bluuebunny/crossref_metadata_2025 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 >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 (>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 <70 mg/dL starting within 2 h of an SGV >180 mg/dL; a rebound high was any series of SGVs >180 mg/dL starting within 2 h of an SGV <70 mg/dL. We used data from a convenience sample of anonymized U.S.-based users of G6 CGM systems (Dexcom) who had uploaded >80% of possible SGVs over >28 days in 3Q2019. Users were stratified into quartiles by CV. Cohorts with CVs <31.2% ("Stable") or >39.1% ("Labile") were compared with respect to rebound highs, iatrogenic lows, the percentage of SGVs <70 or >180 mg/dL (TBR and TAR, respectively), and the fraction meeting TAR and TBR goals of <25% and <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> 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)
2175-PUB: Feasibility and Preliminary Effectiveness of Continuous Glucose Monitoring for Diabetes Prevention
Authors: FORTMANN ADDIE L. , BASTIAN ALESSANDRA , BAGSIC SAMANTHA R.S. , LOUPASI IOANNA , LUU KIMBERLY , HOTTINGER AMIRY R. , BARRY KIMBERLY A. , RUIZ MONICA , WALKER CHRIS , PHILIS-TSIMIKAS ATHENA
Published: June 2020

Continuous Glucose Monitors (CGM) automatically capture interstitial glucose levels every 5 minutes, 24 hours/day, allowing users to view their glucose levels in real-time and make informed decisions about how to manage diet, exercise, and medications. While CGMs are a central component in the glucose management of type 1 diabetes and insulin-dependent type 2 diabetes, less is known about the potential value of CGMs for diabetes prevention. The original Diabetes Prevention Program (DPP) demonstrated that 5-7% weight loss - an outcome reliant upon healthful eating and exercise - was more effective than medication in preventing or delaying the onset of T2D; however, subsequent DPP translations have not consistently achieved the same weight loss outcomes. CGM may represent a way to reinforce and incentivize hard-to-make health behavior changes in real-time that are crucial to the more distal (and often elusive) weight loss outcome. This small (n=7) feasibility pilot examined the preliminary effectiveness and acceptability of integrating CGM in a DPP at Scripps Health, a large, non-profit, private insurance-based health system in San Diego, CA. Following a brief introduction to the CGM and target glucose ranges, DPP participants self-inserted and wore the CGM for 2 weeks. Mean time-in-range (70-140 mg/dL) improved from 70.4% to 76.4%, and time > 140 mg/dL decreased from 29.4% to 23.1% during this period. Individual change in time-in-range ranged from -9.7% to + 38.8% (M ∆ = +6.0%). Participants reported high satisfaction with the CGM, but expressed a desire for more education on blood glucose management. Given these findings, a longer-term, randomized controlled trial is planned to investigate whether a CGM-enhanced DPP leads to greater weight loss than DPP alone. This research will also further our understanding of the potential benefit of improved glycemic control for diabetes prevention even among the subset of cases who do not ultimately achieve the targeted weight loss goal.

Disclosure

A.L. Fortmann: None. A. Bastian: None. S.R.S. Bagsic: None. I. Loupasi: None. K. Luu: None. A.R. Hottinger: None. K.A. Barry: None. M. Ruiz: None. C. Walker: None. A. Philis-Tsimikas: Advisory Panel; Self; Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi.

Funding

Confidence Foundation; Dexcom, Inc.
2183-PUB: Standard Deviation Calculated from the 7-Point SMBG Glucose Profiles Is a Good Index of Glycemic Variability Reflecting MAGE Obtained from CGMS
Authors: LIU ZHIGU , LIN BEISI , XU WEN , GONG LI , YANG XUBIN , YAO BIN
Published: June 2020

Objective: Mean amplitude of glucose excursion (MAGE) obtained from the CGMS is considered a gold standard of glycemic variability (GV). However, the implications of CGMS in routine clinical practice are limited due to its high cost and complexity. This study thus designed to explore whether the GV indices calculated from the more common measurement SMBG can be used to reflect MAGE in T2D patients.

Methods: T2D patients simultaneously underwent a 48-h to 72-h CGM and fingertip blood glucose self-monitoring were included. The GV indices calculated from the 7-point SMBG data (pre- and post- breakfast, lunch and dinner and prior to bedtime) were the means of the following indices during CGM period: the standard deviation (SD) of the 7-point glucose profiles, the largest amplitude of glycemic excursions (LAGE, the difference between the daily maximum and minimum glycemic values) and the mean postprandial glucose excursion (MPPGE, the mean value of the differences between each postprandial and preprandial blood glucose).

Results: Seventy-eight T2D patients (43.6% male, median age: 62 years, median BMI: 23.83 kg/m2) were included. The mean MAGE, SD, LAGE and MPPGE were 4.11, 2.03, 5.66, 2.57mmol/L, respectively. SD, LAGE and MPPGE were significantly correlative with MAGE (r= 0.625, 0.488 and 0.599, respectively; all P<0.05). In the linear regression analysis, significant relationships were shown between MAGE and SD, LAGE and MPPGE (R2=0.391, 0.359, 0.238, respectively; all P<0.001). The area under the ROC curve for SD (0.809, 95% CI: 0.712-0.906, P<0.05) was superior to that for LAGE (0.793, 95% CI: 0.692-0.894, P<0.05) and MPPGE (0.704, 95% CI: 0.588-0.820, P<0.05) in reflecting MAGE.

Conclusions: The GV indices calculated from the SMBG data including SD, LAGE and MPPGE are positively correlated with MAGE obtained from CGM. Among these indices, SD of the 7-point SMBG glucose profiles seems to be a better GV index to reflect MAGE.

Disclosure

Z. Liu: None. B. Lin: None. W. Xu: None. L. Gong: None. X. Yang: None. B. Yao: None.

Funding

National Key Research and Development Program of China (2016YFC1304801)
2188-PUB: Efficacy and Safety in Chinese T2D Patients Discontinued from OAM to Once-Weekly Dulaglutide Monotherapy
Authors: LI YANBING , ZHANG BIN , LIU SIYING
Published: June 2020

Background and Objective: GLP-1RAs including dulaglutide (DU) are recommended as 1st injectable therapy in T2D patients after oral antihyperglycemic medicine (OAM) failure. Efficacy and safety of DU have been studied when adding on OAMs, but not in Chinese population discontinued from OAM. This is the first post-hoc analysis to evaluate the efficacy and safety of DU in Chinese T2D patients discontinued from OAM and started with once weekly DU.

Methods: A total of 292 Chinese patients who discontinued from OAM monotherapy in AWARD-CHN1 study (NCT01644500) were included in this post-hoc analysis as modified intent-to-treat (mITT) population.

Results: Overall, the mITT population had mean age of 55.0 years, with 5.5 years’ mean duration of T2D at baseline. Previous OAM treatment included metformin, acarbose, sulfonylureas, and meglitinides. Table 1 summarized the efficacy and safety outcomes at Week 26. DU 1.5 mg was superior to glimepiride for HbA1c and body weight reduction. Greater improvement in beta cell function was observed for both DU groups, along with fewer hypoglycemia events. The most common adverse events for DU were gastrointestinal in nature, including diarrhea, abdominal distension, vomiting and nausea.

Conclusion: DU is effective and safe for Chinese T2D patients discontinued from OAM and can further improve glucose control and protect beta cell function compared to glimepiride.

Disclosure

Y. Li: None. B. Zhang: Employee; Self; Eli Lilly and Company. S. Liu: Employee; Self; Eli Lilly and Company.
2190-PUB: A Pragmatic Study of Basal and Mid-Mixture Insulins as Insulin Starters in Chinese Patients with T2DM
Authors: CHEN LULU , CHEN HONG , DU LIYING , LOU YING , JI LINONG
Published: June 2020

This study aimed to compare the effectiveness and safety of basal insulin (BI) and mid-mixture insulin (MMI) in a real-world setting. Chinese patients with T2DM uncontrolled on oral antihyperglycemic medications (OAMs) were randomized 1:1 to receive add-on BI (QD) or MMI (BID) for 48 weeks (wks). Insulin titration and OAM dose adjustment were based on clinical practice. Compared to BI, MMI led to numerically greater decrease in HbA1c from baseline to wk 24 and statistically greater decrease in HbA1c at wk 48. Fasting blood glucose (FBG) in both groups further decreased from wk 24 to wk 48, and BI caused greater decrease at wk 48 compared to MMI. Both groups had similar decreases in postprandial glucose. Also, significant intergroup difference in OAM use change was detected (p <0.0001) with more patients increasing OAM use in BI group and decreasing OAM use in MMI group. Noticeably, both groups had very limited insulin titration. Body weight increased subtly in both groups. Total hypoglycemia incidence was higher in MMI group through 48 wks, but both groups had low and similar nocturnal hypoglycemia incidence and no severe hypoglycemia. Both BI and MMI could significantly improve glycemic control in Chinese T2DM patients with OAM adjustment and limited insulin titration without major safety issues. Compared to BI, MMI showed larger improvement on glycemic control in relatively long period of treatment.

Disclosure

L. Chen: Consultant; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. H. Chen: Employee; Self; Eli Lilly and Company. L. Du: Employee; Self; Eli Lilly and Company. Y. Lou: Employee; Self; Eli Lilly and Company. L. Ji: None.
2195-PUB: Use of U500 Insulin in External Pump for Insulin-Resistant Diabetic Patients: A French Experience
Authors: OUALIT YOUSSEF , PÂRIS DOMINIQUE , KESSLER LAURENCE , BAHOUGNE THIBAULT , JEANDIDIER NATHALIE , MEYER LAURENT
Published: June 2020

Use of large insulin doses is more frequent in diabetes due to an increase in the prevalence of severe obesity worlwide. Insulin-associated treatments such as metformin or GLP-1 receptor agonists (GLP-1RA) can help and use of insulin concentrated at 500 IU/ml (U500) has been associated with an improve in glycemic control in previous studies including severe insulin resistant patients. We report our experience of U500 in subjects with high HbA1c despite insulin pump therapy (CSII) combined or not with metformin and/or GLP-1RA. Eighteen T2D and 3 T1D were studied (13M and 8F), age: 59.5 ± 9.6 years, diabetes duration : 18.8 ± 9.8 years. Eight subjects used metformin and 7 used GLP-1RA (5 used metformin and GLP-1RA). Treatment with U500 was carried out during a 5-day hospitalization. Metformin and/or GLP-1RA were continued or not during the follow-up according to the decision of the patient’s diabetologist. Mean duration of follow-up was 9 months. A decrease in HbA1c was found (initial vs. final) : 9.4 ± 1.2% vs. 8.5 ± 1.3% (p =0.05). No change was found for weight : 123.9 ± 26.4 kg vs. 121.0 ± 30.3 kg (NS), BMI : 41.5 ± 7.2 kg/m2 vs. 40.2 ± 7.3kg/m2 (NS), daily total insulin needs (U100 equivalent) : 198.4 ± 70.5 IU vs. 228 ± 121 IU (NS), basal needs : 81.8 ± 29.2 IU vs. 87 ± 36 IU (NS) and prandial needs : 116.5 ± 61.3 IU vs. 143 ± 110 IU (NS). No changes were found for lipidic parameters as total cholesterol (TC) : 1.85 ± 1.10 g/l vs. 1.80 ± 0.92 g/l (NS), HDL-C : 0.36 ± 0.08 g/l vs. 0.31 ± 0.06 g/l (NS), LDL-C : 0.83 ± 0.32 g/l vs. 0.71 ± 0.30 g/l (NS) and TG : 3.98 ± 7.56 g/l vs. 3.4 ± 5.3 g/l (NS). No change in use of metformine and/or GLP-1RA and no side effect were found during the follow-up.

Conclusion: In our practice, use of U500 in insulin-resistant patients treated with CSII is well tolerated and is associated with a decrease in HbA1c despite no change in weight or daily insulin needs. Evolution of glycemic variability (including TIR and hypoglycemias) using continuous glucose monitoring is currently being analyzed.

Disclosure

Y. Oualit: None. D. Pâris: Board Member; Self; Novo Nordisk Inc. Consultant; Self; Eli Lilly and Company, Sanofi-Aventis. L. Kessler: Consultant; Self; Lilly Diabetes, Medtronic, Novartis Pharma K.K., Novo Nordisk A/S, Vertex Pharmaceuticals. T. Bahougne: None. N. Jeandidier: Consultant; Self; Sanofi-Aventis. Research Support; Self; Lilly Diabetes. L. Meyer: Board Member; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S.
220-OR: Plasma Adrenomedullin and Allelic Variation in the ADM Gene and Risk for Lower Extremity Amputation in People with Type 2 Diabetes
Authors: POTIER LOUIS , ROUSSEL RONAN , SAULNIER PIERRE-JEAN , FUMERON FRÉDÉRIC , MOHAMMEDI KAMEL , VELHO GILBERTO
Published: June 2020

Patients with diabetes have an increased risk for lower limb amputation (LLA) but biomarker to assess risk of LLA is lacking. Adrenomedullin (ADM), a vasodilator peptide, has been shown to be associated with cardiovascular and renal risk in diabetes. The aim of this study is to assess the association between plasma MR-proADM (a surrogate of ADM), allelic variation in the ADM gene and the risk for LLA in cohorts of patients with type 2 diabetes. We studied 4532 participants of the DIABHYCAR and SURDIAGENE cohorts (men 70%, mean age 66, mean duration of diabetes 13 years, A1c 8,0%). MR-proADM was measured by immunofluorescence. Five SNPs were chosen in the haplotype block containing the ADM gene (chr11p15.4): rs4399321, rs11042725, rs7944706, rs2957692 and rs2957717. The mean follow-up was 5.3 years. Incidence of LLA by tertiles of MR-proADM (T1, T2, T3) was 1.0% (T1), 1.9% (T2) et 4.7% (T3) (p<0,001). In a Cox multivariable analysis model (adjusted for cohort, age, sex, diabetes duration, hypertension, A1c, cholesterol, history of peripheral arterial disease and glomerular filtration rate eGFR), HR for LLA was 4.21 (2.18-8.66; p<0.001) for T3 vs. T1, 2.46 (1.50-4.12; p=0.003) for T3 vs. T2 and 1.82 (1.25-2.67; p=0.002) for 1 unit of log [ADM]. All SNPs were significantly associated with baseline plasma ADM. Four were significantly associated with LLA: HR adjusted for sex, age, duration of diabetes, A1c, eGFR and cohort: 1.40 (1.046 - 1.84; p=0.02) for the G-allele of rs4399321 in a codominant model; 1.71 (1.13 - 2.54; p=0.01) for the AA vs. CX genotype of rs11042725; 1.61 (1.09 - 2.35; p=0.02, for the GG vs. AX genotype of rs7944706; 1.37 (1.06 - 1.77; p=0.04) for the G-allele of rs2957692 in a codominant model. We observed an association of plasma ADM with LLA and of allelic variations in the AMP locus with plasma ADM and with LLA in a large population of people with type 2 diabetes. This pattern of mendelian randomisation supports the causality of the association of plasma ADM with LLA.

Disclosure

L. Potier: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. R. Roussel: Advisory Panel; Self; Abbott, AstraZeneca, Diabnext, Eli Lilly and Company, Merck & Co., Inc., Mundipharma International, Novo Nordisk A/S, Sanofi-Aventis. P. Saulnier: None. F. Fumeron: None. K. Mohammedi: None. G. Velho: None.
223-LB: Dissecting the BPA-Induced Disruptions in Liver–Gut Microbiota Interactions and Metabolic Health
Authors: DIAMANTE GRACIEL , CELY INGRID C. , LANG JENNIFER , BLINE ABIGAIL , ZAMORA ZACARY O. , SINGH MAYA , LUSIS ALDONS , YANG XIA
Published: June 2020

Bisphenol A (BPA) is an industrial plasticizer widely found in consumer products such as plastic bottles and canned foods. Human and murine studies have shown strong associations between prenatal exposures to endocrine disruptors such as BPA during early development and the prevalence of various diseases including cardiovascular diseases, type 2 diabetes, and obesity. Previous studies have found that the liver tissue is a sensitive BPA target site, and BPA alters the microbial diversity in exposed mice. To understand whether and how the gut microbiome mediates the effects of BPA on liver gene expression to influence metabolic phenotypes, we conducted a multi-dimensional systems biology study. We treated pregnant C57BL/6 mice with a low dose of BPA at 5ug/kg/day during gestation and evaluated metabolic phenotypes, fecal microbial composition and liver transcriptome of both male and female offspring. Prenatal exposure to low dose BPA significantly not only affected liver genes involved in oxidative phosphorylation, PPAR signaling and fatty acid metabolism, but also affected the gut microbial composition in an age-dependent manner, with the most pronounced effect observed at week 20. Bacteria belonging to the S24-7 and Lachnospiraceae families were correlated to offspring body weight and differentially expressed liver genes such as Fabp1, Acadl and Dgat1. This study provides insights into the relationship between gut bacteria and host liver genes that could contribute to metabolic disease risks upon BPA exposure. Future studies will test whether the gut microbiota identified in this study play a direct causal role on the host genomic and phenotypic responses using fecal transplant and bacteria colonization experiments.

Disclosure

G. Diamante: None. I.C. Cely: None. J. Lang: None. A. Bline: None. Z.O. Zamora: None. M. Singh: None. A. Lusis: None. X. Yang: None.

Funding

American Diabetes Association (1-19-PDF-007-R to G.D.)
2232-PUB: Reasons for Treatment Discontinuation in Type 2 Diabetes (T2D): Results from an Online Patient Survey in the UK and U.S.
Authors: DE CLIMENS AUDE ROBOREL , PAIN EMILIE , BOSS ANDERS H. , SHAUNIK ALKA
Published: June 2020

T2D is a chronic condition that requires long-term treatment to achieve and maintain glycemic control. However, up to 50% of people with T2D discontinue treatment by 1 year. To better understand why this occurs, an online questionnaire was presented to people with T2D in the UK (n=72) and U.S. (n=89) on the PatientLive® platform of Carenity, a global online patient community. For those who discontinued at least one of their T2D treatments within the last 6 months, open-ended questions aimed to assess the reasons why, how it could have been prevented, and what would have improved the experience with the discontinued treatment. Thematic qualitative analysis was performed on respondents’ answers to these open-ended questions. Overall, oral antidiabetics were the most commonly discontinued treatment type (93/161), followed by insulin (40/161) and other injectable antidiabetics (13/161). The most common reasons for treatment discontinuation were side effects (57/161), mostly gastrointestinal side effects and weight gain. Drug efficacy issues were the second most reported reason (42/161). In the U.S., cost of treatment played an important role (14/89). For the respondents, key factors to prevent discontinuation would have been an improved care pathway (45/161) and more efficacious treatments with fewer side effects (41/161). In the U.S., a lower price was also noted as an improvement factor (12/89). More information about T2D and associated treatments (56/161), help on how to manage T2D (24/161), and better informing of doctors of patients’ needs (12/161) would have been helpful for many respondents in both the UK and U.S. Notably, however, many respondents confirmed that they were sufficiently informed (64/161). These results emphasize the need for focused education and improved communication to enhance patient experience and prevent treatment discontinuation, and highlight the importance of therapies with attributes preferred by people with T2D that better fit their needs.

Disclosure

A. Roborel de Climens: Employee; Self; Sanofi. E. Pain: Consultant; Self; Sanofi. A.H. Boss: Employee; Self; Sanofi. Stock/Shareholder; Self; Novo Nordisk Inc., Sanofi. A. Shaunik: None.

Funding

Sanofi
2234-PUB: The Impact of a Community Paramedicine Program on Diabetes Outcomes and Health Care Utilization
Authors: EICKEN MEREDITH , LEE DEBBY , EWING JOSEPH A. , BUTLER JOHN N. , LUTZ MARTIN E. , SNOW JENNIFER Z. , HIPP CANDICE , THOMAS DARIN T. , HEAD CHARLES P. , HUDSON-DOBBS ROGER S. , GREEN VINCENT E. , WEBER SANDRA L.
Published: June 2020

Background: As of 2017, South Carolina ranked 5th highest in the U.S. for percentage of adults with diabetes, which has negative health and cost implications. The innovative community paramedicine program (CPP) aims to improve management of patients with chronic diseases and high utilization of the Emergency Department (ED), by providing in-home disease management, education, and care/community resource connection by paramedics. The impact of CPs has not been extensively studied in diabetes.

Objective: To assess impact of CPP participation on health outcomes and healthcare utilization for patients with diabetes.

Methods: Retrospective analysis of CPP participants diagnosed pre-enrollment with diabetes. Demographics and variables reported as percentages, and differences between A1c values pre/post CPP tested using Student’s t-test. Healthcare cost and utilization data was extracted from EMR using SAP BusinessObjects and analyzed with Qlik.

Results: From 2015-2019, 64 people with diabetes enrolled. Participants were primarily insured by Medicare (48.4%) and/or Medicaid (35.9%) or uninsured (32.8%). Comparing pre and post-enrollment average values, participants in CPP for >180 days (d) demonstrated a clinically significant improvement in A1c, although this did not reach statistical significance (181-270d: 10.04+/-1.33 to 8.51+/-1.35, p=0.159; 271-365d: 10.83+/-2.95 to 7.65+/-2.39,p=0.098; 365+d: 9.31+/-2.58 to 7.76 +/-1.45, p=0.23). Participants also showed increased rates of screening for microvascular complications. To date, the utilization analysis for the 52 CPP graduates who participated >14d suggests decrease in average cost of care and ED visits per person comparing 6 months prior and up to 6 months post CPP enrollment ($16,514 vs. $4,717; 2.77 vs. 0.73 ED visits).

Conclusions: The CPP demonstrated improvement in disease control and reduced costs/ED visits for patients with diabetes. This is a promising care delivery innovation that merits further research.

Disclosure

M. Eicken: None. D. Lee: None. J.A. Ewing: None. J.N. Butler: None. M.E. Lutz: None. J.Z. Snow: None. C. Hipp: None. D.T. Thomas: None. C.P. Head: None. R.S. Hudson-Dobbs: None. V.E. Green: None. S.L. Weber: None.
225-LB: A High-Throughput CRISPR-Activation Screen Defines Human LncRNA Metabolic Regulators
Authors: MA YONGHE , CAO HAIMING
Published: June 2020

In the past decade, long noncoding RNAs (lncRNAs) have emerged as important regulators of cellular and systemic metabolism. Deciphering the physiological functions of lncRNA by gain- or loss-of-function analyses in key metabolic organs, such as the liver, is essential to understand their disease relevance. Conventional transgenic or knockout approaches, however, have limitations in defining lncRNA function as lncRNAs transgenically expressed from ectopic genomic loci could be non-functional and partial deletion of lncRNAs. Domain negative Cas9 (dCas9) coupled with transcriptional activators can trigger endogenous lncRNA expression by targeting guide RNA (gRNA) to transcription start sites of lncRNAs, thus increasing their transcription efficiency and targeting multiple different lncRNA isoforms simultaneously. Adenovirus vector is the most commonly used tool for specifically targeting liver-enriched genes both in vitro and in animal models. A CRISPR-activation (CRISPR-a) adenovirus system thus constitutes a powerful means to active liver lncRNAs transcriptionally. In this study, we established a CRISPR-a adenovirus platform by transferring CRISPR-a units into the adenovirus vector, and our system allows one digestion-ligation step to construct the gRNA adenovirus vector seamlessly. Efficacy and versatility of this pipeline has been confirmed by the successful construction of a CRISPR-a adenovirus library containing 96 gRNAs targeting 20 liver-enriched, metabolic sensitive lncRNAs, which shows high CRISPR activation efficiency after primary human hepatocytes infection. Moreover, the expression levels of several lncRNA target genes predicted by co-relation analysis are significantly changed. This method thus provides a fast and efficient way to activate the endogenous liver lncRNAs and simplifies the procedure of lncRNA functional screening using CRISPR-a adenovirus system, which can be scaled up to a genome level to quickly define lncRNA metabolic regulators.

Disclosure

Y. Ma: None. H. Cao: None.