution and possible functions of m5C in different cell types, tissues, and organisms is still extremely limited. Brown adipose tissue is a functional organ for thermogenesis and an important potential target for the treatment of obesity and diabetes. The insights into possible functions of m5C modification and implications in BAT are significant and urgent to be revealed. In our study, we performed an unbiased global analysis of m5C in total and Ribo-minus RNA of brown adipose tissue from mouse after thermoneutrality (29?-30?) and/or cold stimulation (4?) for 1 day. We identified total 8153 sites in mRNA, 570 sites in CircRNA, and 991 sites in LncRNA, with respect to the degree of methylation, functional classification of methylated transcripts, and position bias within the transcript. Interestingly, there are intriguing differences in BAT after thermoneutrality and/or cold stimulation, which may provide us with new ideas to activate or enhance functionality of BAT. Our findings show the first comprehensive picture of m5C in the BAT from the mouse. These data establish and provide an important resource for future studies of function and biological significance of m5C in Ribo-minus RNA in brown adipose tissue.

Disclosure
C. Zhang: None. R. Yin: None. J. Wang: None. W. Quanwei: None.

Funding
National Natural Science Foundation of China (81700684 to C.Z.), (31402075), (31572403)
250-OR: Beta-Cell Rest Induced by Dapagliflozin Improves ß-Cell Secretory Capacity in Type 2 Diabetes Patients: A Randomized Controlled Trial vs. Gliclazide
Authors: VAN BOMMEL ERIK J.M. , MUSKIET MARCEL H. , VAN BAAR MICHAEL JACOBUS , KRAMER MARK H. , NIEUWDORP MAX , VERCHERE CAMERON B. , VAN RAALTE DANIËL H. 
Published: June 2019

Introduction: Disease progression in type 2 diabetes (T2D) is due to a continuous loss of β-cell function, partly driven by chronic secretory stress on remaining islets caused by hyperglycemia. Beta-cell loss may be further enhanced by insulin secretagogues such as sulfonylureas. In contrast, sodium-glucose cotransporter-2 inhibitors (SGLT2is) may improve beta-cell function by reducing β-cell afterload by lowering blood glucose levels through glucosuria.
Methods: Forty-four T2D patients treated with metformin (age 63 ± 7 years; HbA1c 7.3 ± 0.6%; GFR 113±19 mL/min) were randomized to dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD. At baseline and week 12, whole-body insulin sensitivity (M-value) and β-cell function were quantified by gold-standard hyperinsulinemic-euglycemic and hyperglycemic clamp with additional arginine stimulation. First-phase glucose-stimulated and arginine-stimulated incremental area under the C-peptide curves (iAUCCP) were calculated. iAUCCP multiplied by M-value rendered disposition indices (1st phase and ARG-DI; nmol.min/L.mg/kg.min).
Results: HbA1C decreased similarly (-0.47% with DAPA and -0.65% with GLIC; p=ns). DAPA, but not GLIC, decreased fasting hyperinsulinemia (-18.4 pmol/l vs. +2.7 pmol/l, p=0.01). Neither treatment improved insulin sensitivity. GLIC significantly increased 1st phase DI from 0.75 ± 1.21 to 2.89 ± 3.25 (p&lt;0.01), while DAPA did not (1.51 ± 2.81 to 2.15 ± 2.27, p=0.29). ARG-DI increased from 42.4 ± 12.1 to 45.2 ± 15.6 (p=0.03) with DAPA but was not improved by GLIC (52.3 ± 9.9 to 63.7 ± 8.6; p=0.28).
Conclusion: In contrast to the secretagogue GLIC, DAPA lowered fasting insulin levels and did not further enhance C-peptide secretion in response to hyperglycemia. However, it did improve ARG-DI, which may reflect β-cell total secretory capacity. Thus, by lowering beta-cell afterload, DAPA may confer long-term β-cell benefit versus GLIC.

Disclosure
E.J.M. van Bommel: None. M.H. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. M.J. van Baar: None. M.H. Kramer: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. C.B. Verchere: Advisory Panel; Self; Sirona Biochem. Board Member; Self; Integrated Nanotherapeutics. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi.

Funding
AstraZeneca Nederland BV