bluuebunny/crossref_metadata_2025_split huggingface dataset:
179-LB: Confidence of Healthcare Providers to Prescribe Antihyperglycemic Agents with Cardiovascular Benefit
Authors: SHAY CHRISTINA M. , ROBB KAREN J. , MARTIN MEGAN T. , PETERSEN MATTHEW P. , SANCHEZ EDUARDO 
Published: June 2019

Several antihyperglycemic agents have recently been demonstrated to provide additional glucose lowering and CVD risk reduction benefits in people living with type 2 diabetes (T2D). However, little is known about confidence of healthcare providers (HCPs) to utilize these agents in clinical practice. A national sample of 905 physicians and nurse practitioners (NPs) from primary care, cardiology, and endocrinology completed an online survey and were asked: “How confident are you that you can effectively prescribe and manage type 2 diabetes with the following medications?” Answer options included a 5-point Likert-type scale ranging from “Not at All Confident” to “Extremely Confident.” Results were weighted for representation by U.S. specialty-specific distributions of gender, race/ethnicity, years in practice, region, and employment. When compared to other HCPs, endocrinologists reported higher confidence in prescribing antihyperglycemic agents for people living with T2D (Table 1). Large proportions of HCPs in cardiology and primary care expressed low confidence prescribing many antihyperglycemic agents, particularly novel agents with CVD risk reduction benefit. Guideline-based professional education efforts may improve confidence of HCPs to utilize antihyperglycemic agents to optimize glycemic control and cardiovascular risk reduction when treating people living with T2D.

Disclosure
C.M. Shay: None. K.J. Robb: None. M.T. Martin: None. M.P. Petersen: None. E. Sanchez: None.
1793-P: Dopamine D1 plus D2 Receptor Coactivation Ameliorates Metabolic Syndrome (MS) and Nonalcoholic Fatty Liver Disease (NAFLD) in Mice
Authors: EZROKHI MICHAEL , LUO SHUQIN , COMINOS NICHOLAS , RAICHE BENJAMIN , GUSTAFSON MELANIE , CINCOTTA ANTHONY H. 
Published: June 2019

The peak in circadian dopaminergic activity at the biological clock area, suprachiasmatic nucleus is diminished in insulin resistant states and daily co-administration of dopamine D1 and D2 receptor agonists to restore this circadian peak of hypothalamic dopaminergic activity reverses this insulin resistance (IR) in genetic animal models of MS. However, the impact of such dopamine D1D2 receptor agonist therapy on NAFLD in an obesogenic animal model of the disease has never been investigated and such was the focus of the present study. C57B6 mice were maintained on a 40% kcal fat and 29% kcal sucrose diet with 5% fructose in the drinking water for 12 weeks and then randomized to daily treatment with bromocriptine (BC, a D2 agonist) (10 mg/kg), SKF38393 (S, a D1 agonist) (10 mg/kg), BC + S, or vehicle (N=7-8/gr) for 3 weeks while maintained on the diet. At the end of treatment, animals were sacrificed for analyses of metabolic parameters and liver biochemistry. D1D2 but neither D1 nor D2 agonist therapy maximally improved IR, obesity, and NAFLD. The D1D2 improvement in NAFLD was associated with reduced hepatic expression of lipogenic, inflammatory, insulin resistance-inducing, and FFA oxidative genes while normalizing antioxidant gene expressions (Table). This study suggests that circadian-timed daily dopamine D1D2 agonist therapy may be a means of treating both type 2 diabetes and NAFLD.

Disclosure
M. Ezrokhi: Employee; Self; VeroScience LLC. S. Luo: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. B. Raiche: Employee; Self; VeroScience LLC. M. Gustafson: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.
1796-P: A Ventral Medial Hypothalamus Estrogen Receptor a Neural Circuit Controlling Energy Expenditure
Authors: XU PINGWEN , HE YANLIN , WANG CHUNMEI , YANG YONGJIE , CAI XING , XU YONG 
Published: June 2019

Multiple estrogen receptor α (ERα) neuron populations in the brain are required to maintain normal body weight. While the metabolic effects of these ERα neuron populations have been investigated, the neural circuit and associated neurotransmitter signaling underlying the regulatory effects of ERα neurons on energy balance are unknown. Here we combined retrograde and anterograde trans-synaptic tracers, chemogenetics, optogenetic circuit mapping, and genetic mouse models to functionally map the downstream neural circuits of ERα neurons. We found that selective activation of ERα neurons in the ventral medial hypothalamus (VMH) stimulated brown adipose tissue (BAT) thermogenesis and physical activity without affecting food intake. We also showed that VMH ERα neurons provide monosynaptic glutamatergic inputs to serotonergic neurons in the dorsal Raphe nuclei (DRN). Inhibition of DRN serotonergic neurons partially attenuated the stimulatory effects of VMH ERα neurons on BAT thermogenesis and physical activity. More intriguingly, specific deletion of ERα or vesicular glutamate transporter 2 (vGluT2) from a subpopulation of VMH neurons projecting to the DRN results in decreased BAT thermogenesis and physical activity with normal food intake. Together, these findings suggest a model that VMH ERα neurons activate BAT thermogenesis and physical activity by stimulating DRN serotonergic neurons.

Disclosure
P. Xu: None. Y. He: None. C. Wang: None. Y. Yang: None. X. Cai: None. Y. Xu: None.

Funding
American Diabetes Association (1-17-PDF-138 to Y.H.); National Institutes of Health (R01DK093587), (R01DK101379 to Y.X.); (R00DK107008 to P.X.); U.S. Department of Agriculture (3092-5-001-059 to Y.X.); American Heart Association (17GRNT32960003 to Y.X.)
18-OR: Efficacy and Safety of Chiglitazar vs. Sitagliptin in Patients with Type 2 Diabetes: A 24-Week, Randomized, Double-Blind, Noninferiority Phase 3 Trial (CMAS)
Authors: JIA WEIPING , MA JIANHUA , MIAO HENG , WANG CHANGJIANG , WANG XIAOYUE , LI QUANMIN , LU WEIPING , YANG JIALIN , ZHANG LIHUI , YANG JINKUI , WANG GUIXIA , ZHANG XIUZHENG , ZHANG MIN , SUN LI , YU XUEFENG , DU JIANLING , SHI BINGYIN , XIAO CHANGQING , ZHU DALONG , LIU HONG , ZHONG LIYONG , XU CHUN , XU QI , LIANG GANXIONG , ZHANG YING , LI GUANGWEI , GU MINGYU , LIU JUN , NING ZHIQIANG , JI LINONG 
Published: June 2019

Chiglitazar, a novel PPARα/γ/δ pan-agonist, showed favorable effects on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to compare the efficacy and safety of chiglitazar with DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with diet and exercise (ClinicalTrials.gov NCT02173457). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or sitagliptin 100 mg once daily. The primary endpoint was change in HbA1c from baseline at week 24, with a non-inferiority of each chiglitazar dose versus sitagliptin. Analysis was done in all randomized patients who received at least one dose of study drug (n=739). Chiglitazar showed comparable HbA1c lowering effect compared with sitagliptin at 24 weeks (LS mean difference -0.04% [95% CI -0.22 to 0.15] and -0.08% [95% CI -0.27 to 0.10] for 32 mg and 48 mg, respectively), along with different trends in secondary endpoints. Overall adverse events were comparable across study groups. The incidences of weight gain and edema were generally low but relatively higher in chiglitazar 48 mg.
In conclusion, chiglitazar showed non-inferior effect compared with sitagliptin on HbA1c reduction with well tolerated safety profile.

Disclosure
W. Jia: None. J. Ma: None. H. Miao: None. C. Wang: None. X. Wang: None. Q. Li: None. W. Lu: None. J. Yang: None. L. Zhang: None. J. Yang: None. G. Wang: None. X. Zhang: None. M. Zhang: None. L. Sun: None. X. Yu: None. J. Du: None. B. Shi: None. C. Xiao: None. D. Zhu: None. H. Liu: None. L. Zhong: None. C. Xu: None. Q. Xu: None. G. Liang: None. Y. Zhang: None. G. Li: None. M. Gu: None. J. Liu: None. Z. Ning: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.

Funding
Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)
1803-P: Role of Medial Amygdala Neurons in Glucose Regulation
Authors: STANLEY SARAH , DEVARAKONDA KAVYA , ALVARSSON ALEXANDRA , BAYNE MITCHELL 
Published: June 2019

Nearly two-thirds of U.S. adults are overweight or obese, putting them at risk for other serious medical conditions, including diabetes and heart disease. The medial amygdalar nucleus (MeA) regulates the intersection of stress, social behavior, and metabolism. We found that MeA neuronal activity is regulated by glucose. Using viral tracers, we mapped the projections of glucose-sensing neurons in the MeA and found they project to multiple downstream sites that are known to play a role in glucose metabolism. MeA neurons also form part of polysynaptic pathways to organs such as the pancreas, that are critical for glucose regulation. Chemogenetic activation of MeA neurons in both male and female mice alters home cage feeding, an effect that is most prominent when animals are in the fed state and presented with palatable food. This phenotype is not affected by administration of propranolol, a beta adrenergic receptor antagonist that can alleviate hypneophagia. Activation of the MeA does not alter anxiety-related behavior on the elevated plus maze, open field, or light-dark box. Optogenetic activation of MeA neurons expressing glucokinase, a putative marker of glucose-sensing neurons in the brain, mimics the feeding phenotype, suggesting that MeA suppression of feeding may be mediate through these neurons. Future work will delineate the role of specific MeA neural populations in glucose metabolism.

Disclosure
S. Stanley: Consultant; Self; Redpin Therapeutics. K. Devarakonda: None. A. Alvarsson: None. M. Bayne: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); National Institutes of Health (1R01NS097184, OT2OD024912); Alexandrine and Alexander L. Sinsheimer Fund
1806-P: Improvement Brain Insulin Signaling in Antidiabetic Effect of Duodenal Jejunal Bypass Surgery
Authors: YAN QINGTAO , LI NA , PAN RUIYAN , WANG HUAI-JIE , JIANG BIN , WANG WEI-YU , GAO ZHIQIN , QU MEI-HUA 
Published: June 2019

Duodenal-Jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction, while the mechanism underlying remains unclear. The most important characteristic of diabetes is hyperglycemia due to impaired glucose homeostatic regulation, increasing evidences have demonstrated that the brain can directly initiate behavioral and metabolic responses to control energy and peripheral glucose homeostasis. This study mainly focused on exploring the role of brain insulin signaling activation and brain glucose utilization in the antidiabetic mechanism of DJB. The diabetic rats that induced by Streptozotocin (STZ) injection were grouped and proceeded with DJB or Sham operation, respectively. Basal glycemic parameters, such as fasting glucose, fasting plasmid insulin, OGTT, HOMA-IR and Hb1Ac, were detected by ELISA kits. In different treated (DJB, Sham or Control) rats models, 18F-FDG PET scanning was used to detect the glucose uptake in different organs, and of the level of insulin as well as insulin signaling pathway related proteins (InsR, IRS1/2, PI3K, AKT) and glucose utilization related proteins (HK1, PFK2) was evaluated by Q-RT-PCR, Western blot or IHC in the brain. Results showed that DJB surgery significantly improved basal glycemic parameters (Blood glucose, Insulin, HOMA-IR, HbA1c and OGTT) and reversed the decreased glucose uptake in the brain which was caused by type 2 diabetes. DJB surgery not only induced the gene expression of the brain insulin as well activated the insulin related signals, but also increased the expression of glucose utilization enzymes, such as HK1 and PFK2 in the brain. These results indicated that activation of brain insulin signaling and elevation of brain glucose metabolism might play an important role in the antidiabetic effect of DJB.

Disclosure
Q. Yan: None. N. Li: None. R. Pan: None. H. Wang: None. B. Jiang: None. W. Wang: None. Z. Gao: None. M. Qu: None.

Funding
National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)
181-LB: Effect of Obesity and Physical Activity-Based Lifestyle Change on Circulating Amino Acids: A Randomized and Controlled Intervention Study in Adolescents
Authors: HOSSAIN MD JOBAYER , GEORGE DONALD E. , BALAGOPAL P. BABU 
Published: June 2019

Objective: Circulating amino acids (AA) may serve as potential biomarkers for obesity and future type 2 diabetes (T2DM). In children and adolescents, the effects of obesity on circulating AAs are inconsistent. Data on the role of physical activity-based lifestyle (PAL) interventions on circulating AAs are also sparse. We aimed to address these gaps and determine the effect of obesity and PAL on circulating AAs in adolescents.
Method: Age (age,14-18 year) and maturity matched (Tanner stage&gt;IV) adolescents with normal weight (NW, n=7) and obesity (OB, n=15) were studied at baseline; the 15 OB adolescents underwent a 3-month randomized controlled PAL intervention. AAs were measured using high performance liquid chromatography-based amino acid analyzer. Body composition by DXA and glucose, insulin, adiponectin, RBP4, hsCRP and IL-6 were measured and HOMA-IR calculated. Independent t-tests, analysis of covariance and mixed effect models were used for data analysis.
Results: Thirteen AAs were significantly (P&lt;0.05) higher in the OB compared to the NW group. The branched chain AAs, leucine (28%), isoleucine (11%) and valine (17%) were higher (P&lt;0.05) in the OB vs. NW. PAL intervention showed only negligible effects on AA concentration, except for glutamine and glycine; both deceased (P&lt;0.05) post-intervention. Adiponectin increased and RBP4, hsCRP, IL-6 and HOMA-IR decreased (P&lt;0.05 for all) post-intervention, but no correlation with changes in the concentration of AAs. BMI did not change; fat mass decreased; fat free mass increased (P&lt;0.05).
Discussion: Obesity-related alterations in AAs warrant further studies to understand their role as potential biomarkers of obesity and T2DM in children. The post-PAL decrease in glutamine and glycine may suggest their increased demand by other organs in response to the intervention. Despite the beneficial changes in various metabolic factors, the lack of changes in several AAs is intriguing.

Disclosure
M. Hossain: None. D.E. George: None. P. Balagopal: None.

Funding
American Diabetes Association (1-14-CE-04 to P.B.B.); Nemours Biomedical Research
1812-P: Multitissue Single-Cell Analysis Reveals Differential Tissue, Cellular, and Molecular Sensitivity between Fructose and High-Fat Diets
Authors: ARNESON DOUGLAS , MAJID SANA , AHN IN SOOK , KURT ZEYNEB , DIAMANTE GRACIEL , ZHANG GUANGLIN , GOMEZ-PINILLA FERNANDO , YANG XIA 
Published: June 2019

High fructose and high fat diets have been associated with increased prevalence of metabolic syndrome, yet our understanding of the tissue, cellular, and molecular sensitivities of these two risk diets remains limited. Using single cell RNA sequencing, we examined thousands of individual cells from hypothalamus, liver, adipose, and small intestine from mice fed a high fat diet, a high fructose diet, and a chow diet. We found significant differences between the two diets in terms of the vulnerable tissues, cell types, and molecular pathways: both diets had significant impact on liver hepatocytes; high fructose diet induced stronger gene expression perturbations in hypothalamic neurons; high fat diet had more prominent influence on adipose cell types. We also identified key differences in tissue-tissue and cell-cell interactions between diets. Our results indicate that high fat and high fructose diets engage different tissues, cell types and molecular pathways, and rewire cell-cell networks to promote metabolic syndrome.

Disclosure
D. Arneson: None. S. Majid: None. I. Ahn: None. Z. Kurt: None. G. Diamante: None. G. Zhang: None. F. Gomez-Pinilla: None. X. Yang: None.

Funding
National Institutes of Health (R01DK14363)
1819-P: Growth Hormone Receptor (GHR) in AgRP Neurons Modulates Energy Balance and Metabolic Adaptation to Fasting via Sirtuin 1 (SIRT1)
Authors: DEBARBA LUCAS K. , AYYAR IVEN T. , KOCH MADELYNN C. , CADY GILLIAN , SADAGURSKI MARIANNA 
Published: June 2019

We are facing a worldwide public health emergency due to the increasing epidemic of diabetes. In the central nervous system, the hypothalamus is the primary site of integration of the neuroendocrine and autonomic responses which maintain glucose and energy homeostasis. Main physiological effects of growth hormone (GH) in adult brain - is the inhibition of its own secretion, especially critical under fasting states. While the importance of hypothalamic GH receptor (GHR) in GH feedback inhibition is well established, the direct involvement of neuronal GHR signals in the regulation of whole-body homeostasis has not been studied. Previously, we have identified a unique population of hypothalamic leptin receptor (LepRb)-GHR expressing neurons that regulate hepatic glucose production, suggesting a crucial role for these neurons in GHR-neurocircuitry. To characterize hypothalamic GHR-expressing neurons, we have developed GHRcre mice using CRISPR/Cas9 technology. Approximately 60% of GHR+ neurons in the arcuate nucleus (ARC) co-localize with AgRP-expressing neurons and about 25% with GHRH neurons, basically representing most of ARCGHR neurons. By manipulating neuronal activity of neurochemically-defined GHR neurons, we demonstrate that ARCGHR neurons represent distinct neuronal population in glycemic control. Despite similarity in responses in both sexes, only female mice selectively lacking GHR in AgRP neurons showed impaired energy homeostasis and heat production, accompanied by alterations in metabolic adaptation to fasting. Fasting increased the abundance of sirtuin 1 (SIRT1) within ARCGHR+ neurons, while this pattern was diminished in the fasted AgRPEYFP∆GHR female mice. Our data suggests a role of SIRT1 within somatotropic signaling in the AgRPGHR+ neurons in response to alterations in nutritional status and demonstrates the role of AgRP-GHR neurons in assisting the organism in recruiting its resources for survival purposes.

Disclosure
L.K. Debarba: None. I.T. Ayyar: None. M.C. Koch: None. G. Cady: None. M. Sadagurski: None.

Funding
American Diabetes Association (1-18-JDF-063 to M.S.)
1821-P: A Possible Mechanism: Genistein Improves Metabolism and Induces White Fat Browning through Modulating Hypothalamic Expression of Ucn3, Depp, and Stc1
Authors: ZHOU LIYUAN , XIAO XINHUA , DENG MINGQUN , LIU JIEYING , YU MIAO 
Published: June 2019

Bioactive food components have gained growing attention in recent years. Multitude of studies have demonstrated that genistein, as a soy-derived phytoestrogen, has beneficial effects on metabolism. However, the exact mechanism by which genistein improving metabolic disorders remains unclear, especially the central regulation. This study was designed to evaluate whether addition of genistein to the high-fat diet could counter the metabolic disorders and whether these alterations were associated with the gene expression in hypothalamus. C57BL/6 mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.25g/kg diet) (HFG) or a normal control diet (CON) for eight weeks. Body weight were assessed during the study. After eight-week intervention, content of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and brown adipose tissue (BAT) were weighed. Glucose tolerance test, the serum levels of insulin and lipid were assessed. The mRNA of browning marker was detected in the WAT. The hypothalamus was collected for whole transcriptome sequencing and reverse transcription quantitative PCR (RT-qPCR) validation. The results demonstrated that mice fed the HFG diet had lower body weight (p&lt;0.05) and SAT mass (p&lt;0.01), decrease levels of low-density lipoprotein cholesterol (LDL-C) (p&lt;0.01) and free fatty acids (FFA) (p&lt;0.05), higher browning marker of Ucp1 (p&lt;0.01) and Cidea (p&lt;0.05) in WAT and an improvement in glucose tolerance and insulin sensitivity compared with those in the HF group. Transcriptome sequencing showed that there were three differentially expressed genes in hypothalamus among the three groups, including Ucn3 (p&lt;0.05), Depp (p&lt;0.01) and Stc1 (p&lt;0.01). Thus, regulating gene expressions in hypothalamus is a potential mechanism for genistien improving metabolism and inducing WAT browning, which may provide a novel target for the precaution and treatment of T2DM.

Disclosure
L. Zhou: None. X. Xiao: None. M. Deng: None. J. Liu: None. M. Yu: None.

Funding
National Natural Science Foundation of China
1823-P: Evidence that Arcuate Nucleus Neurocircuit Remodeling Ameliorates Hyperglycemia in Type 2 Diabetes
Authors: MIRZADEH ZAMAN , CABRALES ELAINE , SCHWARTZ MICHAEL W. 
Published: June 2019

Abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) is a common feature of genetic and acquired (e.g., postnatal overnutrition) models of obesity and type 2 diabetes (T2D). In leptin-deficient ob/ob mice, developmental defects occur both in efferent projections from the ARC to downstream circuits and in afferent GABAergic input onto ARC neurons. A developmental critical period (CP) has been proposed based on the temporally-restricted requirement for leptin, during the first month of life, to enable normal projections of ARC Agrp neurons in ob/ob mice. We recently described the formation of perineuronal nets (PNNs) around ARC Agrp neurons during the latter half of this CP, shortly following the peak of the postnatal leptin surge. PNNs, which are extracellular matrix specializations that restrict CP plasticity in neurons they enmesh, were overabundant in the ARC of adult ob/ob mice, suggesting that ARC neurocircuit dysfunction contributes to their metabolic phenotype. To remodel ARC neurocircuits containing PNN-enmeshed cells, we engrafted a special population of GABAergic inhibitory interneurons derived from the embryonic brain medial ganglionic eminence (MGE). Here we show that MGE interneurons derived from E13.5 GAD67-GFP embyros and transplanted bilaterally into the ob/ob ARC survive, integrate into local circuits, and form GABAergic synapses. Preliminary metabolic phenotyping shows that compared to vehicle injection, transplanted MGE cells (∼5000 MGE cells/ARC) induce a sustained reduction of hyperglycemia lasting for at least one month (1-month average BG: veh 301±12 vs. MGE 189±12 mg/dl, n=4/group, p=0.022) without significant effects on food intake or body weight. These findings suggest that sustained diabetes remission can be achieved by remodeling ARC neurocircuits through MGE cell transplantation.

Disclosure
Z. Mirzadeh: Consultant; Self; Novo Nordisk A/S. E. Cabrales: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.

Funding
National Institute of Neurological Disorders and Stroke