bluuebunny/crossref_metadata_2025_split huggingface dataset:
1742-P: Targeting the Low Molecular Weight Protein Tyrosine Phosphatase for Obesity-Associated Diabetes Therapy
Authors: STANFORD STEPHANIE M. , DIAZ MICHAEL A. , ZOU JIWEN J. , ARDECKY ROBERT J. , PINKERTON ANTHONY , BOTTINI NUNZIO 
Published: June 2020

Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, acts as a critical regulator of insulin signaling by dephosphorylating the activation motif of the insulin receptor. Human genetics studies suggest that high LMPTP catalytic activity promotes diabetes and insulin resistance in obesity. We recently discovered that LMPTP is a critical promoter of insulin resistance in obesity through an action on the liver and that pharmacological inhibition of LMPTP reverses obesity-induced diabetes in mice. Here we report our progress in the development of a new chemical series of LMPTP inhibitors that is orally bioavailable and effective at treating disease in obese diabetic mice.

Disclosure
S.M. Stanford: None. M.A. Diaz: None. J.J. Zou: None. R.J. Ardecky: None. A. Pinkerton: None. N. Bottini: Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., Kyowa Hakko Kirin Co., Ltd., Roche Pharma.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-15-INI-13 to S.M.S.); National Institutes of Health (R01DK106233)
1744-P: Hepatic and Disposal Insulin Sensitivity with Single Tracer Method: Use of Naturally Abundant 13C-Polysaccharide
Authors: MAN CHIARA DALLA , VISENTIN ROBERTO , SCHIAVON MICHELE , BASU ANANDA , COBELLI CLAUDIO , BASU RITA 
Published: June 2020

We have recently demonstrated successful estimation of postprandial glucose fluxes using a novel triple tracer technique after ingestion of a mixed meal containing complex carbohydrates (CC) that is naturally enriched with 13C polysaccharide ([13C]-PS). We also reported higher insulin sensitivity (SI) with CC than simple carbohydrate (SC) containing mixed meals. The current analysis was designed to determine if [13C]-PS per se could directly measure hepatic (SIH) and disposal SI (SID) during the CC containing mixed meal. Sixteen healthy subjects (9M, age=33±2 y, BMI=23±1 kg/m2) received, in random order, either SC (labeled with [13C]-glucose) or CC (naturally containing [13C]-PS) mixed meals. All meals were isocaloric and contained 50g carbohydrates with similar macronutrient composition. Plasma glucose, [13C]-glucose and insulin were measured and the Single Tracer Oral Minimal Model applied to estimate SIH and SID. The model well predicted the data. SIH was significantly higher, while SID was numerically but not statistically higher in CC than SC meals (Figure 1). This implies that the higher SI with CC meals is likely due to higher hepatic insulin sensitivity. Taken together, the data suggest that a single, naturally occurring [13C]-PS tracer can measure postprandial SI and its components without the need for the triple tracer method.

Disclosure
C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R. Visentin: None. M. Schiavon: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. C. Cobelli: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca.

Funding
National Institutes of Health (DK085516, DK94331, DK29953); Italian Minister for Education
1749-P: The TNFa Inhibitor Infliximab Decreases Inflammation in High-Fat Fed Mice but Does Not Alleviate Insulin Resistance
Authors: ROBY DEBORAH A. , GUAN CHRISTOPHER , JAMES FREYJA , BRACY DEANNA , LANTIER LOUISE , WASSERMAN DAVID 
Published: June 2020

The insulin resistance of diet-induced obesity (DIO) is accompanied by inflammation. Previous studies suggest that the anti-inflammatory effects of infliximab, an anti-TNFα chimeric monoclonal antibody, decreases DIO-associated inflammation in mice fed a 60% fat diet. The effectiveness of infliximab at 10 mg/kg Infliximab (IF10) and 100 mg/kg infliximab (IF100) in C57Bl/6J DIO mice was studied in comparison to C57Bl/6J DIO mice administered chimeric IgG (IgG; 10 mg/kg). Treatment consisted of IP injections of infliximab or IgG once per week for 4 weeks. Body weight and fasting arterial glucose was not different in IF10, IF100, and IgG. IF10 and IF100 mice had a decreased presence of crown-like structures in white adipose tissue compared to IgG treated mice. Infliximab resulted in a dose-dependent reduction in macrophage F4/80 staining in white adipose tissue (4.3±0.7% and 1.8±0.2% in IF10 and IF100, respectively) compared to 8.1±1.6% in IgG, validating the anti-inflammatory effect. Insulin action was measured in mice with arterial and venous catheters using the hyperinsulinemic, euglycemic clamp method (insulin dose of 4 mU/kg/min) combined with [3-3H]glucose in conscious, unstressed mice. Glucose infusion rates (GIR) in IgG mice were higher (25±3 mg/kg/min) as compared to IF10 (17±2 mg/kg/min) and IF100 (19±2 mg/kg/min). The greater GIR in IgG as compared to IF10 was due to changes in hepatic endogenous glucose production (suppression of 12±3 mg/kg/min and 5±1 mg/kg/min, respectively) without a difference in glucose utilization. IF100 exhibited small reductions in both hepatic and peripheral insulin action, neither of which reached significance. Mice treated with saline alone were used as an additional control, but neither IF10 nor IF100 had significant effects on insulin action compared to saline controls.
In summary, despite profound anti-inflammatory effects of the anti-TNFα drug, Infliximab causes a paradoxically greater hepatic insulin resistance.

Disclosure
D.A. Roby: None. C. Guan: None. F. James: None. D. Bracy: None. L. Lantier: None. D. Wasserman: None.
176-LB: Ethnic Differences in Cardiovascular Complications of Young-Onset Diabetes (YOD)
Authors: KE CALVIN , STUKEL THERESE , LUK ANDREA , CHAN JULIANA C. , SHAH BAIJU R. 
Published: June 2020

Introduction: YOD (age at diagnosis [AAD]&lt;40 years) is associated with greater cardiovascular disease (CVD) risk than usual-onset diabetes (UOD, AAD≥40 years). It is unknown whether this pattern varies by ethnicity.
Methods: We included adults in Ontario, Canada with incident diabetes (2002-12, followed to 2018). We matched each case with ≤5 diabetes-free controls by age, sex, and ethnicity. The outcome was CVD (coronary artery disease, congestive heart failure, stroke, peripheral revascularization, lower extremity amputation). We constructed Cox proportional hazards models to estimate the association between AAD and CVD relative to controls.
Results: We included 411,030 cases (3.5% South Asian; 4.3% Chinese) and 2,000,035 controls. The hazard ratios (HR) for CVD in UOD versus controls were higher in Chinese (2.38, 2.2-2.5) and South Asian (2.5, 2.4-2.7) people than White people (1.9, 1.9-1.9; pinteraction&lt;0.0001). The HR for CVD in YOD versus controls were similar across ethnicities (Chinese: 5.2, 3.6-7.3; South Asian: 4.4, 3.7-5.3; White: 4.6, 4.4-4.8). In YOD and controls, Chinese and South Asian people had lower hazard of CVD than White people. In UOD, CVD hazard was lowest in Chinese people, and similar in South Asian and White people.
Discussion: Although Chinese and South Asian people have a lower hazard of CVD compared to White people, YOD is associated with a 4- to 5-fold greater hazard of CVD across ethnicities.

Disclosure
C. Ke: None. T. Stukel: None. A. Luk: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Roche Pharma. Other Relationship; Self; Merck Sharp & Dohme Corp. J.C. Chan: None. B.R. Shah: None.

Funding
Canadian Institutes of Health Research; South Asian Network Supporting Awareness and Research
1761-P: MC4R-Expressing Neurons in the PVH Regulate Glycemia Independent of Insulin
Authors: UNER AYKUT G. , LEE HYON , HAN JUNG SUK , PEREIRA RODRIGO M. , SUN XIAOFANG , KIM HYUN JEONG , KIM YOUNG-BUM 
Published: June 2020

Hypothalamic and extra-hypothalamic neuronal populations play important roles in the regulation of energy balance and glucose homeostasis. However, the underlying mechanisms of this control remain unclear. We have recently reported that inhibition of hypothalamic pro-opiomelanocortin (POMC) neuronal activity leads to a reduction in blood glucose levels of normoglycemic POMC-cre mice. This effect is independent of energy intake. Since hypothalamic POMC neurons project to the paraventricular nucleus of the hypothalamus (PVH) and regulate energy metabolism via melanocortin-4 receptor (MC4R), we hypothesized that changes in the activity of MC4R-expressing neurons in the PVH could alter glycemic levels. To address this, we stereotaxically injected designer receptors exclusively activated by designer drug (DREADD) viruses into the PVH of MC4R-cre mice to chemogenetically and selectively activate or inhibit these neurons. We continuously activated or inhibited these neurons by injecting clozapine-N-oxide (CNO) every 8 hours for 5 days and monitored daily blood glucose levels and energy intake. Interestingly, inhibition of MC4R-expressing neurons in the PVH leads to a significant reduction (∼ 30%) in blood glucose levels despite of increased food intake. On the other hand, blood glucose levels are significantly increased, but food intake is greatly decreased when MC4R-expressing neurons are activated. We further determined the peripheral insulin response via MC4R-expressing neurons in the PVH. We found that CNO-induced inhibition or activation of MC4R-expressing neurons did not affect serum insulin levels. These data suggest that MC4R-expressing neurons in the PVH can regulate blood glucose levels and food intake via divergent cellular mechanisms, which is independent of circulating insulin. Thus, the inhibition of MC4R-expressing neurons may be a promising target for novel antidiabetic medicines.

Disclosure
A.G. Uner: None. H. Lee: None. J. Han: None. R.M. Pereira: None. X. Sun: None. H. Kim: None. Y. Kim: None.
1762-P: Poor Sleep Quality Is Associated with Lower Absolute Cerebral Glucose Levels
Authors: STANLEY THEODORA K. , GUNAWAN FELONA , REDEKER NANCY S. , JIANG LIHONG , COPPOLI ANASTASIA , ROTHMAN DOUGLAS L. , MASON GRAEME F. , HWANG JANICE 
Published: June 2020

Poor sleep quality has been associated with increased risk of metabolic syndrome and type 2 diabetes as well as acceleration of neurodegenerative diseases. In rodents, sleep restriction decreases glucose transport into the brain via downregulation of GLUT1, the primary glucose transporter at the blood-brain barrier. However, little is known about the association between sleep quality and glucose transport and metabolism in the human brain. In this exploratory analysis, we quantified cerebral glucose levels amongst individuals with good and poor sleep quality as defined by the widely used and well-validated Pittsburgh Sleep Quality Index (PSQI), which assesses 7 different components of sleep quality over a 1 month time period (PSQI≥5 = Poor sleep; PSQI&lt;5 = Good sleep). Twelve healthy subjects completed the PSQI questionnaire. Eight (6F, age 27.6 ± 5.7, BMI 26.6 ± 8.2 kg/m2, HgbA1c 5.4 ± 0.2%) had good and 4 (2F, age 29.5± 2.4, BMI 27.8 ± 6.5 kg/m2, HgbA1c 5.2 ± 0.2%) had poor sleep. All subjects underwent 13C magnetic resonance spectroscopy brain scanning at 4 Tesla during a 2-hour hyperglycemic clamp (plasma glucose target ∼180 mg/dl) to measure absolute cerebral glucose levels as part of a larger study to investigate obesity and cerebral glucose metabolism. There were no differences in age, BMI, or HbA1c levels between groups with good and poor sleep. Individuals with good sleep had 63% higher absolute cerebral glucose levels at steady state compared to those with poor sleep (3.4 ± 0.7 mmol/L vs. 2.1 ± 0.9 mmol/L, p=.017). Higher PSQI scores correlated with lower absolute cerebral glucose levels (r= -0.725, p=0.008, PSQI for all subjects (mean±SD) = 4 ± 2). In this pilot and exploratory study, individuals with poor sleep quality have significantly lower absolute cerebral glucose levels, which suggests an association between poor sleep and altered cerebral glucose transport and/or metabolism. These findings may have wide-ranging implications for understanding the effects of sleep on brain function.

Disclosure
T.K. Stanley: None. F. Gunawan: None. N.S. Redeker: None. L. Jiang: None. A. Coppoli: None. D.L. Rothman: None. G.F. Mason: None. J. Hwang: Research Support; Self; General Electric.

Funding
American Diabetes Association (1-17-ICTS-013 to J.H.); National Institutes of Health (1R03DK121048)
1774-P: Neurally Mediated Prandial Islet-Cell Function Is Glucose-Independent and Preserved after Gastric Bypass and Sleeve Gastrectomy
Authors: HONKA HENRI , AL ZUBAIDI ANAS M. , DEFRONZO RALPH A. , GASTALDELLI AMALIA , SALEHI MARZIEH 
Published: June 2020

The weight-loss independent glycemic effects of gastric bypass (GB) are characterized by prandial short-lived hyperinsulinemia as a result of β-cell stimulation by glucose and incretins. To investigate the effect of parasympathetic nervous system (PNS) activity, a neural component of the enteroinsular axis, on islet function, 9 subjects with history of GB, 6 with prior sleeve gastrectomy (SG), and 4 non-surgical controls were recruited. The GB, SG, and CN groups were matched for BMI, FFM, A1C, and age; and the GB and SG for weight loss and time postsurgery; none had diabetes. To measure islet hormone responses to meal ingestion when the effect of GI hormones and glycemia is minimal, subjects consumed a liquid meal (280 kcal, 20% glucose) at 2 hr of a 5-hr hyperinsulinemic (120 mU/m2/min) hypoglycemic (55mg/dl) clamp with and without atropine infusion on two separate studies. Fasting levels of glucose, islet and gut hormones were similar among 3 groups and 2 studies. Despite similar insulin sensitivity among the groups the insulin clearance estimated before meal ingestion was larger in surgical patients (P=0.08). Suppression of endogenous β-cell secretion by hypoglycemia was less in both surgical groups compared to controls (P&lt;0.001), but it was reduced by atropine in 3 groups (P&lt;0.05). Hypoglycemia-induced glucagon secretion was not affected by PNS blockade. Blocking PNS diminished both β- and α-cell secretory response to meal ingestion (P &lt; 0.05) in both surgical and non-surgical groups. Pre- and post-meal pancreatic polypeptide, marker of vagal input to the islet, declined to baseline values during atropine infusion. Meal-induced GIP secretion was similar in studies with and without atropine whereas blocking PNS significantly reduced GLP-1 secretion (P &lt; 0.05) in all subjects. Our data shows that in nondiabetic subjects with prior GB and SG, PNS activity regulates islet and gut hormone secretory response to meal ingestion independent of glucose levels.

Disclosure
H. Honka: None. A.M. Al Zubaidi: None. R.A. DeFronzo: None. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. M. Salehi: None.

Funding
Finnish Cultural Foundation (00180071); National Institutes of Health (DK105379)
1775-P: Molecular Dissection of Brainstem GABA Neurons Regulating Energy Balance
Authors: BHAVE VARUN M. , KAMATKAR NACHIKET , NECTOW ALEXANDER R. 
Published: June 2020

An important goal in metabolism is to identify brain regions capable of regulating energy balance. These brain regions represent potential druggable targets for the modification of food intake and energy expenditure, which could help to combat any number of debilitating disorders relating to metabolic function and body weight. We have recently identified the dorsal raphe nucleus (DRN) as a key node in the central nervous system regulating both food intake and energy expenditure. In particular, we have found that inhibitory, GABAergic neurons residing in the dorsolateral aspect of this nucleus are activated by hunger and in turn induce the appropriate counterregulatory responses – namely, to increase food intake and suppress energy expenditure. Here, using a combination of ensemble-level molecular profiling in tandem with single-nuclear RNA sequencing, we demonstrate that these GABAergic neurons are molecularly heterogeneous and express a host of factors directly implicated in the central control of energy homeostasis. Of note, a few of these subpopulations express abundant levels of transcript for neuropeptides important in regulating energy balance, such as thyrotropin-releasing hormone (Trh) and neuropeptide Y (Npy). These profiling studies thus demonstrate a previously underappreciated level of heterogeneity within GABAergic neurons of the DRN suggesting a multifaceted, and possibly distributed, mechanism through which these neurons may regulate energy balance. Together, this work molecularly characterizes the DRN at a resolution not previously possible and identifies cell subpopulations through which this nucleus may regulate energy homeostasis.

Disclosure
V.M. Bhave: None. N. Kamatkar: None. A.R. Nectow: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-18-ACE-49 to A.R.N.); American Diabetes Association (1-18-IBS-148 to A.R.N.); Foundation for Prader-Willi Research; National Alliance for Research on Schizophrenia & Depression
1777-P: Defining VDR Expression in the Brain Using a Novel VDR-Cre Mouse Line
Authors: LIU HAILAN 
Published: June 2020

The central nervous system mediates the effects of vitamin D on energy and glucose balance, but the distribution of vitamin D receptor (VDR) in the brain is not clear due to the lack of reliable antibodies. Here, we generated a knock-in VDR-Cre mouse line, in which cre recombinase activity is driven by the endogenous VDR promoter. By mating VDR-Cre mice with TdTomato reporter mice, we found that VDR-expressing neurons are located in multiple brain regions, including the cortex, hypothalamus, amygdala and caudate putamen. We further verified the specificity of our model through single cell RT-PCR, which showed significantly higher vdr expression in tomato+ cells. More importantly, our in vitro electrophysiological study revealed that vitamin D can selectively activate tomato+ neurons, without affecting tomato- neurons. By using immunofluorescence staining, we found a small portion of VDR positive neurons also express oxytocin, ß-endorphin, ERα or serotonin. Interestingly, in the ventromedial hypothalamus, ERα co-localized with only 1% tomato+ neurons in males but 8% tomato+ neurons in females. Taken together, we created and validated a novel VDR-Cre mouse line, which provides a useful tool for future studies to investigate the functions of VDR in the brain.

Disclosure
H. Liu: None.
1778-P: A Single Cell Map of Metabolically Regulated Neurons in the Ventromedial Hypothalamic Nucleus
Authors: RUPP ALAN , AFFINATI ALISON , MYERS MARTIN G. 
Published: June 2020

While the ventromedial hypothalamic nucleus (VMN), especially the dorsomedial VMN (dmVMN), plays important roles in the control of blood glucose and energy balance, the subpopulations of VMN neurons that comprise the dmVMN have remained poorly defined. To identify dmVMN subpopulations in an unbiased manner, we performed single nucleus RNA-seq on mouse VMN and clustered the VMN neurons into subtypes based upon their transcriptional profiles (T-types). This analysis revealed over a dozen distinct T-types that can be organized hierarchically into 5 major classes of neurons that exhibit distinct anatomic distributions within the VMN (dm, ventrolateral, and tuberal). Several dmVMN T-types expressed marker genes known to contribute to the control of energy balance and glucose homeostasis (e.g., Lepr, Tcf7l2), and many of these genes were expressed in distinct T-types, suggesting the existence of multiple T-types that modulate metabolism, each of which may play distinct roles in metabolic control. Indeed, exposure to high-fat diet induced obesity (DIO) provoked transcriptional changes only in a subset of VMN T-types. Furthermore, while some DIO-induced transcriptional changes were common to all affected T-types, many changes were unique to a single T-type. Together, these findings not only identify the distinct subpopulations of dmVMN neurons in an unbiased manner, but they also reveal specific dmVMN subpopulations that respond to the metabolic perturbations associated with obesity, as well as the unique transcriptional responses of each subpopulation to these perturbations.

Disclosure
A. Rupp: Research Support; Self; Novo Nordisk A/S. A. Affinati: Research Support; Self; Novo Nordisk Inc. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc.
1784-P: Liraglutide Treatment Stimulates Alpha Cells to Produce Glucagon-Like Peptide-1 via Expression of Prohormone Convertase 1/3 in Mice and Human
Authors: SAIKIA MRIDUSMITA , HOLTER MARLENA M. , GARIBAY DARLINE , GARCIA-OCANA ADOLFO , DANKO CHARLES G. , CUMMINGS BETHANY 
Published: June 2020

Glucagon-like peptide-1 (GLP-1) regulates islet function by enhancing glucose-stimulated insulin secretion (GSIS). We previously found that the beta cell GLP-1 receptor (GLP-1R) contributes to improvements in glucose regulation and islet function in mice that have undergone bariatric surgery, specifically, vertical sleeve gastrectomy (VSG). Further investigation revealed that VSG increases alpha cell GLP-1 production by turning on the expression of prohormone convertase 1/3 (PC1/3, gene: Pcsk1) in a beta cell GLP-1R-dependent fashion. These findings lead us to hypothesize that beta cell GLP-1R signaling increases alpha cell GLP-1 production to augment GSIS in a paracrine positive feedback loop. In the current study, we tested whether the effects of VSG can be recapitulated by pharmacologic stimulation of the GLP-1R, using a GLP-1 analog, liraglutide. We found that liraglutide treatment increases alpha cell GLP-1 expression in a beta cell GLP-1R dependent fashion (GLP-1 area per islet (µm2): Vehicle WT = 132 ± 3, Vehicle KO = 73 ± 2, Liraglutide WT = 241 ± 15, Liraglutide KO = 67 ± 1; P&lt;0.05 Liraglutide WT vs. all groups). We then used an innovative single-cell RNA-sequencing platform, DART-seq, to determine the translational relevance of this new model of islet function. We validated application of DART-seq in human islets, and using this technology we observed that liraglutide induces a 1.5 log-fold increase in Pcsk1 mRNA expression compared with saline treated controls in a subset of alpha cells (P&lt;0.05 saline vs. liraglutide). Additionally, our DART-seq data suggests that liraglutide-induced increase in alpha cell PC1/3 expression may be part of a broader induction of alpha-cell transdifferentiation to beta cells. Thus, our study demonstrates that the effect of beta cell GLP-1R signaling to increase alpha-cell GLP-1 expression can be stimulated by pharmacological activation of the GLP-1R and has translational relevance in humans.

Disclosure
M. Saikia: None. M.M. Holter: None. D. Garibay: None. A. Garcia-Ocana: None. C.G. Danko: None. B. Cummings: None.