bluuebunny/crossref_metadata_2025_split huggingface dataset:
658-P: Sustained Glucagon Effect on Cardiovascular Renal and Metabolic Disorders Mediated by a Long-Acting Glucagon Analog, HM15136, in Animal Disease Models
Authors: LEE JONG SUK , LEE SEON MYEONG , KIM JUNG KUK , PARK EUNJIN , LEE JONGSOO , KIM DAEJIN , KIM YOUNG HOON , CHOI IN YOUNG 
Published: June 2021

Obesity is an increasing health problem worldwide, implicated with various metabolic disorders such as cardiovascular disease and chronic kidney disease (CKD). Previously, we showed that chronic treatment of HM15136, a long-acting GCG analog, led to robust body weight loss (BWL) in rodent obese models. Moreover, recent studies unveiled a novel role of GCG in vasodilation and inflammation. So, we hypothesized that HM15136 improve chronic metabolic disorders via direct action in addition to secondary effect to BWL. Here, we investigated potential therapeutic effect of HM15136 in animal models of cardiovascular renal and metabolic diseases. In DIO mice, BW, liver triglyceride (TG), and blood cholesterol (CHO) were measured, and all measurements were significantly reduced by HM15136 treatment (-37.5, -72.7, -78.4% vs. vehicle for BW, liver TG, blood CHO at day 17). Next, to explore therapeutic effect of HM15136 on cardiovascular renal diseases, spontaneously hypertensive rats, known model for hypertensive CKD, were used. Interestingly, abnormal elevation in blood pressure and renal function markers such as urine albumin/creatinine ratio (-23.6% vs. SHR vehicle at day 46) was meaningfully reduced by HM15136 treatment. In unilateral ureteral obstruction mice, known as acute kidney injury model, similar results were observed (-17.6%, -48.2% vs. vehicle for serum creatinine, kidney pro-collagen1α1 at day 12). Consistently, increase of vasodilation markers in rat aorta and inhibition of human primary podocyte apoptosis were confirmed, explaining underlying mechanism for these beneficial effects. Therefore, HM15136 could mitigate obesity and related complications especially hypertension and CKD. Hence, mechanistic study results highlight the essential role of direct GCG engagement in improvement of cardiovascular renal and metabolic diseases. Further studies are needed to assess a clinical relevance of these findings.

Disclosure
J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharmaceutical.
682-P: Novel Dual Glucagon and Glucagon-Like Peptide-1 Receptor Agonist LY3305677 Improves Glucose Control, Reduces Body Weight, and Increases Energy Expenditure in Mice
Authors: CHEN YANYUN , MEZO ADAM , COSKUN TAMER , SONG MIN , ROELL WILLIAM C. , BOKVIST KRISTER B. , MOYERS JULIE S. , THOMAS MELISSA K. , VALENZUELA FRANCISCO , QU HONGCHANG 
Published: June 2021

LY3305677 (LY) is a synthetic peptide analog of mammalian oxyntomodulin with a fatty acyl side chain to extend time action. LY functions are mediated by binding and activation of both glucagon (GcgR) and glucagon-like peptide-1 (GLP-1R) receptors. LY is bound with potent binding affinity (Ki) to human and mouse GcgR (Ki: 17.7 nM and 15.9 nM, respectively) and GLP-1R (Ki: 28.6 nM and 25.1 nM, respectively). LY dose-dependently stimulated insulin secretion in mouse pancreatic islets (EC50: 5.2 nM) and in mice. In oral glucose tolerance tests of diet-induced obese (DIO) and streptozotocin-induced diabetic mice, a single subcutaneous (SC) dose of LY significantly reduced glucose area under the curve by up to 65%. SC injections of LY to DIO mice dose-dependently reduced serum triglycerides and PCSK9 (proprotein convertase subtilisin/kexin type 9) levels and dose-dependently increased FGF21 (fibroblast growth factor 21) levels. In DIO mice treated over 18 days, LY 30 nmol/kg reduced body weight to a greater extent (33%) than semaglutide 60 nmol/kg (12%), and decreased food intake by 50% compared to vehicle. At Day 18, LY 30 nmol/kg group lost 33% of initial bodyweight, which was primarily due to 70% reduced fat mass. LY reduced liver triglycerides by greater than 70% and increased serum ketones by more than 3-fold compared to vehicle, suggestive of increased fatty acid oxidation. LY decreased body weight in both GcgR knock-out (KO) and GLP-1R KO mice, indicating that activation of both receptors contributed to greater weight loss. To assess potential changes in energy expenditure, DIO mice were treated chronically with SC LY (15 nmol/kg), semaglutide (60 nmol/kg), or vehicle. LY, but not semaglutide, increased energy expenditure as compared with vehicle. These preclinical studies indicate that novel dual GcgR and GLP-1R agonist LY may have potential to enhance metabolic health by improving dyslipidemia, hyperglycemia, or obesity.

Disclosure
Y. Chen: None. H. Qu: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. A. Mezo: None. T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. M. Song: None. W. C. Roell: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. K. B. Bokvist: Employee; Self; Eli Lilly and Company, Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Self; Johnson & Johnson, Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J. S. Moyers: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. F. Valenzuela: None.

Funding
Eli Lilly and Company
700-P: Glucotab-Based Basal-Bolus Insulin Therapy for Inpatient Glycemic Control Using Insulin Degludec
Authors: MADER JULIA K. , BAUMANN PETRA M. , ABERER FELIX , HOCHFELLNER DANIEL A. , SIMIC AMRA , BYTYQI LIRIE , POETTLER TINA , HOELL BERNHARD , FAHRLEITNER-PAMMER ASTRID , PIEBER THOMAS , BECK PETER 
Published: June 2021

Guidelines recommend insulin therapy and the use of clinical decision support systems to manage hyperglycemia and diabetes mellitus in hospitalized patients. The aim of the study was to evaluate glycemic control using insulin degludec in an algorithm driven electronic decision support system in hospitalized patients with type 2 diabetes (T2D). The electronic decision support system GlucoTab® was applied for diabetes management in 30 hospitalized patients with T2D (18 women, age 74.1±10.9 years, HbA1c 71±23mmol/mol, BMI 28.6±5.6kg/m2, diabetes duration 14.9±15.1 years, creatinine 1.5±1.2mg/dl, length of hospital stay 9.1±4.0 days). Insulins degludec and aspart were used for basal-bolus insulin therapy. Blood glucose was tested four times daily using a point-of-care device integrated into the hospital information system. The overall mean blood glucose (BG) value was 144±53 mg/dl (mean pre-enrolment BG 211±84mg/dl). BG measurements were in 74.9% in the range of 70-&lt;180 mg/dl. BG measurements in the ranges &lt;40mg/dl, &lt;70mg/dl, 180-&lt;300 and ≥300mg/dl were observed in 0.0%, 1.5%, 22.9% and 0.7% of all measurements, respectively. Total daily insulin dose was 34.0±19.9 U (bolus insulin dose 18.7±13.1 U, basal insulin dose 16.0±7.9 U). Adherence to the algorithm-calculated total daily insulin dose was 93.2%; adherence to inject the algorithm-calculated basal and bolus insulin doses was high (99.0% and 85.3%). Basal-bolus therapy using GlucoTab® covered 80.8±19.9% of the patients’ total hospital stay. Glycemic control using insulin degludec in an algorithm driven electronic decision support system could safely be established in the hospital setting with high adherence to algorithm advice.

Disclosure
J. K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Roche Diabetes Care, Speaker’s Bureau; Self; Abbott Diabetes, Novo Nordisk A/S, Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; decide Clinical Software GmbH. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. P. Beck: Employee; Self; decide Clinical Software GmbH, Stock/Shareholder; Self; decide Clinical Software GmbH. P. M. Baumann: None. F. Aberer: None. D. A. Hochfellner: None. A. Simic: None. L. Bytyqi: None. T. Poettler: None. B. Hoell: Employee; Self; decide Clinical Software GmbH. A. Fahrleitner-pammer: None.

Funding
Novo Nordisk
714-P: Assessment of the Patient Transition Experience to Hybrid Closed-Loop Insulin Pump Therapy
Authors: DISSANAYAKE ASHINI , CHOW ERIC , WHITE ADAM , KAPELUTO JORDANNA E. , MACKENZIE-FEDER JESSICA , SCHROEDER BENJAMIN , PAWLOWSKA MONIKA 
Published: June 2021

Hybrid closed-loop (HCL) insulin pump therapy is a promising development for the management of type 1 diabetes (T1D), but little is known about the transition period to HCL in a real-world setting. Here, we present novel data evaluating the HCL transition experience and its effect on diabetes distress. We evaluated 32 out of 150 anticipated participants who were about to transition (Arm A), or had recently transitioned (Arm B), from standard pump therapy to the MiniMed™ 670G HCL pump. Patients completed a baseline and 6-month post-transition diabetes distress survey using the T1-DDS. In the follow-up survey, patients’ trust in HCL and treatment satisfaction were also assessed. Finally, post-survey interviews were conducted for patients to elaborate on the successes and struggles of their HCL transition experience. No significant differences were observed between the 2 arms, so the sample was analyzed as a whole. After 6 months on HCL, significant reductions were observed in overall diabetes distress (p&lt;0.0001), as well as powerlessness (p&lt;0.005), management (p&lt;0.001), hypoglycemia (p&lt;0.005), and eating (p&lt;0.0005) distress. Most patients (56%) indicated difficulty trusting HCL, however 80% reported that trust improved over time. Patient satisfaction was high (81%), however only 47% indicated that HCL met their expectations, 56% would recommend HCL to others, and 66% indicated frustration with the transition to HCL. Patients were divided on whether HCL increased (41%) or decreased (47%) the workload required to manage their T1D (12% neutral). Over half of patients (59%) felt that HCL was too complicated. Patients were divided on whether HCL was too much of a “hassle” to use (31% yes, 38% no, 31% neutral). Emerging themes from the qualitative data include numerous alarms, loss of sleep, and necessity of “phantom carbing.” Overall, HCL therapy significantly reduces diabetes distress, but the patient transition experience is varied in terms of trust, satisfaction, and comfort with the technology.

Disclosure
A. Dissanayake: None. E. Chow: None. A. White: Advisory Panel; Self; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Canada Inc. J. E. Kapeluto: None. J. Mackenzie-feder: None. B. Schroeder: Advisory Panel; Self; AstraZeneca, Novartis Pharmaceuticals Canada Inc. M. Pawlowska: Advisory Panel; Self; Novo Nordisk.
72-OR: HDL Particle Concentration Predicts Incident Coronary Artery Disease (CAD) in Type 1 Diabetes (T1D)
Authors: COSTACOU TINA , VAISAR TOMAS , BORNFELDT KARIN , ORCHARD TREVOR J. , HEINECKE JAY 
Published: June 2021

We have shown that elevated HDL cholesterol (HDL-C) levels (≥80 mg/dL) associate with increased CAD risk in women with T1D. Furthermore, HDL-C levels are not necessarily cardioprotective in nondiabetic individuals, suggesting that the cholesterol content of HDL does not accurately assess CAD risk. We thus determined whether two other HDL metrics, HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC), predicted incident CAD in a large cohort of childhood onset T1D (n=550). At baseline, mean age was 27.8 yrs, T1D duration was 19.6 yrs and 49% were women. HDL-P was assessed by calibrated ion mobility analysis and CEC was quantified with validated assays in cAMP stimulated J774 cells and in ABCA1-expressing BHK cells. CAD was defined as CAD death, myocardial infarction and/or revascularization. During a median follow-up of 26 yrs, we observed 203 incident CAD cases (36.9%). At baseline, incident cases were older, more likely to have smoked, have hypertension, longer duration of T1D, higher non-HDL-C and markers of kidney disease and inflammation. Cases were also more likely to have lower HDL-P concentrations but similar CEC to non-cases. Cox models with backward elimination were constructed for each HDL metric, allowing for potential confounding variables, including HDL-C. In separate multivariable models, higher concentrations of total HDL-P (T-HDL-P, HR=0.88, 95% CI: 0.83-0.92) and 3 major HDL subpopulations - small (S-HDL-P, HR=0.78, 0.67-0.92), medium (M-HDL-P, HR=0.79, 0.71-0.88) and large-sized (L-HDL-P, HR=0.74, 0.61-0.89) particles - associated with a lower CAD incidence whereas HDL-C did not. Higher total CEC in J774 cells also predicted lower CAD risk (HR=0.74, 0.55-0.996) after similar adjustments, but became non-significant after further adjusting for HDL-P. ABCA1-specific CEC did not predict CAD. Our results suggest that increased HDL-P levels are cardioprotective in T1D, in contrast to HDL-C and CEC which did not independently predict CAD.

Disclosure
T. Costacou: None. T. Vaisar: Consultant; Self; AstraZeneca. K. Bornfeldt: None. T. J. Orchard: None. J. Heinecke: None.

Funding
National Institutes of Health (HL130153, DK34818)
727-P: The Association between Missed Basal Insulin Injections and Glycemic Control in Adults with Type 1 Diabetes Mellitus
Authors: EKBERG NEDA RAJAMAND , HARTVIG NIELS V. , KAAS ANNE , MOLLER JONAS , MÅRDBY ANN-CHARLOTTE M. , ADOLFSSON PETER 
Published: June 2021

Basal insulin injections are important for glycemic control in patients with type 1 diabetes mellitus (T1DM); however, patients may forget or skip doses. This study explored the adherence to basal insulin injections and the association of the pattern of missed basal insulin doses with glycemic control in patients with T1DM. A prospective real-world study was conducted in Sweden in patients with T1DM who began using a smart insulin pen for basal and/or bolus insulin administration together with their usual continuous glucose monitoring (CGM). This analysis included adults receiving basal insulin degludec, with at least one 14-day period with ≥70% CGM coverage. Outcomes aggregated over each 14-day period included: number of missed basal insulin doses (≥40 hrs between doses), time in range (TIR 70­-180 mg/dL), time above range (TAR level 1 &gt;180-250 mg/dL; level 2 &gt;250 mg/dL), time below range (TBR level 1 54-&lt;70 mg/dL; level 2 &lt;54 mg/dL), mean glucose level, glucose management indicator (GMI) and coefficient of variability (%CV). Data were analyzed by mixed models with patient ID as random effect. Overall, 32 patients (mean age, 35.6 yrs) had 315 14-day periods of acceptable CGM coverage. The probability that a patient missed ≥1 basal insulin dose over a 14-day period was 22% and patients with high %CV had a higher probability (47%) of having a missed dose. Each missed basal insulin dose over a 14-day period was associated with a significant reduction in TIR (−2.61% [−0.63 hrs], p &lt;0.001) and a corresponding statistically significant increase in TAR level 2 (+2.89% [+0.69 hrs], p &lt;0.001), mean glucose level (+7.9 mg/dL, p &lt;0.001) and GMI (+0.19%, p &lt;0.001); no significant association was found with %CV, TBR or TAR level 1. This study demonstrates that missed basal insulin injections are associated with changes in TIR and GMI; as such, there is a significant need for tools, such as smart pens that provide downloadable data, to empower patients to improve insulin adherence.

Disclosure
N. Rajamand ekberg: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi, Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Novo Nordisk. N. V. Hartvig: Research Support; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. A. Kaas: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. J. Moller: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. A. M. Mårdby: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. P. Adolfsson: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Other Relationship; Self; Dexcom, Inc., Glooko, Inc., Novo Nordisk, Tandem Diabetes Care.
753-P: Senolytics Improve Diabetes Measures in Type 2 Diabetic Nonhuman Primates: A Pilot Study
Authors: RUGGIERO ALISTAIRE D. , BLOCK MASHA , DAVIS MATTHEW , VEMURI RAVICHANDRA , ORR MIRANDA E. , KAVANAGH KYLIE 
Published: June 2021

Senescent cells accumulate in adipose tissue (AT) with obesity, causing local inflammation and dysfunction. Senescent cells in aging nonhuman primate (NHP) AT correlated with metabolic disease measures in our previous work. In this pilot study, we evaluated the senolytic combination dasatinib plus quercetin (D+Q) on AT senescent cell burden and systemic metabolic health in obese NHPs with naturally occurring type II diabetes (T2D; n=3). Selected NHPs remained stable on insulin therapy for six months prior to the study. NHPs were given a single oral dose of D (5mg/kg) plus Q (50mg/kg). Blood samples were collected 1 week prior to, and 4 and 8 weeks post-treatment. Abdominal subcutaneous (SQ) AT biopsies were taken before and 1 week after dosing. Senescence-associated beta galactosidase (SA-β-gal) staining showed 24% reductions in AT senescent cell burden. Two animals had large reductions in the senescence biomarker plasminogen activator inhibitor 1 (mean=55%). Dramatic improvements in A1c, fasting glucose (FBG), cholesterol (TPC) and triglycerides (TG) were reported in all subjects, in the absence of weight loss. A1c decreased by 1-2% and FBG by &gt; 100mg/dL (Cohen’s d = 3.81 and 2.78). Post-prandial glucoses were unchanged. Similarly, TPC and TG reduced by &gt;25mg/dL and &gt; 130mg/dL (Cohen’s d = 0.73 and 1.55). Improvements in fasting and overall glycemic measures, and lipid profiles suggest effects on hepatic metabolism. Reductions in creatinine were also seen post-treatment without changes in urea, which may indicate reduced muscle catabolism. Our results show a single D+Q treatment has potent and long-lasting effects for improved metabolism in T2D.

Disclosure
A. D. Ruggiero: None. M. Block: None. M. Davis: None. R. Vemuri: None. M. E. Orr: None. K. Kavanagh: None.

Funding
National Heart, Lung, and Blood Institute (R01HL142930)
757-P: Cardiometabolic Disease Risk Assessment of HIV Medication Regimens
Authors: ELZARKI ADRIAN , NANDULA SESHAGIRI RAO , AWAL HASSAN , SEN SABYASACHI 
Published: June 2021

Objective: To determine the effect of non-nucleoside reverse transcriptase inhibitor (NNRTI) or integrase strand transfer inhibitor (IIh) based regimens on cardiovascular and metabolic disease risk in HIV +ve patients without diabetes, with normal CD4:CD8 count. Our goal was to use hematopoietic progenitor cells (CD34+ve) as the biomarker while examining the traditional serum markers.
Methods: 21 male subjects ages 32-66 years with BMI 21.0- 36.0, were enrolled. This was a single time point analysis study. Subjects were stratified into 2 groups (IIh with 11 and NNRTI with 10 subjects) who were taking stable doses of HAART. The medication regimens were a combination of two NRTI (typically tenofovir-emtricitabine) plus one IIh or NNRTI. We used CD34+ve cells, arterial stiffness measures and serum for the analysis.
Results: The IIh group had a higher average CD34+ve cell count 0.93% vs. 0.75% in NNRTI group. However, colony forming units (CFU) were lower in IIh group, 7.54 vs. 20.62. LDL levels were similar at 103.9 ±40.3 (IIh) vs. 107.8 ±37.5 (NNRTI). Average HDL were also similar. Inflammatory markers such as hs-CRP were lower in IIh at 1.726±1.45 vs. 1.832±1.50 in NNRTI group. Vitals such as average systolic BP in the IIh arm was 126.18±13.53 vs. 141.2±30.0 in NNRTI group. The diastolic BP averages were similar. The average augmentation index-75 (a measure of arterial stiffness) was avg.12.8 in IIh vs. 16.7 in NNRTI group. The average augmentation index (AI) were 15.2 in IIh vs. 20.2 in NNRTI group, with higher values indicating increased arterial stiffness. Average urinary albumin: creatinine ratio was 15.53 in IIh group vs. 76.72 in NNRTI group. No differences were noted in HbA1C, Leptin and adiponectin however average fasting insulin was 11.24 (IIh) vs. 22.96 (NNRTI). No significant differences were noted in CD34+ve cell gene expression assays.
Conclusion: Considering all parameters we conclude that Integrase Inhibitor based regimens may have a better cardiometabolic disease risk profile compared to NNRTI based regimens.

Disclosure
A. Elzarki: None. S. Nandula: None. H. Awal: None. S. Sen: None.

Funding
District of Columbia Center for AIDS Research (to S.S.)
759-P: Effect of Elexacaftor/Tezacaftor/Ivacaftor on Glycemic Control in Cystic Fibrosis-Related Diabetes Mellitus: A Chart Review
Authors: KRAVCHENKO MARIA , WARREN WHITTNEY 
Published: June 2021

Introduction: Cystic fibrosis related diabetes mellitus (CFRD) affects up to 50% of adults with cystic fibrosis (CF), causing significant morbidity. CFRD primarily causes insulin deficiency, but exacerbations of CF may result in periods of insulin resistance. Anecdotal reports have suggested improved glycemic control and reduced insulin needs with CFTR modulators. Small pilot studies have shown improved insulin secretion and glycemic control with use of cystic fibrosis transmembrane regulator (CFTR) gene modulators, but the data are conflicting. This is a retrospective observational study investigating the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), the newest CFTR modulator, on glucose metabolism in CF.
Methods: We identified patients enrolled in the CF clinic at Brooke Army Medical Center who were started on ELX/TEZ/IVA in the last 12 months. Chart review was performed to identify diagnosis of CFRD, glucose and HbA1c values, and insulin dose. Glycemic control was compared for the periods 6 months prior to starting ELX/TEZ/IVA vs. 6 months afterward using paired t-tests.
Results: There were 10 patients with adequate data for analysis; 6 had CFRD and 4 did not. Median duration of CFRD was 10 years. Among patients without CFRD, there was no difference in FPG (p = 0.80), HbA1c (p = 0.20), or 2-hour OGTT (p = 0.09). In patients with CFRD, an improvement was seen in FPG (p=0.006) but not HbA1c (p=0.29) or insulin dose per kilogram (p=0.51). One patient did have a 55% reduction in insulin dose.
Conclusion: ELX/TEZ/IVA may improve FPG in patients with CFRD but does not have a significant effect on glucose metabolism in patients without CFRD. Further research is needed to elucidate metabolic effects of CFTR modulators and patient characteristics associated with improved glycemic control.

Disclosure
M. Kravchenko: None. W. Warren: None.