bluuebunny/crossref_metadata_2025_split huggingface dataset:
2125-P: Incretin-Stimulated Insulin Secretion Is Mediated by Gas Dependent and Independent Mechanisms
Authors: CAPOZZI MEGAN , GRAY SARAH M. , EMMERSON PAUL , WILLARD FRANCIS S. , SLOOP KYLE , D’ALESSIO DAVID , CAMPBELL JONATHAN 
Published: June 2020

The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) stimulate insulin secretion in β-cells by binding to cognate receptors. The GIPR and GLP-1R are family B G-protein coupled receptors generally thought to mediate signaling through G-αs and generation of cAMP. However, the GLP-1R has also been reported to signal through alternative pathways beyond Gαs, and the relative contributions of Gαs vs. non-Gαs are unknown. The GLP-1R is essential for basal levels of cAMP and normal β-cell tone. We hypothesized that elimination of Gαs would render mouse islets insensitive to GLP-1R agonists. Induction of β-cell specific Gnas knockout with tamoxifen inducible cre caused a &gt;90% reduction in Gαs mRNA in purified β-cells (Gnasβcell-/-). Perifusion of control and knockout islets demonstrated reduced glucose-stimulated insulin secretion, but persistence of an insulin response to GLP-1R agonists that was ∼40% of control. Similarly, insulin secretion in response to either GIP or glucagon was only partially reduced in Gαs knockout islets. A Gq inhibitor partially reduced insulin secretion in control islets, but abolished GLP-1 stimulated insulin secretion in Gnasβcell-/- islets. These results demonstrate that the incretins can signal through both Gαs and non-Gαs mechanisms. Interestingly, Gnasβcell-/- mice were severely hyperglycemic (&gt;400 mg/dl) and had no reduction of glycemia in response to GLP-1R or GIPR agonists. Thus, non-Gαs signaling by either GLP-1R or GIPR is unable to stimulate sufficient insulin secretion to maintain euglycemia in vivo.

Disclosure
M. Capozzi: None. S.M. Gray: None. P. Emmerson: None. F.S. Willard: None. K. Sloop: None. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.

Funding
American Diabetes Association (1-17-JDF-074 to J.C.); National Institutes of Health (R01DK123075, F32DK116542)
213-LB: Identification of Olfactory Circuits Modulating Energy Homeostasis
Authors: RIERA CELINE 
Published: June 2020

Olfactory inputs are important for hedonic evaluation of food, resulting in food choice and possible consumption. The hypothalamus is a master regulator of whole-body energy homeostasis, integrating internal and external stimuli to modulate energy intake and expenditure accordingly. However, how the hypothalamus adjusts circuits regulating energy homeostasis depending on external stimuli, such as smell, remains an intriguing mystery. Here, we determined the role of olfactory inputs on energy homeostasis by using chemogenetic approach and chemical ablation of OSN to inhibit or stimulate olfaction. Acute inhibition of olfaction changed gene expression of some key neuropeptides in hypothalamus in fasted and refed mice. Chronic silencing of mitral cells in OB promotes resistance to diet-induced obesity, mainly by decreasing food intake. Additionally, chemical ablation of mature OSNs decreases neuronal activity in olfactory cortex and in ARC suggesting that loss of smell, in addition to impacting olfactory pathways, also affects neuronal activity in the ARC, and therefore is likely to alter energy homeostasis. Acute stimulation of mitral cells layer in OB increases neuronal activity in ARC as well as dorsomedial hypothalamus (DMH). Observed increase in ARC neuronal activity is mainly due to activation of glutaminergic neurons. Acute stimulation of olfaction led to increased oxygen consumption and heat production, with no changes observed upon chronic stimulation. Further studies are required to determine specific neuronal cell types within the ARC and DMH that respond to inhibition/stimulation of olfaction and therefore modulating energy homeostasis.

Disclosure
C. Riera: None.

Funding
American Diabetes Association Pathway to Stop Diabetes (1-15-INI-12)
213-OR: Obesity-Induced Astrogliosis Is Regulated by the Diabesity Factor HMG20A
Authors: MELLADO-GIL JOSE M. , FUENTE-MARTIN ESTHER , LORENZO PETRA I. , COBO-VUILLEUMIER NADIA , GUERRERO-MARTÍNEZ JOSE A. , ROMERO-ZERBO SILVANA Y. , FRANCO JAIME M. , PEREZ-CABELLO JESÚS ÁNGEL , ALVAREZ-DOLADO MANUEL , POZO DAVID , BERMUDEZ-SILVA FRANCISCO J. , REYES JOSE C. , GAUTHIER BENOIT R. 
Published: June 2020

It is well established that systemic glucose homeostasis is imparted by an intricate cross-talk among several organs including the central nervous system (CNS) and pancreatic islets. In analogy to islet beta cells, hypothalamic astrocytes are glucose sensors that facilitate the CNS response to changing metabolic environment. Therefore, astrocytes and beta cells may share a common genetic signature implicated in coupling glucose metabolism to cellular output. We recently demonstrated that the diabesity factor HMG20A is essential for beta-cell functional maturity and adaptation to physiological stress (obesity, type 2 diabetes and pregnancy). As this chromatin remodelling factor also dictates CNS development, we sought to determine whether HMG20A is expressed in astrocytes and whether it potentiates astrocyte function in response to environmental cues. We found that HMG20A is expressed in hypothalamic astrocytes and is upregulated in diet-induced obesity and glucose-intolerant mice, correlating with increased transcript levels of GFAP and IL-1β, indicative of reactive astrocytes (astrogliosis). High glucose, but not lipids, transiently decreased HMG20A expression in isolated mouse primary astrocytes. HMG20A silencing in astrocytes resulted in repression of pro-inflammatory as well as lipid and glucose metabolism genes. These pathways are up-regulated in activated astrocytes (astrogliosis) to resolve stress conditions. As such astrocyte depleted of HMG20A were more susceptible to cell death. Furthermore, motor neuron viability in astrocyte conditioned media was significantly hindered after HMG20A depletion in astrocytes. We posit that HMG20A is involved in the astrocyte polarization state. Under physiological pressure such as obesity, HMG20A expression may be transiently decreased by high glucose but long-term it is increased to induce astrogliosis in an attempt to preserve the neuronal network and glucose homeostasis.

Disclosure
J.M. Mellado-Gil: None. E. Fuente-Martin: None. P.I. Lorenzo: None. N. Cobo-Vuilleumier: None. J.A. Guerrero-Martínez: None. S.Y. Romero-Zerbo: None. J.M. Franco: None. J. Perez-Cabello: None. M. Alvarez-Dolado: None. D. Pozo: None. F.J. Bermudez-Silva: None. J.C. Reyes: None. B.R. Gauthier: None.

Funding
ISCIII (PI13/00593 to B.R.G.), (PI13/00309 to F.J.B-S.); Ministerio de Economia y Competidividad/Fondos FEDER (PI10/00871, PI13/00593, BFU2017-83588-P to B.R.G.); BFU2017-85420-R (to J.C.R.); (JCI-2012-12491, IJCI-2015-26238 to E.F-M.); Consejería de Salud Junta de Andalucía (PI-0006-2016 to E.F-M.)
2134-PUB: Clinical Pearl: Overtreatment of Hyperglycemia and Hypoglycemia Contributes to Excessive Glycemic Variability
Authors: LEONE KERI J. , ACCIAROLI GIADA , PARKER ANDREW , WELSH JOHN , WALKER TOMAS C. , PRICE DAVID A. 
Published: June 2020

The coefficient of variation (CV) of CGM-derived sensor glucose values (SGVs) is the preferred metric for glycemic variability. However, a high CV is not directly actionable. We hypothesized that overtreatment of hyperglycemia (leading to iatrogenic lows) and overtreatment of hypoglycemia (leading to rebound highs) contribute to excessive CVs. An iatrogenic low was defined as any series of SGVs &lt;70 mg/dL starting within 2 h of an SGV &gt;180 mg/dL; a rebound high was any series of SGVs &gt;180 mg/dL starting within 2 h of an SGV &lt;70 mg/dL. We used data from a convenience sample of anonymized U.S.-based users of G6 CGM systems (Dexcom) who had uploaded &gt;80% of possible SGVs over &gt;28 days in 3Q2019. Users were stratified into quartiles by CV. Cohorts with CVs &lt;31.2% ("Stable") or &gt;39.1% ("Labile") were compared with respect to rebound highs, iatrogenic lows, the percentage of SGVs &lt;70 or &gt;180 mg/dL (TBR and TAR, respectively), and the fraction meeting TAR and TBR goals of &lt;25% and &lt;4%, respectively. Compared to "Stable" users, the iatrogenic lows and rebound highs of "Labile" users were more frequent and longer. Users in the "Stable" cohort also had lower TAR and TBR percentages than users in the "Labile" cohort and were more likely to meet consensus goals for these metrics (Table). Patients may lower CV and improve other CGM metrics by focusing on avoiding overtreatment of high and low glucose values.

Disclosure
K.J. Leone: Employee; Self; Dexcom, Inc. G. Acciaroli: Employee; Self; Dexcom, Inc. A. Parker: Employee; Self; Dexcom, Inc. Stock/Shareholder; Self; Dexcom, Inc. J. Welsh: Employee; Self; CSL Behring. T.C. Walker: Employee; Self; Dexcom, Inc. D.A. Price: Employee; Self; Dexcom, Inc.
2138-PUB: Determining Early Stage CVD in Patients of T2DM Using Flow-Mediated Dilatation Score
Authors: CHAVDA VIPUL , HASNANI DHRUVI , SABOO BANSHI D. , SHAH SHIVESH , SAIYED MAHIRA , HASNANI SHRIJI 
Published: June 2020

Objective: To determine early stage CVD risk in type 2 DM patients using Flow Mediated Dilatation score -correlating it with acceleration of inflammatory process of vascular injury.
Methodology: Total 97(70 F 27 M) patients with T2DM of more than 10 years with age&gt; 50years were screened for FMD score along with 60 (34 F, 26 M) healthy controls (without DM same age group), using Angiodefender (Everist Genomics Ann Arbor, MI, USA). Pro inflammatory cytokines- TNF alpha, IL-6, IL-1 were measured using standard ELISA kits. As surrogates for disease activity C-reactive protein and ESR levels were determined. A Framingham risk score was assessed in order to evaluate coronary heart disease risk at 10years in per cent. A Treadmill Stress Test (TMT) was done in patients showing endothelial dysfunction to correlate the results.
Result: The FMD score in 97 T2DM patients showed that 70.1% (n=68, 59F 9M) patients suffered from impaired endothelial function and increased arterial thickness; 16.5% (n=16, 9F 7M) patients suffered from endothelial dysfunction, arterial stiffness and atherosclerosis whereas the remaining 13.4% had normal endothelial function. In the healthy counterparts, the FMD score was normal in 80% (n= 48, 26F 22M) patients. The pro inflammatory cytokines were either normal or high in the patients with impaired endothelial function. C-reactive proteins and ESR levels varied from high to normal in patients with endothelial dysfunction. The TMT test done for the patients with impaired endothelial dysfunction and arterial stiffness showed positive results.
Conclusion: The flow mediated dilatation score can be effectively used as a marker to determine the vascular injury and endothelial dysfunction in patients with type 2 DM. 70 % of patients showed impaired endothelial function and increased arterial thickness which can be considered for counseling of patients for prevention of CVD, using the FMD tool. Acceleration of Inflammatory process could also be effectively correlated with the FMD score.

Disclosure
V. Chavda: None. D. Hasnani: None. B.D. Saboo: None. S. Shah: None. M. Saiyed: None. S. Hasnani: None.
2153-PUB: Deep Learning and Laterality of Retinal Images
Authors: DÍAZ LARS , VISTISEN DORTE , JØRGENSEN MARIT E. , VALERIUS MARIANNE , HAJARI JAVAD N. , LUND-ANDERSEN HENRIK , BYBERG STINE 
Published: June 2020

Background: Retinal fundus images, obtained from routine eye screenings, contain important information, not only concerning microvascular lesions of the retina, but potentially also of the progression and manifestation of various other diabetes complications. Recent advances in the field of machine learning, so-called deep learning neural networks (DNN), make it possible to automatically detect retinal lesions from fundus photos. Our overall aim is to develop a DNN to detect retinal vascular lesions. In this abstract, we describe a pre-processing step consisting of application of a DNN.
Methods: For each eye, 5 retinal images of parts of the eye are taken, and collected into a joint mosaic image, used for image grading. There is no automated labelling of the images to identify left or right eyes. To distinguish left- from right eye images, we used a set of 1,916 unique, high-definition retina mosaic fundus images from diabetes patients followed at Steno Diabetes Center Copenhagen (SDCC) between 2003-2017. We trained and validated a DNN, using 964 left-eye (training set: 713, validation: 251) and 952 right-eye images (training set: 706, validation: 246). A DNN is a method that finds the optimal algorithm for relating a large set of input (mosaic fundus images) to output (left or right eye). The DNN used was based on the InceptionV3 architecture and run for 100 epochs with 100 gradient descent steps pr. epoch.
Results: The DNN classification obtained a validation AUC-ROC of 0.92 and a validation accuracy of 0.86.
Conclusions: The DNN successfully distinguished left-eye from right-eye images. We plan to use the DNN to identify right- and left-eye images in the SDCC image database comprising ∼ 80,000 left-eye and right-eye images. We will subsequently develop a DNN for automated detection of referable diabetic retinopathy of retinal fundus images, for use in the clinic.

Disclosure
L. Díaz: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. M. Valerius: None. J.N. Hajari: None. H. Lund-Andersen: None. S. Byberg: None.
2155-PUB: Diabetic Foot Ulcer Regeneration Platform Based on 4D Bioprinting Technology
Authors: KIM JEEHEE 
Published: June 2020

Diabetic foot ulcers have a significantly negative impact on patients and are highly prone to contamination, which can lead to amputation. The best possible wound management treatment was essential for diabetic foot ulcers. However, since 4D bio printing is the best way to recapitulate complex and functional human tissue and organ, we have developed the therapeutic 4D bio printer called INVIVO to use in skin regeneration. To find advanced treatment method particularly for wound healing, we tested our own 4D bio printing system with autologous fat tissue for DFU treatment. The extracellular matrix (ECM) derived from Nano-fat consisting of supportive proteins, growth factors and cytokines, has been reported as an important player to provide efficient 3D environments during cell proliferation and differentiation. In the clinical study, we printed autologous ECM (MA-ECM) with bio-inks to apply onto the chronic wound site. Most of DFU patients showed significant reduction of wound size with distinct epithelization only after a week treatment. Therefore, we suggest 4D bio printing system with MA-ECM as an alternative method for dressing materials that successfully promote the mechanism of skin reconstruction for DFU treatment. Reduction in size of wound was measured using ImageJ NIH software and almost all the subjects revealed complete closure of wound maximum of 2∼5 weeks post MA-ECM membrane application. The present study provided a significantly higher healing rate of the subjects and the primary outcome of our study complete epithelization with wound closure was achieved. The autologous fat by nature is loaded with adipocytes and growth factors which could have played a vital role in the healing of non-healing diabetic wounds. Therefore, we suggest 4D bio printing system with MA-ECM as an alternative method for chronic wound healing that successfully promote the mechanism of skin reconstruction for DFU treatment.

Disclosure
J. Kim: None.
216-LB: A Novel GPR119 Agonist, DA-1241, Reduces Hepatic Inflammation and Fibrosis in Preestablished Diet-Induced NASH Mice
Authors: PARK HANSU , LEE SEUNG HO , KIM MI-KYUNG 
Published: June 2020

There are no reports of the treatment effects of GPR119 agonists in pre-established NASH animal models yet. The aim of this study was to investigate the efficacy of DA-1241 monotherapy and to explore its combined effects with a dipeptidyl peptidase 4 (DPP-4) inhibitor in pre-established NASH mice. DA-1241 in the absence or presence of a DPP-4 inhibitor was given to biopsy-proven diet-induced NASH mice for 8 weeks. Plasma and liver tissue were tested for biochemical and/or histological analyses. Changes in gene expression profiles in the liver were evaluated by RNAseq method. Plasma profiles of a panel of cytokines were assessed. After 8-week administration, DA-1241 treatment significantly decreased hepatic lipid accumulation (-51.4%) and co-treatment of a DPP-4 inhibitor showed a further reduction (-60.6%). DA-1241 monotherapy and its combination reduced liver fibrosis score (-20.6% and -36.5%) with lower levels of hepatic type 1 collagen and plasma TIMP-1. Notably, DA-1241 alone and its combination significantly reduced the infiltration of immune cells into the liver (-25.0% and -49.1%) with drastically decreased the hepatic galectin-3 levels (-58.3% and -67.2%). Liver enzyme values decreased in both treatment groups. In line with these results, DA-1241 treatment alone prominently improved gene expression profiles associated with stellate cell activation, monocyte recruitment, inflammation signaling, and hepatocellular cell death. Moreover, plasma levels of clinically-related plasma cytokines such as CCL2, TNFα, and CXCL10 were also reduced in DA-1241-treated mice. All the effects augmented by its concomitant use with a DPP-4 inhibitor were supported by the increase of plasma active GLP-1 (6.6 folds vs. NASH control). To the best of our knowledge, this is the first report to comprehensively demonstrate the in vivo therapeutic efficacy of GPR119 agonist as monotherapy and combination therapy with DPP-4 inhibitors for the treatment of NASH.

Disclosure
H. Park: Employee; Self; Dong-A ST Co., Ltd. S. Lee: Employee; Self; Dong-A ST Co., LTD. M. Kim: Employee; Self; Dong-A ST Co., Ltd.
2162-PUB: Diabetes Education for Technology Applications in Learning Study (DETAILS)
Authors: LEBLANC JENNIFER , EL SAYED NUHA ALI 
Published: June 2020

Introduction: New diabetes technology and software require substantial training and understanding by healthcare providers in order to effectively make treatment decisions and manage patients. This study uncovers healthcare providers’ learning preferences, experiences, and barriers in the field of diabetes technology education and training.
Methods: This mixed methods study utilized an anonymous survey using Lickert scales and/or completing open ended questions. Quantitative data from this study was analyzed on survey monkey and open ended questions were tagged independently. The sample included 118 multidisciplinary healthcare providers who treat patients with T1 and T2 diabetes and come from more than 18 different U.S. states and diverse practice settings.
Results: Participants reported the most typical education format received for diabetes technology was clinical trials followed by training by industry representatives. The majority of participants expressed lack of confidence in being trained by industry representatives and many shared negative feelings and concerns when receiving training. Perceptions and preferences in training methods as well as significant barriers to learning will be discussed in the presentation. Results showed that participants’ effective learning affects their prescribing habits and practices. Key themes around perceptions of patient education and ability to self-manage will also be discussed.
Conclusion: Diabetes technology education is critical for better patient care and outcomes. Our study has unveiled many barriers to ensuring this transfer of knowledge is done seamlessly, effectively, efficiently and without bias. There was a clear disconnect between provider’s typical methods of learning about diabetes technology, their preferred methods and what they perceived as most effective. The concept of patient empowerment and indications of initiating technology in patients with diabetes is in need of further investigation.

Disclosure
J. LeBlanc: Consultant; Self; Insulet Corporation. Employee; Spouse/Partner; Insulet Corporation. N. El Sayed: None.
217-OR: ADA Presidents’ Select Abstract: The Affordable Care Act Medicaid Expansion Correlated with Reduction in Lower Extremity Amputation among Minorities with Diabetic Foot Ulcerations
Authors: TAN TZE-WOEI , CALHOUN ELIZABETH , KNAPP SHANNON M. , MARRERO DAVID G. , ZHOU WEI , ARMSTRONG DAVID G. 
Published: June 2020

Objectives: Lack of insurance and non-white race are associated with increased risks of amputation. It is unclear how expanded insurance coverage affects the care of minorities with diabetes. The aim was to evaluate the effect of Medicaid expansion under the Affordable Care Act (ACA) on outcomes of minorities with diabetic foot ulcerations (DFUs).
Methods: We analyzed the State Inpatient Databases from 19 states to identify people who were either uninsured or on Medicaid with DFUs from 2013 to 2015. Patients were categorized into early-adopter states (implemented the ACA expansion by January 2014) and non-adopter states. Logistic regression was performed to examine the effects of state type (early vs. non-adopter), time (pre- vs. post-ACA), and their interaction on the proportion of amputation.
Results: The study included 25,493 non-white Medicaid beneficiaries and 9,863 uninsured patients with DFUs. Among the minorities aged 20 to 64 years, there was an increase (180.7%) in the number of admissions for Medicaid beneficiaries and a reduction (21.5%) in the admissions of uninsured patients in early-adopter states after expansion. In comparison, there was an increase in the number of admissions of the uninsured patients (78.2%) in non-adopter states during the same period. The odds of major amputation among non-white Medicaid beneficiaries with DFUs decreased 17.3% in early-adopter states and increased 0.9% in non-adopter states (p=0.045), while the odds of minor amputation increased 14% in early-adopter states and decreased 8.1% in non-adopter states (p=0.003).
Conclusion: The ACA Medicaid expansion appears to have substantial positive effects on the care of minorities with DFUs. Racial and ethnic minorities in states that expanded Medicaid experienced a significant reduction in the number of uninsured with DFUs and a reduction in major amputations. The broadening of the ACA may reduce disparities in diabetes-related amputations.

Disclosure
T. Tan: None. E. Calhoun: None. S.M. Knapp: None. D.G. Marrero: None. W. Zhou: None. D.G. Armstrong: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK122126)