bluuebunny/crossref_metadata_2025_split huggingface dataset:
325-OR: ß-Arrestin 1 Regulates Glucagon-Like Peptide-1 Receptor Mediated Insulin Secretion in a Ligand-Dependent Manner
Authors: DOUROS JONATHAN D. , SLOOP KYLE , CAMPBELL JONATHAN , D’ALESSIO DAVID 
Published: June 2020

Incretin-based drugs are widely thought to act via a Gαs/adenylate cyclase (AC)/cAMP pathway in β-cells. This model has been challenged by data demonstrating various glucagon-like peptide 1 receptor (GLP-1R) ligands differentially activate multiple signaling pathways including Gαs, Gq, ERK, and β-arrestins. This ligand-mediated signaling bias implicates an array of intracellular mechanisms that regulate GLP-1R action and raises the possibility GLP-1R agonists can be optimized to enhance insulin secretion. We tested the hypothesis that β-arrestin 1 (βarr1), a critical GPCR effector, is necessary for the full insulinotropic action of GLP-1R agonists. The β-cell βarr1 knockout mice (βarr1βcell-/-) used here have reduced Arrb1 expression in the β-cell, but not α- or Δ-cells; Arrb2 expression was unaffected. Islets isolated from βarr1βcell-/- mice have increased glucose stimulated insulin secretion (GSIS) compared to controls. The enhanced GSIS in the knockout islets was ablated by the GLP-1R antagonist exendin-9. In addition, βarr1βcell-/-islets treated with GLP-1 or exendin 4 (Ex4) have increased insulin release compared to controls. Conversely, βarr1 deletion did not impact the insulinotropic actions of glucagon, which signals through both the GLP-1R and the glucagon receptor (GCGR). Moreover, control and βarr1βcell-/- islets produced similar insulin secretion in response to a GCGR specific agonist that does not signaling through GLP-1R and to glucose-dependent insulinotropic polypeptide. Together, these results indicate that βarr1 in β-cells selectively dampens the insulinotropic actions of the GLP-1R, but not the GCGR or GIP receptor. Thus, there is a specific interaction between the GLP-1R and βarr1 that points to divergent regulation between the insulinotropic class B G-protein coupled receptors in β-cells. This data implies that GLP-1R agonists that bias away from βarr1 may be more effective at stimulating insulin secretion.

Disclosure
J.D. Douros: None. K. Sloop: None. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. 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.

Funding
1F32DK115031-01
33-LB: Role of Cav3.2 Channels in Sensory Neuron Abnormalities during Early Hyperglycemia
Authors: NEAPETUNG JOSEPH T. , CAMPANUCCI VERONICA A. 
Published: June 2020

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. It is characterized by a constellation of sensory abnormalities, including numbness, tingling, burning, and painful sharp, shooting sensations in the extremities. Patients with DPN are also at high risk for infection and amputation. Traditionally, neuropathy has been considered to result from peripheral nerve damage after long term diabetes, however more recent indicate that functional changes take place in early stages of diabetes. One of those changes is the increased expression and signalling of the receptor for advance glycation end-product (RAGE), which is known to have a pivotal role in the development of diabetic complications. In the current study we concentrate on T-type (Cav 3.2) channels, which are low voltage-activated calcium channels that play a key role in cellular excitability, and have been reported to contribute to pain abnormalities in rat models of DPN. The goal of this project is to elucidate the role of Cav 3.2 during early stages of diabetes in sensory neurons from the dorsal root ganglion (DRG) of mice, and its possible regulation through the RAGE pathway. We used cultured DRG neurons from wilt-type (WT) and RAGE knock-out (RAGE KO) mice maintained in control (5mM) or high glucose (25 mM) for up to 14 days, as well as intact DRG ganglia from streptozotocin (STZ)-induced diabetic mice (WT and RAGE KO) for 4 weeks. Using whole cell patch-clamp electrophysiology and protein biochemistry we revealed changes in the activation kinetics and expression levels of Cav 3.2 channels. Our data suggest that RAGE-dependent changes in Cav 3.2 expression and function may contribute to functional abnormalities in sensory neurons during early hyperglycemia.

Disclosure
J.T. Neapetung: None. V.A. Campanucci: None.
34-OR: SGLT2 Inhibitors: A Comparison of Cardiovascular, Medical, and Cost Outcomes
Authors: SCHWAB PHIL , BOWE ANDY , TINDAL MICHAEL , MEAH YUNUS A. , POONAWALLA INSIYA 
Published: June 2020

Since 2016, empagliflozin (EFZ) has been known to reduce cardiovascular (CV) events in patients with type 2 diabetes; however, similar label expansions for dapagliflozin (DFZ) and canagliflozin (CFZ) are quite recent. To date, limited evidence has been published comparing these drugs in real-world practice. This retrospective cohort study address that gap, and used administrative claims data from a nationwide Medicare Advantage Prescription Drug and commercial health plan to compare CFZ, EFZ and DFZ on CV outcomes, treatment persistence, healthcare utilization and costs. Eligible patients naïve to the SGLT2 inhibitor drug class for 6 months from January 2015 to June 2017 were identified. Patients had at least 12 months of continuous enrollment pre- and post-index date (i.e., date of first new prescription). Propensity score method using inverse probability of treatment weighting was used to adjust outcomes. A total of 5,503, 2,052 and 587 patients used CFZ, EFZ and DFZ, respectively. Weighted comparisons showed no difference in the risk of primary composite CV outcome (myocardial infarction, stroke, or mortality) between treatments, but a lower risk of secondary CV outcome (heart failure or death) in the DFZ cohort (hazard ratio 0.82, 95% CI 0.75-0.88) compared to CFZ. Patients indexed to use EFZ were more likely to remain persistent to treatment (odds ratio [OR] 1.09, 95% CI 1.03-1.16), and patients who used DFZ had lower odds of an emergency department visit encounter (OR 0.85, 95% CI 0.79-0.92), relative to the use of CFZ. There were no differences in inpatient hospitalization stays and outpatient services between treatment groups. This population-based study showed minor differences in clinical and cost outcomes between CFZ, EFZ and DFZ, including a post-hoc analysis showing slight variations in use of adjuvant glucose lowering therapies across the SGLT2 inhibitor cohorts. With the ever-evolving landscape of treatment in the care of patients with diabetes, these findings may be helpful to providers.

Disclosure
P. Schwab: Employee; Self; Humana. Employee; Spouse/Partner; Humana. A. Bowe: Employee; Self; Humana. M. Tindal: None. Y.A. Meah: None. I. Poonawalla: None.
341-OR: Expanding Diabetes Self-Management Education to Include Chronic Kidney Disease Education
Authors: PRITHIVATHI PREETHA , SPIGLER MICHAEL , PARIS MELANIE , ALAWODE MOLLY , BELLO MORENIKE , FATIMA UROOJ 
Published: June 2020

Background: Diabetes is the leading cause of kidney failure. Thirty million Americans have diabetes and 1 in 3 adults with diabetes has chronic kidney disease (CKD). While the Diabetes Self-Management Education and Support (DSMES) curriculum cites CKD risk within one of its eight core content areas, increasing rates of kidney failure among diabetics warrants more robust content devoted to diabetes’ association with CKD.
Methods: From October 2017-April 2019, TMF Health Quality Institute recruited clinical and peer educators in Arkansas, Missouri, Oklahoma, Puerto Rico, and Texas to complete the American Kidney Fund (AKF) Kidney Health Coach (KHC) online training as a means of equipping them with content and strategies to incorporate into DSMES or stand-alone CKD education sessions for Medicare beneficiaries at risk for CKD. Upon completing KHC, three CKD education delivery methods were piloted: 1) in-person educator-led 2) recorded video shown in class 3) video on-demand. The effectiveness of each method was determined by assessing participant knowledge and comprehension using the AKF Kidney Health Education Session pre/post-test.
Results: 615 educators became KHCs and delivered CKD education to a total of 2,250 individuals. Pre/post test scores indicated collective effectiveness among the three delivery methods in increasing understanding of the relationship between CKD and diabetes (relative improvement rate (RIR)= 36.5%). In-person CKD education showed most effective in increasing knowledge gain (RIR=38.8%), compared to the recorded video shown in class (RIR=25.3%) and on-demand video (RIR=18.7%) methods.
Conclusion: This study supports the expansion of KHC integration into DSMES, as educating people with diabetes on CKD prevention is critical to reducing the burden of CKD and improving health outcomes, and that an educator-led presentation modality was most effective in improving understanding of CKD.

Disclosure
P. Prithivathi: None. M. Spigler: None. M. Paris: None. M. Alawode: None. M. Bello: None. U. Fatima: None.

Funding
Centers for Medicare & Medicare Services (HHSM-500-2014-QIN0051)
345-OR: First Home Evaluation of the Omnipod Horizon Automated Glucose Control System at Specific Glucose Targets in Children with Type 1 Diabetes
Authors: FORLENZA GREGORY P. , BUCKINGHAM BRUCE A. , CRIEGO AMY B. , BROWN SUE A. , BODE BRUCE W. , LEVY CAROL J. , LY TRANG T. ,   OMNIPOD HORIZON STUDY GROUP
Published: June 2020

The Omnipod Horizon™ System is a hybrid closed-loop system (HCL) consisting of a tubeless insulin pump and Dexcom G6 sensor which provides automated insulin delivery with customizable glucose targets from 110-150mg/dL, adjustable by time of day to allow therapy personalization. This outpatient study assessed the safety and effectiveness of HCL use at higher targets of 130-150mg/dL.
Participants aged 6-13.9y with T1D&gt;6mo and A1C&lt;10.0% used the HCL system at home for 14 days (first 2 days hotel, n=8) over winter holidays with unrestricted eating and exercise. The target was 130, 140, and 150mg/dL for 3 days each, followed by 5 days of free choice of 110-150mg/dL. Primary outcomes were safety measures and percent time 70-180mg/dL over the first 9 days of HCL use, stratified by target glucose.
Participants thus far (n=15) had a mean±SD age of 11±2y, T1D duration 5±3y, and A1C 7.7±0.9%. At the 130, 140, and 150mg/dL targets, percent time from 70-180mg/dL was 63.4±7.9%, 64.2±11.6%, and 52.1±11.7%, respectively (Table). Percent time &lt;54 and &lt;70mg/dL was low, and tended to decrease with increased target. There were no severe adverse events.
The HCL system was safe and performed well in children with T1D when used at home with higher glucose targets. Participants were invited to continue in a 3mo outpatient study of the system, which is currently underway.

Disclosure
G.P. Forlenza: Advisory Panel; Self; Medtronic. Consultant; Self; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. A.B. Criego: Other Relationship; Self; Dexcom, Inc., Lilly Diabetes, Medtronic, Omnipod. S.A. Brown: Research Support; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Tolerion, Inc. B.W. Bode: Advisory Panel; Self; InPen, Medtronic. Consultant; Self; ADOCIA, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Medtronic, Novo Nordisk A/S, Provention Bio, Inc., Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., InPen, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Glytec. C.J. Levy: Consultant; Self; Dexcom, Inc. Employee; Spouse/Partner; Allergan plc. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation.

Funding
Insulet Corporation
348-OR: Metabolic Phenotype of Autoantibody Positive (AbPos) Long-Term Nonprogressors (LTNPs) to Type 1 Diabetes (T1D)
Authors: EVANS-MOLINA CARMELLA , SAEED ZEB I. , SOSENKO JAY , ATKINSON MARK A. , HEROLD KEVAN C. , ISMAIL HEBA M. , LARSSON HELENA ELDING , LUNDGREN MARKUS , MORAN ANTOINETTE , MOORE DANIEL J. , NATHAN BRANDON M. , PALMER JERRY P. , SIMS EMILY K. , STECK ANDREA , WHERRETT DIANE K. , REDONDO MARIA J. 
Published: June 2020

Few studies have described the metabolic phenotype of AbPos individuals who remain T1D free for an extended period of time. We aimed to compare C-peptide and glucose (Glu) data from oral glucose tolerance tests (OGTTs) performed longitudinally in 646 AbPos TrialNet Pathway to Prevention (PTP) participants who remained T1D free for ≥5.0 yrs (LTNPs; mean follow-up: 7.8±2.3 yrs) versus 405 Rapid Progressor (RP) PTP participants who progressed to T1D within &lt;2 yrs of study entry (mean follow-up 0.97±0.54 yrs) and 150 Ab negative (AbNeg) controls. At study entry, 48% of LTNPs were single AbPos and 52% were multiple AbPos; 45.8% of single AbPos LTNPs became multiple AbPos during follow-up. LTNPs were older (mean age 18.8 ± 14.1 yrs) compared to RPs (11.8 ± 9.3 yrs) and AbNeg individuals (16 ± 10 yrs) (p&lt;0.001). LTNPS exhibited an intermediate metabolic phenotype, with age and BMIZ-adjusted C-peptide area under the curve (AUC) and 30-0 min C-peptide values that were lower than AbNegs but higher than RPs (p&lt;0.001), and Index60 levels (a composite of glucose and C-peptide values from OGTTs) that were higher than AbNegs but lower than RPs (p&lt;0.001). Longitudinal trends in LTNPs were analyzed using fitted linear mixed models. Multiple AbPos LTNPs had higher Glu AUC (p=0.01) and Index60 values (p=0.032) compared to single AbPos LTNPs. However within both AbPos groups, metabolic patterns were remarkably stable over extended follow-up. When measures were evaluated for non-linear interactions using a regression tree analysis, the combination of Index60&lt;1.06 + Glu AUC&lt;137.7 at baseline was associated with an odds ratio of 8.55 (p&lt;0.001) of being a LTNP. These data suggest that, while β cell function is reduced in LTNPs at the time of AbPos identification, longitudinal Glu and C-peptide patterns are largely stable without evidence of a relapsing or remitting course. Baseline OGTT measures (here, Index 60 and Glu AUC) may be able to predict AbPos individuals with lower risk of progression to T1D.

Disclosure
C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. Z.I. Saeed: None. J. Sosenko: None. M.A. Atkinson: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. H.M. Ismail: None. H. Elding Larsson: None. M. Lundgren: None. A. Moran: Research Support; Self; Abbott, Intrexon, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Provention Bio, Inc. Other Relationship; Self; Novo Nordisk Inc. D.J. Moore: None. B.M. Nathan: None. J.P. Palmer: None. E.K. Sims: None. A. Steck: None. D.K. Wherrett: None. M.J. Redondo: None.

Funding
National Institutes of Health (U01107014, U01DK106993)
35-LB: Reliability of an Artificial Intelligence (AI) Diabetic Retinopathy (DR) Detection System
Authors: IPP ELI , LILJENQUIST DAVID R. 
Published: June 2020

A prospective study (NCT04302012) evaluated the reliability of the EyeArt AI DR detection system (Eyenuk, Inc.) across repeated examinations, operators, and cameras. Using retinal images from off-the-shelf color fundus retinal cameras, this AI system is intended to detect patient eyes with referable DR (rDR) [moderate non-proliferative DR (NPDR) or higher on the International Clinical DR (ICDR) severity scale or clinically significant diabetic macular edema (CSDME)] and vision-threatening DR (vtDR) [severe NPDR or higher on the ICDR scale or CSDME].A total of 62 subjects with diabetes were enrolled at 2 U.S. primary diabetes care centers and completed digital DR examination using the AI system (including retinal imaging) multiple times. Of these, 31 subjects underwent 12 AI exams for each eye performed by 3 operators on 4 cameras, and another 31 subjects underwent 6 AI exams for each eye performed by 1 operator on 2 cameras. Subjects had a median age of 50 (22-70) years, 42% were female, 79% were White, 6.5% were Black or African-American, and 6.5% were Asian. Mean (± std. dev.) diabetes duration was 12.5 ± 9 years and 66% had type 2 diabetes. Of the 1116 repeated exams (= 31 subjects x 12 exams x 2 eyes/subject + 31 subjects x 6 exams x 2 eyes/subject), 16 eye exams had missing data (due to minor protocol deviations) and 22 eye exams (all from the same subject) did not have sufficient exam quality to rule out presence of disease. Of the remaining 1078 eye exams, 97.5% were in agreement for the referable DR detection results with a majority of the disagreements limited to only 5 eyes. For the vision-threatening DR detection results, 99.5% were in agreement. This study demonstrates that the EyeArt AI system is robust to variations and can be used to reliably detect diabetic retinopathy in non-ophthalmology settings across different operators and cameras.

Disclosure
E. Ipp: Research Support; Self; Eyenuk, Inc. D.R. Liljenquist: None.
35-OR: Risk of Cardiovascular Outcomes in Diabetes Patients following the Addition of SGLT2 Inhibitors vs. Sulfonylureas to Baseline GLP-1RA Therapy
Authors: DAVE CHINTAN , KIM SEOYOUNG C. , GOLDFINE ALLISON , GLYNN ROBERT , PATORNO ELISABETTA 
Published: June 2020

SGLT2 inhibitors (SGLT2i) may provide cardiovascular (CV) benefit when added to GLP-1 receptor agonists (GLP-1RA) given the orthogonal mechanisms of action, although combined use is incompletely understood. Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 U.S. datasets (2013-2018) and were 1:1 propensity score matched (PSM) adjusting for &gt;95 baseline covariates. Primary outcomes were 1) a composite CV endpoint (comprised of myocardial infarction, stroke, or all-cause mortality) and 2) heart failure hospitalization. We estimated pooled hazard ratios (HR) and 95% confidence intervals (CI). Among 12,584 1:1 PSM pairs (mean [SD] age 58.3 [10.9]; male (48.2%)), there were 102 composite CV events (incidence rate per 1,000 person-years (IR) = 9.4) among SGLT2i initiators compared to 124 events (IR = 12.5) among sulfonylurea initiators, with an adjusted HR of 0.76 (95% CI: 0.59, 0.99), over a mean 10-month follow-up (Table). For the outcome of heart failure hospitalization, there were 141 (IR = 13.0) v 206 (IR = 20.8) events, with an adjusted HR of 0.65 (95% CI: 0.52, 0.80). Thus, adding SGLT2i to GLP-IRA therapy confers greater CV benefit compared to adding sulfonylureas, with a magnitude of risk reduction comparable to the benefit seen in CV outcome trials of SGLT2i vs. usual care in patients with minimal background GLP-IRA use.

Disclosure
C. Dave: None. S.C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb. A. Goldfine: Employee; Self; Novartis AG. R. Glynn: Research Support; Self; Amarin Corporation, AstraZeneca, Kowa Research Institute, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH.
352-OR: Combination Therapy with Dapagliflozin plus Exenatide on Endogenous Glucose Production: A Mechanism of Action Study
Authors: ALATRACH MARIAM , AGYIN CHRISTINA , ADAMS JOHN M. , LAVRYNENKO OLGA , LAICHUTHAI NITCHAKARN , CERSOSIMO EUGENIO , TRIPLITT CURTIS L. , GASTALDELLI AMALIA , ABDUL-GHANI MUHAMMAD , DEFRONZO RALPH A. 
Published: June 2020

Aim: To examine the mechanisms with which GLP-1 RA plus SGLT2i improve glycaemia versus each agent as monotherapy.
Study Design: 21 T2D patients (Age= 51±2; BMI=31.2±0.7; A1C=7.9±0.2%, FPG= 172±8; mean PG OGTT [0-5h] =249±8) received 5-hour double tracer (3-3H-glucose IV/1-14C-glucose orally) OGTT and then were randomized to dapagliflozin (DAPA) 10 mg/d, exenatide (EXEN) 2 mg/wk, dapagliflozin plus exenatide (DAPA/EXEN) for 4 months.
Results: Combination DAPA/EXEN therapy produced a completely additive effect to reduce HbA1c and near additive effect to decrease FPG and mean PG during OGTT. The additive effect of DAPA/EXEN resulted from: (1) decreased basal EGP; (2) increased urinary glucose excretion (UGE); (3) decreased rate of oral glucose appearance (RaO); (4) enhanced insulin secretion; (5) increased tissue glucose clearance. Of note, exenatide could not overcome the impaired suppression of EGP by dapagliflozin.

Disclosure
M. Alatrach: None. C. Agyin: None. J.M. Adams: None. O. Lavrynenko: None. N. Laichuthai: None. E. Cersosimo: None. C.L. Triplitt: Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Xeris Pharmaceuticals, Inc. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. M. Abdul-Ghani: None. R.A. DeFronzo: None.