bluuebunny/crossref_metadata_2025_split huggingface dataset:
200-OR: Effects of Glucose Target on the Performance of a Bihormonal Bionic Pancreas
Authors: TUFFAHA MARWA , BALLIRO COURTNEY A. , HILLARD MALLORY , EL-KHATIB FIRAS , SELAGAMSETTY RAJENDRANATH , DAMIANO EDWARD , RUSSELL STEVEN J. 
Published: June 2020

We performed a non-blinded, random-order, cross-over study in 20 volunteers with type 1 diabetes comparing glycemic regulation by the bihormonal bionic pancreas (BHBP) at three glucose targets (130, 115, and 100 mg/dl). Subjects went about their daily routines during each 3-day test period. In the BHBP arms, lower glucose targets (130 to 115 to 100 mg/dl) were associated with correspondingly lower mean CGM glucose levels (156±12 to 146±14 to 135±14 mg/dl, p&lt;0.005 for each comparison). There was no corresponding difference in percent time &lt;60 mg/dl (0.6±1.0 % to 0.9±1.2% to 0.8±1.1%, p≥0.22 for each comparison). However, there was a corresponding significant increase in glucagon total daily dose (2.2±1.2 to 5.3±2.3 to 8.3±3.0 µg/kg/day, p≤0.001 for each comparison). Mean daily nausea scores reported on a 10 cm visual analog scale were low and not significantly different between BHBP arms (0.5, 0.8 and 1.1 cm for the 130, 115, and 100 mg/dl glucose targets, respectively, p&gt;0.05 for each comparison). There were no significant differences between the different BHBP arms in average hypoglycemia symptoms per day, average hypoglycemia interventions per day, or average grams of oral carbohydrates taken by subjects to prevent or treat hypoglycemia. The 100 mg/dl glucose target had a higher satisfaction score when compared to the 115 and 130 mg/dl glucose targets (4.3 versus 4.15 and 4.18, respectively; p&lt;0.005 for both comparisons). There was no significant difference in satisfaction score between the 115 and 130 mg/dl glucose targets. The results of the present study show that for the BHBP, the lowest glucose target in this comparison was associated with better glycemic control, no statistically significant increase in side effects, and greater user satisfaction than higher glucose targets.

Disclosure
M. Tuffaha: None. C.A. Balliro: None. M. Hillard: None. F. El-Khatib: Other Relationship; Self; Beta Bionics, Inc. R. Selagamsetty: Employee; Self; Beta Bionics, Inc. Stock/Shareholder; Self; Beta Bionics, Inc. E. Damiano: Board Member; Self; Beta Bionics, Inc. Employee; Self; Beta Bionics, Inc. Stock/Shareholder; Self; Beta Bionics, Inc. Stock/Shareholder; Spouse/Partner; Beta Bionics, Inc. S.J. Russell: Consultant; Self; Beta Bionics, Inc., ConvaTec Inc., Novo Nordisk A/S, Senseonics. Research Support; Self; Beta Bionics, Inc., Novo Nordisk A/S, Zealand Pharma A/S. Stock/Shareholder; Self; Companion Medical. Other Relationship; Self; Ascensia Diabetes Care, Roche Diabetes Care.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust
2001-P: Glycemic and Energy Homeostasis Profiles in Women with Different Metabolic Phenotypes of Obesity in Nutritionist Health Study
Authors: RIBEIRO FRANCIELI B. , SOLAR ISABELA , FREITAS RENATA G. , HANADA ALFREDO S. , BARBOSA MARINA G. , XAVIER CAMILA M. , CROUCHAN NAJLA S.K. , SANTOS VINICIUS F.D. , NETO BRUNO G. , SILVA ISIS T. , FOLCHETTI LUCIANA G.D. , PITITTO BIANCA ALMEIDA , FERREIRA-VIVOLO SANDRA ROBERTA G. , VASQUES ANA CAROLINA J. 
Published: June 2020

Objective: To compare components of glycemic and energy homeostasis in women with metabolically healthy normal weight (MHNW) and metabolically unhealthy (MUNW), metabolically unhealthy overweight/obese (MUO) and metabolically healthy (MHO) phenotypes.
Methodology: Cross-sectional study with 104 women (18-45 years): 30 MHNW, 17 MUNW, 27 MHO, 30 MUO. Overweight was considered BMI ≥ 25 kg/m² and metabolic health without of changes in blood pressure, glycemic, lipemic levels and cardiovascular disease. The standard mixed meal tolerance test and indirect calorimetry were performed (assessments at -15, 0, 30, 60, 120 and 180 min). The quantifications were: areas under the curve (AUC) for glucose, insulin, C peptide, glucagon and GLP-1; insulin sensitivity (IS) by oral glucose insulin sensitivity index; energy expenditure, respiratory quotient, and carbohydrate and lipid oxidation rate were measured at rest and after oral stimulation.
Results: The groups did not differ regarding age and HbA1c levels. IS was decreased in MUO compared to MHNW and MHO (p&lt;0.001). Insulin AUC was lower in MUO compared to MHNW (p=0.02), and C-peptide AUC was increased in MHO and MUO compared to MHNW (p&lt;0.001). Resting energy expenditure was increased in overweight individuals compared to lean individuals (p &lt;0.01). The lipid oxidation rate at time 30 min. was lower in MHNW and MUNW compared to MUO (p &lt;0.01).
Conclusion: In young and normoglycemic women, there was lower IS and insulin secretion for the MUO phenotype. The greater rate of lipid oxidation in this group compared to the lean ones may be a reflection of the lower IS, and the inability to switch the use of energy substrate to the higher carbohydrate availability after oral stimulation. BMI is not an ideal indicator of the presence or absence of metabolic health. However, even in MHO individuals’, physiological adaptations may happen to maintain the metabolic parameters within normal range.

Disclosure
F.B. Ribeiro: None. I. Solar: None. R.G. Freitas: None. A.S. Hanada: None. M.G. Barbosa: None. C.M. Xavier: None. N.S.K. Crouchan: None. V.F.D. Santos: None. B.G. Neto: None. I.T. Silva: None. L.G.D. Folchetti: None. B. Almeida Pititto: None. S.G. Ferreira-Vivolo: None. A.J. Vasques: None.

Funding
Fundação de Apoio a Pesquisa do Estado de São Paulo (2017/10185-9)
2014-P: Obesity Phenotypes and Subclinical Atherosclerosis among Whites, African Americans, and South Asians: The Genestar and Masala Studies
Authors: AL-SOFIANI MOHAMMED , VAIDYA DHANANJAY , KANAYA ALKA M. , YANEK LISA , MONGRAW-CHAFFIN MORGANA , KANDULA NAMRATHA R. , BECKER LEWIS , KRAL BRIAN G. , BECKER DIANE , MARUTHUR NISA M. , LEE CLARE 
Published: June 2020

Background: Whether obesity in the absence of cardiometabolic abnormalities increases the risk of subclinical atherosclerosis remains debatable.
Methods: We compared coronary artery calcium (CAC) across obesity phenotypes in 505 Whites and 306 African Americans (AAs) from the Genetic Study of Aspirin Responsiveness (GeneSTAR); and 875 South Asians (SAs) from MASALA (Mediators of Atherosclerosis in South Asians Living in America). Using BMI and the International Harmonized Definition of metabolic syndrome, participants were categorized as Metabolically Healthy Non-Obese (MHNO), Metabolically Healthy Obese (MHO), Metabolically Unhealthy Non-Obese (MUNO), and Metabolically Unhealthy Obese (MUO).
Results: The prevalence of any detectable CAC was similar in MHNO versus MHO among all ethnic groups (Whites 35 versus 30%, AAs 30 versus 23%, SAs 29 versus 26%; respectively, all p&gt;0.05). In contrast, the prevalence of CAC was the highest in the MUNO and MUO groups in all ethnic groups. After adjusting for potential confounders; the odds of CAC in MUNO and MUO compared to MHNO were significantly higher in Whites and SAs; but not in AAs.
Conclusion: Metabolically unhealthy Whites, AAs, and SAs had higher CAC scores regardless of obesity status suggesting that metabolic health is more closely associated with atherosclerosis than obesity alone especially in Whites and SAs.

Disclosure
M. Al-Sofiani: Speaker’s Bureau; Self; Novo Nordisk Inc. D. Vaidya: None. A.M. Kanaya: None. L. Yanek: None. M. Mongraw-Chaffin: None. N.R. Kandula: None. L. Becker: None. B.G. Kral: None. D. Becker: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. C. Lee: Employee; Self; Eli Lilly and Company.

Funding
National Institutes of Health (R01HL093009, K24HL112827); National Center for Research Resources (UL1RR024131, M01-RR000052); National Heart, Lung, and Blood Institute (U01HL72518)
2018-P: Whole-Genome Sequence Identifies Potentially Functional Variants in Cytochrome B5 Type A (CYB5A) that Associate with Obesity in Southwest American Indians
Authors: DAY SAMANTHA E. , TRAURIG MICHAEL , PIAGGI PAOLO , KUMAR PANKAJ , KOBES SAYUKO , HANSON ROBERT L. , BOGARDUS CLIFTON , BAIER LESLIE 
Published: June 2020

Southwest American Indians (SAI) suffer from a high obesity prevalence. We previously reported that rs7238987, in cytochrome B5 type A (CYB5A), strongly associated with increased body mass index (BMI) in a population-based study of SAI. CYB5A plays a role in fatty acid oxidation (FAO) and reductions in FAO have been linked to weight gain. However, in vitro studies did not confirm a functional effect of this variant. Therefore, the goal of the current study was to assess variation across the entire CYB5A locus to identify the causal variant contributing to obesity in this population. Genotypic data from a custom Axiom genotyping array on 7,700 SAI was merged with whole-genome sequence data from 335 SAI to impute variation within and 10,000 bp surrounding the CYB5A gene. This region contained 316 variants with a minor allele frequency &gt;0.01; 3 variants had a Combined Annotation Dependent Depletion (CADD) score &gt;10 (top 10% most likely to be deleterious) and a BMI association P ≤ 0.001 (adjusted for age, sex, birth year and the first 5 genetic principle components). Among these potentially deleterious variants, the obesity-risk T-allele in rs548402150, also significantly associated (P = 0.00003) with decreased CYB5A expression in skeletal muscle from biopsy data (n=207). Therefore, rs548402150 was prioritized for functional studies. This C/T variation falls within a CTCF consensus site in the 5’-UTR, which could have the ability to effect gene expression levels. In vitro luciferase reporter assays were used to assess altered promoter activity in human skeletal muscle cells. A 30% decrease in luciferase expression was identified for the promoter carrying the obesity-risk T-allele compared to the non-risk C-allele (P = 0.003).
In summary, the further exploration of CYB5A using imputed data has identified a potential casual variant for the observed decreased CYB5A expression and increased risk of obesity in this population.

Disclosure
S.E. Day: None. M. Traurig: None. P. Piaggi: None. P. Kumar: None. S. Kobes: None. R.L. Hanson: None. C. Bogardus: None. L. Baier: None.
2023-P: Effect of Combination Therapy with a ß3 Adrenergic Receptor and PPARγ Agonist on Adipose Beiging in Obese Humans
Authors: KERN PHILIP A. , MEMETIMIN HASIYET , ZHU BEIBEI , CONFIDES AMY L. , JOHNSON ZACHARY , VEKARIA HEMENDRA J. , WESTGATE PHILIP , SULLIVAN PATRICK G. , DUPONT-VERSTEEGDEN ESTHER E. , FINLIN BRIAN 
Published: June 2020

Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately.
We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment.

Disclosure
P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None.

Funding
National Institutes of Health (DK112282)
2040-P: Chronic Activation of CREB by Islet Amyloid Increases Star (Steroidogenic Acute Regulatory Protein) Expression in Islets
Authors: HOGAN MEGHAN F. , ESSER NATHALIE , TEMPLIN ANDREW T. , CASTILLO JOSEPH J. , ZRAIKA SAKENEH , HULL REBECCA L. , KAHN STEVEN E. 
Published: June 2020

Star, which we have shown to be produced in beta cells, is responsible for transport of cholesterol into mitochondria for the production of steroids. We previously found that Star is upregulated with islet amyloid deposition and this is associated with mitochondrial dysfunction. In steroidogenic tissues, StAR transcription is acutely regulated by cAMP Regulatory Element Binding protein (CREB).
To determine whether upregulation of Star expression by islet amyloid deposition is regulated by CREB activation, we studied the effects of amyloid formation in human islet amyloid polypeptide (hIAPP) transgenic islets in vitro (16.7 mM glucose for 144 hrs) and in vivo (high fat diet; HFD for 6 months).
In vitro phosphorylation of CREB (pCREB) and Star expression increased only with amyloid formation (Table; Expt 1a), as did expression of other known CREB target genes (Expt 1b). When islets were cultured with the amyloid inhibitor Congo red (CR; 200 μM), the increase of CREB target genes was abrogated (Expt 2), suggesting chronic activation of CREB is downstream of amyloid deposition. Amyloid deposition in vivo was also associated with upregulation of Star and other CREB target genes (Expt 3).
In summary, chronic CREB activation is associated with increased Star expression, suggesting a novel pathway for amyloid-induced mitochondrial dysfunction in beta cells.

Disclosure
M.F. Hogan: None. N. Esser: None. A.T. Templin: None. J.J. Castillo: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc.

Funding
American Diabetes Association (1-18-PDF-174 to M.F.H.); U.S. Department of Veterans Affairs (I01BX001060)
2060-P: RFX6, a Causative Gene of Mitchell-Riley Syndrome, Regulates ParaHox Genes in Early Endodermal Differentiation
Authors: NAKAMURA TOSHIHIRO , FUJIKURA JUNJI , ITO RYO , INAGAKI NOBUYA 
Published: June 2020

Background: RFX6 was identified as a causative gene of Mitchell-Riley syndrome (MRS), an autosomal recessive disease associated with neonatal diabetes and morphological disorders in development of the endodermal lineage such as pancreatic hypoplasia and intestinal atresia. However, little is known of RFX6 regulation of other genes, especially in the early developmental stage of the endoderm.
Aim: To clarify the mechanism of human early development for clues to understanding the pathophysiological features of MRS.
Method: We established human induced pluripotent stem cell (hiPSC) reporter lines, RFX6 +/eGFP and RFX6 eGFP/eGFP, by homologous recombination using a bacterial artificial chromosome vector containing eGFP-pA-loxP-Pgk-NeoR-loxP cassette following 5’UTR of RFX6. Their locus specificity was validated by fluorescent in situ hybridization. We then compared gene expression at the primitive gut stage using the in-vitro differentiation method.
Results: We compared bulk gene expression between RFX6 +/+ with RFX6 eGFP/eGFP using RNA-seq. Among downregulated genes in the latter, we focused on PDX1 and CDX2, which are marker genes of posterior foregut and mid-hindgut, respectively. mRNA expression of these genes was significantly decreased in RFX6 eGFP/eGFP compared to those in RFX6 +/eGFP. Immunocytochemistry and FACS studies showed that most PDX1+ cells were GFP+ in RFX6 +/eGFP; however, the number of PDX1+GFP+ cells was highly decreased in RFX6 eGFP/eGFP while GFP+ cells were observed similarly to those in RFX6 +/eGFP. Regarding CDX2, most CDX2+ cells were GFP+ in RFX6 +/eGFP; however, CDX2+GFP+ cells were observed less frequently in RFX6 eGFP/eGFP than in RFX6 +/eGFP.
Conclusion: Our present findings show that RFX6 deficiency results in downregulation of the major ParaHox genes, PDX1 and CDX2, in early endodermal differentiation. These findings may underlie the association between the genetic and pathophysiological features of MRS.

Disclosure
T. Nakamura: None. J. Fujikura: None. R. Ito: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
207-OR: Liver-Preadipocyte Cross Talk Reverses Lipodystrophy-Induced Insulin Resistance
Authors: BRANDAO BRUNA , SAKAGUCHI MASAJI , BATISTA THIAGO M. , QIAN WEIJUN , KAHN C. RONALD 
Published: June 2020

Insulin and IGF1 receptors (IR/IGF1R) control adipose tissue development. We previously demonstrated that mice with an inducible adipocyte-specific knockout of IR/IGFR (Ai-DKO) develop severe lipodystrophy, insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia. This phenotype resolves over 10-30 days due to proliferation of preadipocytes (PAds) and regeneration of adipose tissue. Here, we sought to identify circulating factors that trigger PAds proliferation by treating primary wild type PAds with serum from either WT or Ai-DKO mice. To exclude the hyperglycemia effect, we also incubated cells with serum from WT and Ai-DKO mice treated with the SGLT2 inhibitor Remogliflozin (Remo). Serum from either, chow or Remo-treated Ai-DKO mice, induced primary PAds proliferation of approximately 30%. Serum proteomics analysis revealed that Cathepsin D and multiple apolipoproteins, including C2 and C3, were significantly upregulated in Ai-DKO serum (FC&gt;1 and FDR&lt;0.1). Cathepsin D is known to induce fibroblast proliferation, however, when serum Cathepsin D was neutralized with its antibody, we observed an increase of 25% in PAds proliferation, indicating that, in this context, this protein has the potential to block proliferation. Apolipoproteins are mainly secreted by the liver. We found that ex-vivo liver culture conditioned media from Ai-DKO mice induced PAds proliferation in approximately 40% compared to control. Striking, this phenomenon was mimicked when PAds were treated with purified Apo C2 or C3. Taken together, our data suggest that loss of insulin signaling in mature adipocytes initiates a complex crosstalk between liver and preadipocytes resulting in PAds proliferation and adipose tissue regeneration. Further characterization of these factors will provide important insights into adipose tissue biology during insulin resistant states and contribute to reverse the metabolic syndrome associated with lipodystrophy.

Disclosure
B. Brandao: None. M. Sakaguchi: None. T.M. Batista: None. W. Qian: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.

Funding
National Institutes of Health (R01DK082659-11)
2071-P: C2CD4A, Pancreatic Beta-Cell Function, and Type 2 Diabetes Susceptibility
Authors: KUO TAIYI , ACCILI DOMENICO 
Published: June 2020

To this day, intergenic single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) are still a geneticist’s nightmare, because these SNPs are steps away from revealing the disease causative gene, relevant tissue(s), and mechanism of action. For instance, fine mapping and validation of genes causing β cell failure from susceptibility loci identified in type 2 diabetes GWAS poses a significant challenge. The VPS13C-C2CD4A-C2CD4B locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1, a transcription factor, is involved in the pathogenesis of β cell dysfunction, but its link to human diabetes GWAS has not been explored. To this end, we generated a genome-wide map of FoxO1 super-enhancers in chemically identified β cells using 2-photon live-cell imaging to monitor FoxO1 localization. Super-enhancers mark genes underpinning β cell identity, and comparing super-enhancers in mouse and human bridge the mouse data to human relevance. When parsed against human super-enhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved super-enhancer in C2CD4A, a gene encoding a β cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in β cells of mice phenocopied the metabolic abnormalities of human carriers of C2CD4A-linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2cd4a regulates glycolytic genes, and notably represses key β cell “disallowed” genes, such as lactate dehydrogenase A, Aldolase B, and monocarboxylate transporter. We propose that C2CD4A is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.

Disclosure
T. Kuo: None. D. Accili: Board Member; Self; Lilly Diabetes. Other Relationship; Self; Forkhead BioTherapeutics Inc.

Funding
National Institutes of Health (K01DK114372)