bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of CREBRF Variants with BMI and Diabetes in Pacific Islanders
Authors: HANSON ROBERT L. , SAFABAKHSH SAIED , CURTIS JEFFREY , MAHKEE DARIN K. , BAIER LESLIE , KNOWLER WILLIAM C. , NELSON ROBERT , HSUEH WEN-CHI 
Published: June 2018

A recent genome-wide association study (GWAS) in Samoans (a Polynesian population) identified strong associations of CREBRF variants with BMI. The G allele at rs12513649 (frequency=25.8%) was associated with ∼1.3 kg/m2 higher BMI per copy, as was the Gln allele at rs373863828 (which codes for an ArgGln substitution). The Gln allele at rs373863828 has frequency of 25.9% in Samoans and is rare in most global populations, although it has been observed at low frequency in some other Oceanic populations. The alleles associated with higher BMI were suggestively associated with lower risk of type 2 diabetes [T2D, odds ratio (OR)=0.69 per copy, P=4.7×10-7]. We investigated the associations of rs12513649 and rs373863828 with BMI and T2D in 2029 Pacific Islanders from Guam and Saipan, who participated in a GWAS. Frequencies of the G allele at rs12513649 and the Gln allele at rs373863828 were 8.1 and 5.4% respectively in full-heritage Chamorros (N=928), 4.1 and 0.2% in Filipinos (N=249), 6.1 and 3.7% in Chuukis (N=153), 2.2 and 1.1% in Carolinians (N=43), and 20.7 and 2.2% in Palauans (n=45). Using a genomic control procedure with adjustment for age, sex, end-stage renal disease and the first four genetic principal components, the G allele at rs12513649 and the Gln allele at rs373863828 were associated with higher BMI (β=1.60 kg/m2, P=0.002 and β=1.36 kg/m2, P=0.058 respectively). They were also modestly associated with taller height (β=0.8 cm, P=0.11, and β=1.5 cm, P=0.019). The alleles conferring higher BMI were associated with lower prevalence of T2D (OR=0.62, P=0.0and OR=0.45, P=0.001). When combined with previously published results for Samoans via meta-analysis, the association of rs373863828 with T2D achieved genome-wide statistical significance (OR=0.67, P=2.9×10-8). These results suggest that CREBRF variants may be important contributors to obesity in Oceanic populations, and they confirm the associations of the allele conferring higher BMI with lower risk of T2D.

Disclosure
R.L. Hanson: None. S. Safabakhsh: None. J. Curtis: None. D.K. Mahkee: None. L. Baier: None. W.C. Knowler: None. R. Nelson: None. W. Hsueh: None.
The Different Effect of Sucrose on Transcriptomic Profile in Adipose and Muscle Tissues in Model of Metabolic Syndrome and Insulin Resistance
Authors: HÜTTL MARTINA , MARKOVÁ IRENA , MALINSKA HANA , KAZDOVA LUDMILA , SEDA ONDREJ 
Published: June 2018

The development and progression of insulin resistance is driven by genetic and enviromental factors and their interactions. Sucrose belongs to nutrition factors with lipogenic impact, induces de novo lipogenesis, reduces fatty acid oxidation and can deteriorate insulin sensitivity. The aim of study was to investigate transcriptome profile in adipose and muscle tissues under standard or high sucrose diet (HSD) (70 kcal% as sucrose) in two strains of rats - Wistar and a strain of hereditary hypertriglyceridemic rats (HHTg) as a polygenic model of metabolic syndrome and insulin resistance. The transcriptome analysis was evaluated in the context of development and progression of insulin resistance. HSD feeding in 2 weeks increased epididymal adipose tissue (EAT) weight in both strains (P diet&lt;0.05), but not body weight. In addition, HSD feeding resulted in elevated levels of fasting glucose (P diet&lt;0.05), insulin (P diet&lt;0.01) and FFA (P diet&lt;0.05, P strain&lt;0.05), but adiponectin was decreased only in HHTg rats (P&lt;0.01). Insulin sensitivity of EAT was significantly reduced (P diet&lt;0.05, P strain&lt;0.05), but HSD did not change triglycerides or insulin sensitivity in muscle. In skeletal muscle, HSD significantly changed expression (FDR&lt;0.05) of 20 transcripts in HHTg and 21 in Wistar (only 2 common). In EAT, HSD significantly changed expression of 810 transcripts in HHTG and 1823 in Wistar (344 common). The most affected pathways were insulin receptor signaling in HHTg and mitochondrial dysfunction and oxidative phosphorylation in Wistar rats. Major regulator nodes of the mechanistic networks included insulin, SCD and miR-27 for HSD effect in HHTg and LIPE, miR-27 and VEGF in Wistar strain.
In conclusion, HSD feeding impaired insulin sensitivity in both rat strains. Transcriptomic alterations in adipose tissue precede muscle changes caused by HSD and show distinct patterns in genetically susceptible HHTg model of metabolic syndrome.

Disclosure
M. Hüttl: None. I. Marková: None. H. Malinska: None. L. Kazdova: None. O. Seda: None.
Chronic Low Grade Inflammation in Type 2 Diabetes—Activation of the Inflammasomes by Circulating Metabolites
Authors: MONLUN MARIE , RIGALLEAU VINCENT , BLANCO LAURENCE , MOHAMMEDI KAMEL , BLANCO PATRICK 
Published: June 2018

Type 2 diabetes (T2D) is associated with chronic low-grade inflammation. We studied its mechanisms by addressing the role of inflammasomes in monocytes and their activation by circulating metabolites to produce inflammatory cytokines IL1β and IL18. Blood samples were collected from patients with T2D. Serum was filtered at 3 kDa to remove macromolecules. Inflammasome activation was analyzed by gene expression of various Nod Like Receptors by RT-quantitative PCR as well as IL1β and IL18 secretion from these monocytes in culture (ELISA). Twenty-one patients (38% women) were included in 2016. They were 57±10 years old, BMI were 33.1±6.3 kg/m2. They had T2D for 14±9 years and HbA1c at 9.5±1.2%. Their C Reactive Protein levels was 8.1±8.0 mg/L. Each subject was sampled twice at 4 days of interval: in hyperglycemia (2.56±0.86g/L) then in normoglycemia (1.23±0.41g/L). Two inflammasomes were transcripted: NLRP1 and NLRC4, with significant high level whether in normoglycemia (fold-change 1.47, p=0.01 and 1.33, p=0.02) and hyperglycemia (fold-change 1.41, p=0.02 and 1.31, p=0.04). This transcriptional priming seems to have a functional consequence with IL1β production by monocytes of some T2D patients. Healthy monocytes were collected from voluntary blood donors (Glycaemia: 0.97±0.17g/L). Incubation of them with filtered serum of T2D patients recapitulated the priming signal. The same two inflammasomes were transcripted: NLRP1 and NLRC4, whether in normoglycemia (fold-change 1.35, p=0.002 and 1.23, p=0.02) and hyperglycemia (fold-change 1.31, p=0.01 and 1.30, p=0.052). Although it did not induce activation of mature cytokines. We have shown the activation of NLRP1 and NLRC4 inflammasomes and their secretion of inflammatory cytokine in T2D patients. Some soluble serum metabolites seem directly involved in this inflammatory cascade. Our next objective will be to identify these molecules, which are potential biomarkers of predictive of chronic immune activation in T2D.

Disclosure
M. Monlun: None. V. Rigalleau: None. L. Blanco: None. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. P. Blanco: None.
New 2017 ACC/AHA Hypertension Guidelines—Cost-Effectiveness among U.S. Adults with Type 2 Diabetes
Authors: SHAO HUI , LAXY MICHAEL , ROLKA DEBORAH B. , GREGG EDWARD W. , ZHANG PING 
Published: June 2018

Introduction: The new 2017 American College of Cardiology (ACC) and American Heart Association (AHA) hypertension guideline defines hypertension as either systolic blood pressure (SBP) &gt; 130 mmHg or diastolic blood pressure (DBP) &gt; 80 mmHg, compared with the old guideline of SBP &gt;140 mmHg or DBP &gt; 90 mmHg. The new definition would increase number of persons eligible for hypertension treatment. Our objectives were to estimate how many more persons with type 2 diabetes would be eligible for hypertension treatment under the new guideline and to assess the cost-effectiveness (CE) of treating this newly eligible population.
Method: Data from the 2011-2016 National Health and Nutrition Examination Survey and the 2015 Census were used to estimate the numbers of persons with diabetes who would be eligible for hypertension treatment under the new and old guidelines. The CDC-RTI cost-effectiveness diabetes simulation model was used to project the lifetime health and cost (2017 USD) consequences of treating newly eligible persons. Two hypertension treatments were modeled: moderate BP treatment as defined in the guidelines and intensive BP treatment using multiple antihypertensive drugs as implemented in the UK Prospective Diabetes Study trial. The CE of the new guideline was measured using costs per quality-adjusted life year (QALY).
Results: The number of persons with diabetes eligible for hypertension treatment would increase from 8.4 (27.7%) to 15.7 million (51.9%) under the new ACC/AHA guideline. Treating hypertension persons defined by new guideline would result in $3038/QALY if the moderate BP treatment were implemented and would be cost-saving if intensive BP treatment were implemented, compared to treating persons defined through old guideline.
Conclusion: The new ACC/AHA hypertension guideline would nearly double the number of persons with diabetes who would be eligible for hypertension treatment. Treating those newly eligible is likely to be cost-effective or even cost-saving.

Disclosure
H. Shao: None. M. Laxy: None. D.B. Rolka: None. E.W. Gregg: None. P. Zhang: None.
Measure Real-Time cAMP Signaling in the Living Cell
Authors: LIU XIPING , HONG SEAN , WU SHIJUAN , YAO ZHIWEN , YAO QIANG X. 
Published: June 2018

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that plays a key role in regulating glucose homeostasis via its activity at the GLP-1 receptor (GLP-1R). To date, GLP-1R has become an attractive therapeutic target for type 2 diabetes (T2D). Several GLP-1R agonists have been developed or are in clinical trials such as: Exenatide, Liraglutide, Lixisentide, Dulagutide, Semiglutide, Efpeglenatide, and Albenatide. These drugs stimulate G-protein-coupled receptors (GPCR) resulting in adenylated cyclase activation and consequently cyclic adenosine mono-phosphate (cAMP) production. This makes the cAMP assay platform is useful for identifying GLP-1 functional activities. However, current cAMP assays have two major limitations: 1) low accuracy with infeasibility of real time measurements of cAMP levels and 2) low precision among separate sample preparation from live cells. In order to overcome those restrictions and design a rapid and homogeneous protocol, a living cell based real-time potency assay has been developed for measuring bioactivity of GLP-1r agonists such as Albenatide. This assay, which combines the stimulating cell, lysis, and cAMP measurement in-situ, provides fast, accurate, reproducible, and highly sensitive results. The assay linearity has been tested with the proportionality of concentration/amount of analyte. The r2 of the linear curve in measuring relative potency (RP) vs. nominal RP was &gt;0.99 and the recovery of the expected relative potency in the range of 50∼200% were 102.6∼112.4%. Compared with the traditional ELISA-based assay, this assay requires less sample volume (20ul vs. 100ul), low matrix effect with wide assay window (5 fold higher), high sensitivity (pM vs. nM), and shorter procedure time (hours vs. days). Thus, applications of this novel cell-based cAMP assay can be extended to high-throughput screening for the potency of GLP-1r agonists, and more specifically characterizing the anti-drug antibody (ADA) capabilities.

Disclosure
X. Liu: None. S. Hong: None. S. Wu: None. Z. Yao: None. Q.X. Yao: None.
Change in Circulating Monocyte Profile with Foot Ulcer Healing in Diabetic Patients
Authors: MIN DANQING , NUBE VANESSA L. , TAO ANH , YUAN XIN , BROOKS BELINDA , WONG JENCIA , TWIGG STEPHEN M. , MCLENNAN SUSAN 
Published: June 2018

Poor wound healing in diabetes is associated with increased chronic inflammation and alterations in macrophage accumulation. Chronic inflammation can alter the phenotype of macrophage precursors, monocytes but whether their phenotype is changed in association with wound healing is not known. Blood was obtained from 21 patients (14 male: 7 female) attending the High Risk Foot Clinic at RPA Hospital at their initial visit (V1), week 4 (V2) and week 8 (V3). Wound area was measured and wound type was assessed by a podiatrist. Monocyte number (CD14+), phenotype as classical (CD16−), non-classical (CD16++), and intermediate (CD16+), anti-inflammatory (CD163+) subset and expression of receptors CCR2, CCR5 and TLR2, TLR4 were determined by flow cytometry. The MMPs and TIMP-1 were measured in plasma by zymography and ELISA. Over the 8 weeks, 6 ulcers healed (H) and 15 failed to heal (NH). The age, duration of diabetes, HbA1c, wound size and duration at V1 were not different between the groups but the % CD16++ monocytes was higher in H vs. NH at V1 (23.5 vs. 8.3) and V3 (17.4 vs. 7.2) and monocyte CCR2+ was lower in H at V3 (P&lt;0.05). Interestingly plasma MMP-3 and MMP-9/TIMP-1 ratio were higher in H at V1 but MMP-9 was lower in H at V3 (P&lt;0.05). The wound area at V1 was not associated with wound closure rate (WCR: r=0.39, P=0.08). However for all samples at V2+V3, the WCR correlated with monocyte %CD16++ (r=0.42), CD16+ (r=0.39), CD163+ (r=0.37), and CD14+ (r=-0.39), CD16- (r=-0.52), as well as plasma MMP-2 (r=-0.67) and MMP-9 (r=-0.41)(P&lt;0.05). At either V2 or V3, the relationship was maintained for monocyte %CD16++and CD16- and plasma MMP-2 (P&lt;0.05). These results in people with diabetic foot ulcers suggest that circulating monocyte phenotype is altered as the wound heals. The positive relationship in WCR with monocyte anti-inflammatory profile suggests a predictive role for these markers. Whether the transition of monocytes from a pro- to an anti-inflammatory phenotype plays a mechanistic role in wound healing remains to be elucidated.

Disclosure
D. Min: None. V.L. Nube: None. A. Tao: None. X. Yuan: None. B. Brooks: None. J. Wong: Speaker's Bureau; Self; Novo Nordisk A/S, AstraZeneca, Eli Lilly and Company. S.M. Twigg: Advisory Panel; Self; Abbott. Consultant; Self; Abbott. Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp.. Other Relationship; Self; Abbott. S. McLennan: None.
Glycolysis-Dependent Inflammasome Activation by Carbon Monoxide
Authors: KIM DAEYEON , CHUN SUNG WAN , KIM YEOJOO , KIM SANG JIN , MOON JONG-SEOK 
Published: June 2018

Low dose of carbon monoxide (CO) has anti-inflammatory role through various signaling pathways. Cellular metabolism has been implicated in the activation of inflammation in immune cells.
Here we show that CO-dependent metabolic pathway regulates the activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome. CO-releasing molecule-3 (CORM-3) resulted in reduced glycolysis-dependent NLRP3 inflammasome activation in macrophages. The reduced mTORC1 activation by CORM-3 resulted in less glycolysis during NLRP3 inflammasome activation. CORM-3 suppressed caspase-1 activation and the secretion of IL-1β and IL-18 in macrophages in response to LPS and ATP. Moreover, CORM-3 inhibits the oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which is required for NLRP3-dependent caspase-1 activation. Furthermore, CORM-3-treated mice showed substantial reduction in IL-1β production by hyperglycemia in a mouse model of STZ-induced diabetes.
Our results suggest that CO regulates glycolysis-dependent NLRP3 inflammasome activation and may provide a therapeutic approach for inflammation in metabolic diseases.
Figure. CORM-3 Treatment Suppresses NLRP3 Inflammasome Complex Formation During NLRP3 Inflammasome Activation.

Disclosure
D. Kim: None. S. Chun: Research Support; Self; Handok Inc.. Other Relationship; Self; Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Eli Lilly and Company. Y. Kim: None. S. Kim: None. J. Moon: None.
Pax4 Gene Transfer Induces α-to-ß Transdifferentiation and Improves the Therapeutic Efficacy of Islet Transplantation
Authors: PARAJULI KESHAB R. , ZHANG YANQING , WU HONGJU 
Published: June 2018

Pax4 is a transcriptional factor which plays a critical role in the generation of insulin producing β-cells during embryonic development. Our group previously demonstrated that Pax4 delivered by adenoviral vector induces insulin expression and reduces glucagon in αTC1.9 cells and primary human islets. The purpose of the present study was to determine whether Pax4 gene expression induces pancreatic α-cells to become β-cell using lineage tracing techniques and confers therapeutic benefits in the context of islet transplantation. In this study, we generated α mouse model in which their α cells are labelled with YFP, namely αYFP mouse. Using this mouse model, we found that Ad5.Pax4 induced glucagon secreting α-cells to become insulin secreting β-cells in isolated αYFP islets. Quantification of YFP+/Pax4+/insulin+ cells confirmed that Pax4 induced α-to-β cell conversion as assessed by the presence of YFP reporter in new β-cells. In addition, these Pax4-treated islets increased glucose-stimulated insulin secretion compare to control group. Furthermore, we transplanted Pax4-treated primary mouse islets into kidney capsule of the streptozotocin-induced diabetic mice and found that they significantly reduced the blood glucose and improved glucose tolerance compared to control groups. These data indicate that Pax4 induced α- to functional β-cell conversion, and proved therapeutic benefits for islet transplantation.

Disclosure
K.R. Parajuli: None. Y. Zhang: None. H. Wu: None.
Development of Perfluorodecalin Contained Microcapsules for Islet Survival and Function
Authors: KIM JIWON , PARK HEON SEOK , YOON KUN-HO , LEE EUN YOUNG 
Published: June 2018

Hypoxic injury of islets is a major obstacle for encapsulated islet transplantation into the peritoneal cavity. To improve oxygen delivery to encapsulated islets, we integrated 20% of the oxygen carrier material, perfluorodecalin (PFD) contained alginate capsules with islets (PFD-alginate). Integration of PFD clearly improved islet viability and decreased reactive oxygen species production compared with islets encapsulated with alginate only (alginate) and naked islets exposed to hypoxia in vitro. In PFD-alginate capsules, HIF-1α expression was minimal, also insulin expression was well secreted. Furthermore, the best islet function represented by glucose-stimulated insulin secretion was observed for the PFD-alginate capsules. In vivo study, the marginal number naked islets and encapsulated islets (alginate and PFD-alginate) were transplanted into streptozotocin-induced diabetic mice. Non-fasting blood glucose levels and intraperitoneal glucose tolerance tests in the PFD-alginate group was lower than in the alginate group. The harvested islets stained positive for insulin in all groups, but the ratio of dead cell area was 4 times higher in the alginate group was than in the PFD-alginate group.
In conclusion, PFD contained alginate microcapsules improved islet function and survival by minimizing the hypoxic damage of islets after intraperitoneal transplantation.

Disclosure
J. Kim: None. H. Park: None. K. Yoon: None. E. Lee: None.
Ten-Year Trends in Consumer-Directed Health Plan Enrollment and Out-of-Pocket Costs among Commercially Insured Members with Diabetes
Authors: GARABEDIAN LAURA F. , ROSS-DEGNAN DENNIS , ZHANG FANG , CALLAHAN MATTHEW X. , LECATES ROBERT , WALLACE JAMIE , SOUMERAI STEPHEN B. , WHARAM JAMES F. 
Published: June 2018

Background: Diabetes is a major cause of morbidity and mortality and a driver of escalating health care costs in the U.S. In attempts to reduce costs, U.S. employers are increasingly offering consumer-directed health plans (CDHPs) that include Health Savings Accounts (HSA) or Health Reimbursement Arrangements (HRA) and high annual deductibles. Recent research has found that CDHPs are associated with concerning impacts on diabetes patients, but growth in CDHP enrollment and their out-of-pocket (OOP) cost trends in this vulnerable population are unknown.
Methods: We used a time series design to assess 2005-2014 annual trends among ∼70 million unique members of all ages insured by a large national commercial insurer from 2005-2014. We analyzed mutually exclusive populations of interest, identified by ACG, comprising: (1) diabetes mellitus with no cardiovascular disease (DM), (2) diabetes with co-morbid cardiovascular disease (DM+CVD), and (3) “healthy” (i.e., ACG score &lt;=1). We used linear models, t-tests and chi-square tests to assess (a) CDHP and non-CDHP prevalence and (b) total annual OOP costs in 2014 dollars.
Results: CDHP prevalence among DM members increased by 2.5% per year (p&lt;0.001), from 1.3% in 20to 23.2% in 2014. DM+CVD members had a similar increase. In 2014, 19.5% of DM+CVD members and 28.7% of healthier members were in CDHPs (p&lt;0.001 for both compared to DM). Annual OOP costs for non-CDHP members were significantly lower than for CDHP members throughout the study period. For example, in 2014, CDHP DM members had average OOP costs of $2103.62 compared to $1379.87 for non-CDHP DM members (p&lt;0.001).
Conclusions: CDHP enrollment has increased markedly over the last 10 years among members with and without diabetes. However, diabetes members were less likely than healthier members to be in CDHPs, particularly if they had co-morbid CVD. Among diabetes patients, OOP costs were significantly higher for CDHP than non-CDHP members.

Disclosure
L.F. Garabedian: Other Relationship; Self; Harvard Pilgrim Health Care. D. Ross-Degnan: None. F. Zhang: None. M.X. Callahan: None. R. LeCates: None. J. Wallace: None. S.B. Soumerai: None. J.F. Wharam: None.
Fibroblast Growth Factor-21 Maintains Glucose Homeostasis through Influencing the Expansion and Function of Subcutaneous Adipose Tissue
Authors: LI HUATING , QIAN LINGLING , WU LIANG 
Published: June 2018

Fibroblast growth factor 21 (FGF-21) has been extensively studied in recent years due to its multiple therapeutic benefits for a cluster of obesity-related cardiometabolic complications. However, an unsolved puzzle is that despite its pleiotropic metabolic benefits, FGF-21 is paradoxically elevated in obesity and diabetes in both animals and humans. Its pathophysiological relevance in response to excess energy intake remains poorly understood. Here we provide both clinical and animal evidences demonstrating that elevated endogenous FGF-21 in obesity serves as a defense mechanism against systemic insulin resistance. Serum FGF-21 levels were positively associated with subcutaneous fat area in subjects with insulin-sensitive overweight/obesity. Furthermore, FGF-21 knockout mice (FGF-21KO) showed much less subcutaneous adipose tissue (SAT) mass and were more insulin resistant when fed with high-fat diet. Replenishment of recombinant FGF-21 to a level equivalent to those occurring in diet-induced obesity restored SAT mass and reversed insulin resistance in FGF-21KO but not in adipose-specific βklotho knockout mice. Moreover, transplantation of SAT from wild type to FGF-21KO mice improved insulin sensitivity in the recipient mice. Mechanistically, circulating FGF-21 acts in an endocrine manner on subcutaneous fat to promote the healthy expansion. FGF-21 upregulates adiponectin in subcutaneous adipose tissue, accompanied with an increase of M2 macrophage polarization. This study raises the possibility that targeting subcutaneous fat through manipulation of FGF-21 may represent a promising therapeutics to combat insulin resistance.

Disclosure
H. Li: None. L. Qian: None. L. Wu: None.