bluuebunny/crossref_metadata_2025_split huggingface dataset:
306-LB: Adipocyte Subpopulations Mediate the Inflammatory Response in Adipose Tissue
Authors: LUONG QUYEN , HUANG JUN , SHARMA RITA , LEE KEVIN Y. 
Published: June 2019

Recent studies suggest that, even within a single adipose depot, there may be distinct subpopulations of adipocytes. Our lab has uncovered three developmentally distinct subpopulations of white adipocytes. These adipocyte subpopulations have unique gene expression signatures, and display differential responses to exogenous stimuli including insulin, inflammatory cytokines, and insulin. These three adipocyte subtypes are distinguished by high expression of specific marker genes: Wilms’ tumor 1 (type 1), transgelin (type 2), and myxovirus 1 (type 3). Utilizing Cre transgenic mice, transcription of which is directed by the promoters of these marker genes, lineage tracing analysis indicate that these three preadipocyte subpopulations independently gave rise to adipocytes in vivo, and differentially contribute to the adipose tissue depots. During high fat diet (HFD) induced obesity, macrophages, organized into crown like structures (CLS) around dead and dying adipocytes, are detected in the vicinity of type 1 adipocytes, as assessed by kernel density estimation. This association between type 1 adipocytes and CLS is secondary to a ∼10-fold increase in the expression of macrophage chemoattractant protein 1 at both the mRNA and protein level. Furthermore, although CLS are found in the vicinity of type 1 cells, with very few of the CLS are in direct contact with type 1 adipocytes. Instead, over 80% of CLS are found in direct contact with type 2 adipocytes, indicating an increased death of these adipocytes during HFD-induced obesity. Taken together, these data suggest that type 1 and type2 adipocytes coordinately regulate the inflammatory response in adipose tissue.

Disclosure
Q. Luong: None. J. Huang: None. R. Sharma: None. K.Y. Lee: None.

Funding
American Diabetes Association (1-17-JDF-055 to K.Y.L.)
314-OR: Mechanisms of AgRP Neuron-Induced Hunger
Authors: KNIGHT ZACHARY 
Published: June 2019

Neural circuits express a remarkable diversity of neuropeptides, yet the specific function of most of these peptides remains unclear. Agouti-Related Peptide (AgRP) neurons in the arcuate nucleus are critical for the regulation of energy balance. These cells are activated by food deprivation and their activity promotes food seeking and consumption. When food is discovered, AgRP neurons are inhibited within seconds, yet their potentiation of feeding persists for tens of minutes. The mechanisms underlying this sustained hunger drive remain unknown. I will describe data showing that Neuropeptide Y (NPY) is uniquely required for the long-lasting effects of AgRP neurons on feeding behavior. We systematically blocked the ability of AgRP neurons to signal through AgRP, NPY, and GABA, and then stimulated these cells using an optogenetic paradigm that mimics their natural regulation. We found that genetic deletion of NPY abolished optically stimulated food intake and lever-pressing for food, whereas inactivation of AgRP or GABA signaling had no effect. Re-expression of NPY selectively in AgRP neurons rescued these deficits. These findings reveal that NPY plays a critical role in enabling AgRP neurons to drive feeding behavior, due its unique ability to sustain hunger in the interval between food discovery and consumption.

Disclosure
Z. Knight: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-29 to Z.K.); National Institutes of Health; Howard Hughes Medical Institute
321-LB: The Link between Obesity and Changes in Epigenetic Marks in Adipose Tissue—In Vivo Study
Authors: ALAMA ANETA , PAWE?KA DOROTA , MYSZCZYSZYN ANETA , MALODOBRA-MAZUR MALGORZATA 
Published: June 2019

Obesity is a leading problem in modern civilization. It is also the main risk factor of metabolic disorders like insulin resistance or type 2 diabetes. Numerous studies indicate in obesity the aberrant profile of various genes expressions like insulin signaling, adipokines, and cytokines genes as well as transcription factors regulating adipocytes development and metabolism. One of the reasons that might lead to dysregulation in genes expression is epigenetic changes in chromatin. In our study, we compared the global and site-specific DNA methylation and histones modifications (activate expression: H3K4me3 and H3K9ac, responsible for chromatin repression: H3K9me3) between subcutaneous (SAT) and visceral (VAT) adipose tissue from patients in a wide range of BMI with equal distribution of sex and in similar age. We have displayed a slight difference between epigenetic marks between SAT and VAT of enrolled patients, however, when classified into two groups according to BMI (lean group &lt;25 kg/m2 and obese group ≥25 kg/m2) the difference in analyzed epigenetic markers were major. We found that global DNA methylation was increased in the obese group compared to lean, both in SAT and VAT. What is more, a similar correlation occurs in the case of site-specific methylation. The increased methylation of CpG islands was observed within promotor of the two important genes - PPARγ and CEBPα, transcription factors that regulate numerous genes in adipocytes metabolism, including insulin pathway. The observed epigenetic modifications in obesity may suggest a role of epigenetic regulation in the development of obesity. In addition, in the obese group, apart from increased methylation within DNA, we also observed disorders in the level of expression of genes which are important for the metabolic pathway, including the insulin pathway. These results may suggest a potential mechanism with an epigenetic regulation basis, which is responsible for the coexistence of metabolic disorders with obesity.

Disclosure
A. Alama: None. D. Pawe?ka: None. A. Myszczyszyn: None. M. Malodobra-Mazur: None.

Funding
National Science Centre, Poland (2016/21/D/NZ5/00155)
325-LB: Circadian Clock Nuclear Receptor REV-ERBa Is a Novel Regulator of Beta-Cell Function, Survival, and Autophagy under Diabetogenic Conditions
Authors: COSTES SAFIA , LAOUTEOUET DAMIEN , RAVIER MAGALIE A. , DELOBEL MORGANE , BERTRAND GYSLAINE , DALLE STéPHANE , MATVEYENKO ALEKSEY 
Published: June 2019

The circadian clock regulates diverse cellular and molecular rhythms employing CLOCK-BMAL1 transcriptional heterodimer with nuclear receptor REV-ERBα (encoded by gene Nr1d1) playing an important role as a clock repressor through modulation of Bmal1 transcription. Importantly, in addition to its core circadian clock function, recent studies have identified REV-ERBα as a potent transcriptional repressor of autophagy. Therefore, in the current study we set out to address whether impaired beta-cell function and survival associated with exposure to diabetogenic stressors (e.g., glucotoxicity and inflammation) is attributed in part to REV-ERBα-mediated inhibition of autophagy. Exposure of beta-cells (INS-1E cell line) to either glucotoxicity (30 mM glucose) or cytokines (cytomix of IL-1β, TNFα and IFNγ) resulted in robust induction of REV-ERBα expression (1.5-2 fold, p&lt;0.05) and corresponded with impaired autophagy flux characterized by increased protein levels of p62 (also known SQSTM1) (1.5-2 fold, p&lt;0.05). Consistent with these data, exposure of beta-cells to a REV-ERBα agonist (SR9011) was characterized by impaired autophagy (increased p62 levels and aggregated forms, p&lt;0.05), defective glucose-stimulated insulin secretion (70% decrease) and increased beta-cell apoptosis (increased cleaved caspase-3, p&lt;0.01 vs. vehicle). In contrast, REV-ERBα specific antagonist (SR8278) partly protected beta-cells from deleterious effects of glucotoxicity or cytokines-induced inflammation by enhancing autophagy flux and attenuating beta-cell apoptosis (∼30%). Taken together, these data reveal for the first time an underexplored link between the core circadian clock nuclear receptor REV-ERBα, autophagy and beta-cell failure under diabetogenic conditions. These data also suggest a therapeutic potential of modulating REV-ERBα levels in beta-cells to enhance function and survival in diabetes.

Disclosure
S. Costes: None. D. Laouteouet: None. M.A. Ravier: None. M. Delobel: None. G. Bertrand: None. S. Dalle: None. A. Matveyenko: None.
328-OR: Degree of Glycemic Improvement in Patients with Diabetes Enrolled in Real-World Intensive Lifestyle Intervention in Relation to Baseline A1C: Five-Year Longitudinal Observation
Authors: TASABEHJI MHD WAEL , TOMAH SHAHEEN , ASHRAFZADEH SAHAR , MOTTALIB ADHAM , HAMDY OSAMA 
Published: June 2019

We previously reported that weight loss in patients with diabetes and obesity through real-world Intensive Lifestyle Intervention (ILI) is associated with significantly lower A1C for up to 5 years. However, it is unclear if baseline A1C has any impact on the magnitude of glycemic improvement in this population. Over 5 years, we evaluated a cohort of 129 patients with diabetes and obesity (90% type 2 diabetes, 67% female, mean age 53±10 years, diabetes duration 10±9 years, body weight 110±19 Kg, BMI 38±5.3 Kg/m2) enrolled in a 12-week ILI program. According to baseline A1C, we divided participants into group A with A1C&lt;7.5% (73 patients, 56.6%, mean A1C 6.5±0.5%), group B with A1C 7.5-9% (41 patients, 31.8%, mean A1C 8.1±0.4%), and group C with A1C &gt;9% (15 patients, 11.6%, mean A1C 9.8±0.8%). Compared to baseline, body weight decreased at 5 years by 6.6 Kg, 9.6 Kg, and 8.3 Kg in groups A, B, and C, respectively (p&lt;0.05 for all). A1C in group A decreased by 0.5±0.9% at 12 weeks (p&lt;0.0001) but increased over the following 5 years by 0.1±0.1%, 1.2±0.9%, 0.3±0.1%, 0.4±0.1%, and 0.6±0.2%, respectively (p&lt;0.01 at 5 years compared to baseline). A1C in group B decreased by 1.1±0.2% at 12 weeks (p&lt;0.0001), was maintained significantly lower at 1 year by -0.5±0.2% (p&lt;0.001), rose to baseline at 3 years and maintained at the same level for up to 5 years. A1C in group C decreased by 2.4%±0.3% at 12 weeks (p&lt;0.0001), was maintained significantly lower at 1 year by 0.9±0.5% (p&lt;0.001), also rose to baseline at 3 years, and was maintained at the same level for up to 5 years (p&lt;0.05 between groups at 5 years). We conclude that patients with diabetes and obesity who enroll in real-world ILI with baseline A1C ≥7.5% are more likely to maintain improvements in A1C for at least 3 years before returning to baseline values compared to patients with baseline A1C&lt;7.5%. This finding may help clinicians use baseline A1C to set realistic long-term expectations for patients considering ILI.

Disclosure
M. Tasabehji: None. S. Tomah: Stock/Shareholder; Self; Amarin Corporation. S. Ashrafzadeh: None. A. Mottalib: None. O. Hamdy: Advisory Panel; Self; AstraZeneca, Sanofi-Aventis. Consultant; Self; Abbott, Merck & Co., Inc. Research Support; Self; National Dairy Council. Stock/Shareholder; Self; Healthimation, LLC.
329-LB: Exocrine Pancreas Proteases Are Drivers of ß-Cell Proliferation
Authors: HOSTELLEY TIMOTHY L. , DUNLEAVEY JESSICA , LARKIN EMILY J. , JONES AMANDA J. , BOYES DANIEL L. , FONTAINE MAGALI J. , ZAGHLOUL NORANN A. 
Published: June 2019

The clinical link between loss of β-cell mass and diabetes susceptibility provides a promising avenue of research for novel therapeutics targeting the proliferative axis. To identify potential new pathways involved we utilized two zebrafish genetic models Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS) that exhibit strikingly different diabetes rates, ∼75% in AS and ∼4% in BBS. We have previously shown β-cell loss in AS and increase in BBS, corresponding to their diabetes rates. RNA-Sequencing of these models identified several exocrine pancreas proteases that were differentially expressed between AS and BBS. Thus, we hypothesized that the exocrine pancreas proteases affect endocrine pancreas function. To test our hypothesis, we overexpressed each enzyme in transgenic zebrafish embryos in which β-cells can be visualized. In control animals, overexpression of exocrine pancreas proteases significantly increased the β-cell number. Overexpression rescued the loss of β-cells observed in animals depleted of alms1. We found ctrb1 overexpression led to increased β-cell proliferation in transgenic larvae and rescued the AS model reduction in proliferation. To test for endogenous protease uptake, we generated a transgenic GFP-tagged CTRB1 and found that 10% of β-cells were GFP+, suggesting a direct interaction between the exocrine and endocrine pancreas. We also found that the inactive, zymogen, form of these enzymes are taken up by β-cells in vitro and induce proliferation in cultured MIN6 β-cells and freshly isolated ex vivo islet cultures, suggesting this effect is conserved in mammalian systems. These data support an important role for exocrine pancreatic enzymes in the modulation of β-cells in diabetes.

Disclosure
T.L. Hostelley: None. J. Dunleavey: None. E.J. Larkin: None. A.J. Jones: None. D.L. Boyes: None. M.J. Fontaine: None. N.A. Zaghloul: None.

Funding
National Institutes of Health (F31DK115179-01A1, T32DK098107, R01DK102001, R25GM055036)
329-OR: Shared Medical Appointments (SMA) with Weight Management vs. SMA Alone for Overweight or Obese Patients with Type 2 Diabetes
Authors: YANCY WILLIAM S. , COFFMAN CYNTHIA , CROWLEY MATTHEW , DAR MOAHAD , JEFFREYS AMY S. , MACIEJEWSKI MATTHEW L. , VOILS CORRINE I. , BARTON ANNA E. , EDELMAN DAVID 
Published: June 2019

Background: Shared medical appointments (SMA) improve outcomes in diabetes. SMAs often address lifestyle but infrequently lead to weight loss. Because weight loss reduces glycemia and medication use, we hypothesized an SMA intervention with weight management (WM/SMA) would be non-inferior for glycemic control and superior for patient-centered outcomes versus SMA alone.
Methods: In a 48-week, randomized trial with primary outcome of HbA1c (non-inferiority margin 0.5%), we recruited outpatients with uncontrolled T2DM and BMI ≥27 from two Veterans Health Administration sites. WM/SMA participants received baseline medication reduction and low-carbohydrate diet counseling with medication optimization every 2 weeks for 16 weeks, then an abbreviated SMA intervention every 8 weeks. SMA participants received group counseling on diabetes-related topics with medication optimization every 4 weeks for 16 weeks, then every 8 weeks. HbA1c, diabetes medication effect score (MES) and hypoglycemic events were analyzed using linear mixed models.
Results: In 263 participants, baseline mean age was 61, HbA1c 9.1% and BMI 35.3; 10.6% were women and 54.4% were black. At 48 weeks, HbA1c decreased 0.9% for WM/SMA and 0.8% for SMA (mean difference -0.1%, 95% CI -0.5, 0.3; non-inferiority criterion met), and decreased more with WM/SMA than SMA alone at interim weeks 16 (-0.7%, 95% CI -1.0, -0.4) and 32 (-0.5%; 95% CI -0.8, -0.2). At 48 weeks, diabetes medication use was lower in the WM/SMA than SMA group (mean difference in MES -0.5, 95% CI -0.6, -0.3; p&lt;0.0001). WM/SMA participants had 51% fewer hypoglycemic events than SMA participants over 48 weeks (Incident Rate Ratio=0.49; 95% CI 0.27, 0.71; p&lt;0.001).
Conclusion: Compared with conventional SMA-based medication management for patients with T2DM, SMA with intensive low-carbohydrate diet counseling yielded similar glycemic control while improving hypoglycemia and decreasing medication burden.

Disclosure
W.S. Yancy: None. C. Coffman: None. M. Crowley: None. M. Dar: None. A.S. Jeffreys: None. M.L. Maciejewski: Employee; Spouse/Partner; Amgen Inc. Stock/Shareholder; Spouse/Partner; Amgen Inc. C.I. Voils: None. A.E. Barton: None. D. Edelman: None.

Funding
U.S. Department of Veterans Affairs
337-LB: Combined Oral Administration of GABA and GLP-1 Promotes Human ß-Cell Proliferation and Reduces Apoptosis
Authors: LIU WENJUAN , JIN TIANRU , WANG QINGHUA 
Published: June 2019

Gamma-aminobutyric acid (GABA) and glucagon-like peptide-1 (GLP-1) improve rodent β cell survival and function. In human β cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1-based drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin, a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β cells. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, sitagliptin, or both. The oral administration of either GABA or sitagliptin ameliorated blood glucose levels, increased transplanted human β cell mass and plasma human insulin levels. However, combined administration of the drugs generated significantly superior results in all these responses, as compared to monotherapy. Proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, pancreatic and duodenal homeobox-1 (PDX-1+), or Nkx6.1+ β cell numbers. Protection against apoptosis was also significantly improved by the combined therapy. GABA and GLP-1 in combination notably increased Akt phosphorylation and insulin secretion, as well as the expression of sirtuin-1 and α-Klotho, both of which have been reported to have protective effects on β-cells. Our study indicates that combined use of GABA and sitagliptin produced greater therapeutic benefits, which was likely due to an enhancement of β cell proliferation and a decrease of apoptosis.

Disclosure
W. Liu: None. T. Jin: None. Q. Wang: None.

Funding
National Natural Science Foundation of China (81570518, 81630020); JDRF (2-SRA-2017-64-G-R to Q.W., T.J.), (2-SRA-2015-64 to Q.W., T.J.); Canadian Diabetes Association (OG-3-13-4066 to Q.W.)
339-OR: Yo Puedo! A Self-Management Group and mHealth Program for Low-Income Adults with Type 2 Diabetes in Mexico City
Authors: WHITTEMORE ROBIN , VILAR-COMPTE MIREYA , LA CERDA SELENE DE , DELVY ROBERTA , JEON SANGCHOON , BURROLA-MÉNDEZ SORAYA I. , LOZANO-MARRUFO ANNEL A. , PEREZ-ESCAMILLA RAFAEL 
Published: June 2019

The purpose of this study was to evaluate the preliminary efficacy of a self-management group + mHealth program (Yo Puedo!) on clinical (A1C, BP, BMI), self-management (diet, exercise, blood glucose monitoring), depressive symptom, and self-efficacy outcomes in adults with type 2 diabetes (T2D) at Seguro Popular clinics in Mexico City. Participants were randomly assigned to treatment (n=26) or wait-list control groups (n=21) with data collected at 3 and 6 months. The Yo Puedo! Program included 7 weekly sessions and 6 months of daily text messages. Descriptive statistics and generalized linear mixed model (GLMM) with random intercept were calculated. Adults with T2D were 55.5 years of age (±8.6), 68% female, 59% married/partnered, 88.6% overweight/obese, 50% lived in moderate/severe food insecure households, 35.7% had increased depressive symptoms, and 80% had A1C above 7.0%. Mean duration of T2D since diagnosis was 11.5 years (±7.1). There were no between-group differences on baseline characteristics. There was 89% attendance at sessions and 6% attrition at 6 months. Group by time effects were seen in blood glucose monitoring (p&lt;.01), diabetes self-efficacy (p&lt;.04); with a trend for lower A1C in the intervention group at 6 months (-1.76% in treatment group vs. -.97 in control group, p=.08). Time effects for the intervention group included improved diet, exercise, blood glucose monitoring, diabetes self-efficacy, depressive symptoms and A1C at 6 months (p&lt;.05). Adults with T2D in Mexico City positively responded to the Yo Puedo! group + mHealth program with improvements in self-management, depressive symptoms, self-efficacy, and A1C. Empowering patients with T2D self-management skills can improve key behaviors, mental health and blood glucose outcomes in vulnerable populations. A fully powered clinical trial is warranted.

Disclosure
R. Whittemore: None. M. Vilar-Compte: None. S. De La Cerda: None. R. Delvy: None. S. Jeon: None. S.I. Burrola-Méndez: None. A.A. Lozano-Marrufo: None. R. Perez-Escamilla: None.

Funding
National Institute of Nursing Research
340-LB: Optogenetic Control of a-Cell Electrical Activity and Glucagon Secretion in Intact Islets
Authors: MIRANDA CAROLINE A. , DOU HAIQIANG , TOLö JOHAN , TARASOV ANDREI I. , RORSMAN PATRIK 
Published: June 2019

Glucagon, the body's main hyperglycemic hormone, is produced by α-cells of the islets of Langerhans. A fall in plasma glucose stimulates glucagon release and it acts by increasing hepatic glucose production. How glucose regulates glucagon secretion remains debated and both intrinsic and paracrine mechanisms have been proposed. The fact that glucagon secretion becomes dysregulated in diabetes warrants detailed studies of the cell physiology of its release. We generated mice that express the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under the control of the proglucagon promoter in the α-cells. This allowed us to selectively depolarize the plasma membrane of α-cells within intact isolated islets (using 488 nm laser) and record membrane potential, cytoplasmic Ca2+ ([Ca2+]i) glucagon release in response to the optical activation. At low (1mM) glucose, optoactivation depolarized the α-cells, induced a transient increase in [Ca2+]i, decreased peak voltage of the action potentials (from -2±1mV to -11±1mV, n=5, p&lt;0.01) and reduced glucagon secretion by 50%. At elevated glucose (6-20mM, which inhibited secretion by ∼50% relative that at 1 mM glucose), α-cell action potential firing persisted and optoactivation remained capable of depolarizing the α-cell but now without affecting action potential peal voltage. Under these conditions, optoactivation did not reduce glucagon secretion beyond the inhibition produced by high glucose alone. It was ascertained that optoactivation of α-cells did not affect insulin secretion. The data reinforce earlier reports that membrane depolarization (despite increasing [Ca2+]I and stimulating action potential firing) produces a paradoxical inhibition of glucagon secretion via reduced action potential height. We propose that further optogenetic studies represent a means for non-invasive interrogation of the complex regulation of glucagon secretion in intact pancreatic islets.

Disclosure
C.A. Miranda: None. H. Dou: None. J. Tolö: None. A.I. Tarasov: Employee; Spouse/Partner; Vaccitech Ltd, Oxford, UK. P. Rorsman: None.

Funding
Swedish Research Council