bluuebunny/crossref_metadata_2025_split huggingface dataset:
792-P: A Novel Gene Therapy Platform Using GLP1 and EX4 Attenuates Hyperglycemia in a Preclinical Model of Type 2 Diabetes
Authors: LOURIE JARED , GORALTCHOUK ALEX , FUJISHIRO ATSUTARO , BERGER NICOLAS , ROSEN HANNAH G. , HOLLANDER JUDITH , LUPPINO FRANCESCO , SEREGIN ALEXEY , ZOU KAI 
Published: June 2024

Introduction and Objective: We recently reported the development of the first dose adjustable lipid nanoparticle (LNP) gene delivery platform with high durability and functional up/down-titration. Incretin therapies are effective in treating type 2 diabetes (T2D) but require frequent dosing and are plagued by high discontinuation rates. To overcome these challenges, we aimed to develop an adjustable-dose incretin gene therapy using LNP and evaluate its efficacy in a mouse model of T2D.
Methods: C57BL6 mice were fed either low-fat or high-fat diet, followed by low-dose streptozotocin (40mg/kg BW) to induce T2D. T2D mice were treated subcutaneously with LNP-GLP1, LNP-EX4 or vehicle. Animals were followed for 14 weeks. Body weight, GTT and ITT tests were measured.
Results: LNP-GLP1 and EX4 treatment produced 20% and 14% weight loss at 4 weeks relative to vehicle, 37% and 38% reduction in fasting glucose, 29% and 26% reduction in area under the curve of GTT, and 25% and 22% reduction in ITT, respectively (p≤0.05). The transgene was localized to the injection site with no detection in the liver, heart, spleen, or kidney. There were no significant changes in systemic markers of inflammation (IL6 and TNFα) or liver damage (ALP).
Conclusion: Our study demonstrates the ability of a novel incretin gene therapy delivered by LNP to induce weight loss, improve insulin resistance, and glycemic control in T2D.

Disclosure
J. Lourie: None. A. Goraltchouk: Board Member; Remedium Bio, Inc. Employee; Remedium Bio, Inc. A. Fujishiro: None. N. Berger: None. H.G. Rosen: None. J. Hollander: Employee; Remedium Bio, Inc. Stock/Shareholder; Remedium Bio, Inc. F. Luppino: None. A. Seregin: Employee; Remedium Bio. K. Zou: Research Support; Remedium Bio.

Funding
National Science Foundation (#2240683)
795-P: Balancing the Scales—The Effect of Tirzepatide on Lean Body Mass and Fat Mass
Authors: BODENSTAB MONICA , ISKANDER MINA , MINTZ JOEL , LIEBERMAN-ULM MONICA P. , SOLIMAN DIANA , GALINDO RODOLFO J. 
Published: June 2024

Introduction & Objective: Tirzepatide is a novel GIP/GLP-1 receptor agonist recently approved for diabetes and chronic weight management. Its effects on bodyweight loss are well-established. However, its effect on lean body mass (LBM) and fat mass (FM) loss is less established. This review aims to assess the effects on LBM and FM in patients treated with tirzepatide, with or without type 2 diabetes (T2DM). Methods Following PRISMA guidelines, this systematic review included data from randomized controlled and observational studies evaluating tirzepatide’s effect on body composition. The ratio of FM/LBM loss was then assessed.
Results: Of 5847 prospective abstracts, three studies were included in the final analysis (Table 1). The FM/LBM loss ratio in patients with T2DM treated with tirzepatide doses of 5-15 mg ranged from 2.9-6.1 across two studies. Ratios could not be calculated from the SURMOUNT-1 trial but a change from baseline of -33.9% in FM and -10.9% in LBM in patients without diabetes was reported. Significant heterogeneity existed among the included studies due to varying therapy duration, dosing schedules, inclusion criteria, and body composition assessment modalities.
Conclusion: Data is limited on tirzepatide’s effect on LBM loss, but our study suggests a decrease in LBM with its use. Further research should address LBM loss with these therapies. Clinicians should counsel patients on methods to preserve LBM.

Disclosure
M. Bodenstab: None. M. Iskander: None. J. Mintz: None. M.P. Lieberman-Ulm: None. D. Soliman: None. R.J. Galindo: Consultant; Abbott. Other Relationship; Dexcom, Inc. Consultant; Bayer Inc. Other Relationship; Novo Nordisk, Eli Lilly and Company. Consultant; Boehringer-Ingelheim, AstraZeneca.
798-P: Potential Cardioprotective Effects of HM15275, a Novel, Long-Acting GLP-1/GIP/GCG Triple Agonist, in Animal Models of Hypertension
Authors: MYEONG LEE SEON , KUK KIM JUNG , PARK EUNJIN , REYEON KANG HYE , KIM JEONG A. , KIM YOHAN , HONG SUNGHEE , BAE SUNGMIN , HYUN LEE SANG , YOUNG CHOI IN 
Published: June 2024

Introduction & Objective: Obesity is a major risk for development of cardiovascular disease (CVD). Both cardiac output and total blood volume are elevated in obesity, which eventually leads to cardiac hypertrophy and fibrosis. To date, therapeutic benefits of several incretin drugs were observed in cardiovascular outcomes trials. Based on these findings, the present study evaluates the cardioprotective effects of HM15275, a novel long-acting GLP-1/GIP/GCG triple agonist, in animal models of hypertension.
Methods: Spontaneously hypertensive rat (SHR) was administered with HM15275 for 16 weeks. In angiotensin II (Ang II)-infused mice and AMLN mice, HM15275 was administered for 2 ~ 6 weeks, followed by the determination of cardiomyocytes size, and cardiac fibrosis (MT staining, collagen levels). To highlight CV benefits of HM15275, tirzepatide (TZP) was included as comparative control.
Results: In SHR, cardiomyocytes cell size determined by WGA staining was significantly reduced by HM15275 treatment compared to TZP (-52.3% vs. TZP; p&lt;0.001). In line with these results, both interstitial and perivascular fibrosis (% of extracellular collagen area using MT staining) were significantly improved by HM15275 treatment (-52.8% vs. TZP; p&lt;0.001). In Ang II mice, the levels of pro-collagen-1α1 were significantly decreased by HM15275 in the heart (-40.5% vs. TZP; p&lt;0.001). Moreover, cardiomyocyte enlargement caused by Ang II was significantly reduced by HM15275 treatment for 2 weeks. Similar benefits were also confirmed in AMLN mice.
Conclusion: Collectively, the results showed that HM15275 could have more potent cardioprotective effects than TZP in hypertension mediated cardiac damage. Further mechanistic studies are needed to elucidate the MoA for the beneficial effects of HM15275.

Disclosure
S. Lee: None. J. Kim: None. E. Park: None. H. Kang: None. J.A. Kim: None. Y. Kim: None. S. Hong: None. S. Bae: None. S. Lee: None. I. Choi: None.
815-P: Performance of Previously Identified Predictors of &gt;=15% Body Weight Reduction with Tirzepatide in Participants with Type 2 Diabetes in SURMOUNT-2
Authors: LINGVAY ILDIKO , MALECKI MACIEJ , BENABBAD IMANE , FALCON BEVERLY , LEE CLARE , WANG HUI , DUNN JULIA P. 
Published: June 2024

Introduction and Objective: In SURPASS-1-4 (SP), baseline factors associated with higher likelihood of achieving body weight (BW) reduction ≥15% at WK 40/42 with tirzepatide (TZP) in participants with T2D were: higher TZP dose, female sex, White or Asian race, metformin use, better glycemic status and lower non-HDL-C. We assessed performance of these predictors in BW reduction ≥15% at WK 48 in SURMOUNT-2 (SM-2), a study of TZP in chronic weight management in adults with T2D with obesity or overweight.
Methods: The multivariate model from SP was run in SM-2 participants who were on TZP at WK 48, ≥75% compliance and no rescue medication during the study treatment period. The AUC (area under curve) of the SM-2 model was calculated to determine its accuracy.
Results: BW reduction ≥15% was achieved in 41.8% (n = 230) participants on TZP at WK 48 and 91.3% (n = 210) sustained BW reduction ≥15% at WK 72. Factors identified in SP that were replicated with respect to the estimated effect size in SM-2: higher TZP dose, female, and lower HbA1c, FSG and non-HDL-C (Table 1). In SM-2, unlike in SP, Asian race and metformin use were not positively associated with BW reduction ≥15%. The AUC was 65.6%.
Conclusion: In the current study there are some consistencies in SM- 2 when applying the SP model. However, the overall performance of the predictors of the model demonstrates a need for refinement.

Disclosure
I. Lingvay: Consultant; Altimmune, Astra Zeneca, Bayer, Biomea, Boehringer-Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Sanofi. Research Support; NovoNordisk, Sanofi, Mylan, Boehringer-Ingelheim. Consultant; TERNS Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. M. Malecki: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott, Dexcom, Inc., Boehringer-Ingelheim. Speaker's Bureau; AstraZeneca, Merck & Co., Inc. Advisory Panel; Krka. Speaker's Bureau; Servier Laboratories. I. Benabbad: Employee; Eli Lilly and Company. B. Falcon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company, Sangamo Therapeutics. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Wang: None. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding
Eli Lilly and Company
821-P: Comparison of In-Hospital Glucose Management of People with Type 2 Diabetes Made by Artificial Intelligence Chatbot vs. Physicians—A Cross-Sectional Study
Authors: ROJAS-LÓPEZ TATIANA , ALVAREZ-MARTIN DANIEL , PUJOL-DECASTRO ANTONIO , MORENO-DOMINGUEZ OSCAR , BARQUIEL BEATRIZ , GARCIA-PEREZ-DE-SEVILLA ELENA , PARRA-RAMÍREZ PAOLA , GONZALEZ-PEREZ-DE-VILLAR NOEMI 
Published: June 2024

Introduction and Objective: in-hospital glucose management of people living with type 2 diabetes (PLWT2D) has a direct impact on morbidity and mortality. Artificial intelligence (AI) tools could improve patient care. This study aimed to assess the correlation between in-patient glucose management suggested by an AI chatbot and hospital protocols and compare it with real life medical management.
Methods: we conducted a cross-sectional study of PLWT2D hospitalized in a tertiary care center in 2023 who required an Endocrinology consultation during their hospital stay. We excluded patients with corticosteroid treatment or need for intravenous insulin.  We provided Chat-GPT4 with the protocol for T2D management used in the hospital and asked for a suggested prescription based on individual de-identified variables. We assessed the accuracy of the output using Spearman (r) and interclass correlation (ICC) coefficients. We then analyzed the correlation between the treatment prescribed by physicians on the first day of hospital stay and the protocol.
Results: 85 patients met the inclusion criteria. There was a strong correlation between the dose of basal insulin suggested by Chat-GPT and the protocol (r=0.995), CCI=0.996 [IC 95% 0.994;0.998] as opposed to a weak correlation between the basal insulin dose prescribed by physicians and the protocol (r=0.223), ICC=0.134 [IC95% -0.072;0.331]. The same strong correlation was found between the dose of prandial insulin suggested by Chat-GPT and the protocol (r=0.978), CCI=0.984 [IC 95% 0.975;0.990], and a moderate correlation between physicians and the protocol (r=0.399), CCI=0.466 [IC95% 0.283;0.616]. The chatbot suggested the discontinuation of non-insulin therapies in all patients, as stipulated in the protocol.
Conclusions: the use of an AI chatbot resulted in a higher correlation with established protocols compared with medical prescription.

Disclosure
T. Rojas-López: None. D. Alvarez-Martin: None. A. Pujol-deCastro: None. O. Moreno-Dominguez: Speaker's Bureau; Novo Nordisk, Lilly Diabetes. Research Support; Sanofi. B. Barquiel: None. E. Garcia-Perez-de-Sevilla: None. P. Parra-Ramírez: None. N. Gonzalez-Perez-de-Villar: Speaker's Bureau; Abbott Diagnostics. Advisory Panel; Medtronic. Speaker's Bureau; Air Liquide.
836-P: Adherence to App-Based Dose Guidance for Once-Weekly Insulin Icodec in Insulin-Naive Type 2 Diabetes—Post Hoc Analysis of ONWARDS 5
Authors: BAJAJ HARPREET S. , DONATSKY ANDERS M. , ENGBERG SUSANNE , MARTINY JOHANNES H.J. , VIANNA ANDRE G. , LINGVAY ILDIKO 
Published: June 2024

Introduction & Objective: In ONWARDS 5, a 52-week, phase 3a trial, participants in the insulin icodec (icodec) group used a dosing guide app to assist titration. This post hoc analysis assessed adherence to app-based dose guidance and its association with prebreakfast self-measured blood glucose (SMBG).
Methods: The app provided weekly algorithm-driven icodec dose guidance based on prebreakfast SMBG. Regardless, investigators could suggest manual dose changes. Estimated mean prebreakfast SMBG over time was compared across app-based guidance adherence subgroups (Figure).
Results: On average 5.0% of administered icodec doses differed from app guidance (dose change by participant). Of 541 participants assessed, 56.7% had ≥1 manual dose change during the trial; most changes (82%) were increases to the dose recommended by the app. Estimated mean prebreakfast SMBG improved from baseline irrespective of adherence to app guidance. Medium/high adherence subgroups had statistically significantly lower mean prebreakfast SMBG (p&lt;0.0001) with earlier achievement of target level (80-130 mg/dL) than the low adherence subgroup (Figure).
Conclusion: Most administered icodec doses were adherent with app guidance; medium/high vs low adherence to app guidance was associated with improved estimated SMBG. The findings support the use of dose guidance apps to assist real-world insulin titration.

Disclosure
H.S. Bajaj: Research Support; Abbott, Amgen Inc., Anji Pharmaceuticals, Boehringer-Ingelheim, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc. A.M. Donatsky: Employee; Novo Nordisk A/S. S. Engberg: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. J.H.J. Martiny: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. A.G. Vianna: Board Member; Abbott, Lilly Diabetes, Novo Nordisk, Medtronic. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk, Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Research Support; Servier Laboratories. I. Lingvay: Consultant; Altimmune, Astra Zeneca, Bayer, Biomea, Boehringer-Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Sanofi. Research Support; NovoNordisk, Sanofi, Mylan, Boehringer-Ingelheim. Consultant; TERNS Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma.

Funding
Novo Nordisk A/S
844-P: Insulin-Like Growth Factor Binding Protein 3 Levels Modulate the Glucose-Lowering Effect of Intensive Lifestyle Intervention for Weight Loss in Type 2 Diabetes
Authors: MAURYA PRIYANSHI , YANG JUN , EVERETT ALLEN D. , BENNETT WENDY L. , VAIDYA DHANANJAY 
Published: June 2024

Introduction: Insulin-like Growth Factor-1 (IGF1) and its primary binding protein IGFBP3 are markers of insulin resistance and may characterize an internal milieu affecting the course of diabetes. We examined if IGF1 and IGFBP3 levels modify the efficacy of intensive weight-reducing lifestyle intervention on glucose metabolism among people with overweight/obese and Type 2 Diabetes.
Methods: The Look AHEAD Study randomized persons aged 45-74 years with BMI ≥ 25 kg/m2 and verified Type 2 diabetes, to assigned to Intensive Lifestyle Intervention (ILI) versus Diabetes Support and Education (DSE). A random sample (n=80, male 50%, African Americans 16%) had measurement of IGF1 and IGFBP3 by ELISA at baseline. We examined changes in fasting glucose levels from baseline to 1 year by treatment assignment and biomarker levels.
Results: In the ILI group, lower baseline IGFBP3 levels predicted larger decreases in fasting glucose (p = 0.02), while there was no significant association in the DSE group (Figure, baseline IGFBP3 by treatment interaction, p = 0.055). There was no treatment by baseline level interaction for IGF1.
Conclusion: In overweight/obese Type 2 diabetes, the efficacy of ILI in reducing fasting glucose level is greater at lower IGFBP3 levels. Our findings, if confirmed, can guide personalization of intensive treatment of diabetes.

Disclosure
P. Maurya: None. J. Yang: None. A.D. Everett: Advisory Panel; Merck & Co., Inc. W.L. Bennett: None. D. Vaidya: None.

Funding
National Institutes of Health (DK127222)
874-P: Bromocriptine-QR Reduces Elevated Postprandial Cardiometabolic Risk Factors in Type 2 Diabetes Subjects
Authors: CHAMARTHI BINDU , EZROKHI MICHAEL , CINCOTTA ANTHONY H. 
Published: June 2024

Bromocriptine-QR (BQR), a unique quick release formulation of micronized bromocriptine, is the only FDA-approved sympatholytic insulin sensitizer for T2D. Previously, circadian-timed (~0600-0800 hr) B-QR dosing reduced a prespecified cardiovascular disease (CVD) composite endpoint in the Cycloset Safety Trial by 40 - 50% within 1 year. Chronically elevated sympathetic tone is a driver of increased postprandial (PP) plasma glucose (G), triglyceride (TG) and free fatty acid (FFA) levels which composite is a major risk factor for CVD, especially in hypertensive (HT) T2D subjects. This study therefore explored the impact of 24 wks BQR therapy versus placebo on average daylong PP G, TG and FFA levels obtained at 1 and 2 hrs following standardized meals at breakfast, lunch, and dinner in normotensive T2D subjects with normal fasting plasma TG (FPTG) levels (&lt; 150 mg/dl) or with FPTG levels ≥ 150, 200, or 300 mg/dl (hyperlipidemic [HL] groups) or in HL - HT T2D subjects. BQR therapy increasingly reduced PP plasma G, TG, and FFA levels (and HbA1c) in the HL groups versus placebo as FPTG level increased from ≥ 150 to ≥ 300 mg/dl, but not in normal lipidemic, normotensive subjects. Moreover, this BQR effect was accentuated in the HL - HT group (See Table). This BQR-induced reduction in all these CVD risk factors in HL and HL - HT T2D subjects may contribute to the therapy’s observed impact to reduce CVD outcomes in the T2D population.

Disclosure
B. Chamarthi: Employee; VeroScience LLC. M. Ezrokhi: Employee; VeroScience LLC. A.H. Cincotta: Employee; VeroScience LLC.
890-P: Ultraselective DYRK1A/B Inhibitors Mediated ß-Cell Proliferation and Insulin Production In Vitro and In Vivo
Authors: KUMAR MITTAPALLI GOPI , MAK CHI-CHING , BOSSARD CARINE , REDDY VAKITI RAMKRISHNA , CREGER EMILY , GUTIERREZ ERIK , HORSLEY ERICH A. , SWEARINGEN CHRISTOPHER , HILL JOHN S. 
Published: June 2024

Introduction and Objective: Non-selective DYRK1A/B inhibitors have been reported to stimulate pancreatic β-cell proliferation and insulin production. However off-target kinase inhibition remains a concern. Development of 2 novel highly selective DYRK1A/B inhibitors and results of in vitro and in vivo studies showing their ability to stimulate β-cell proliferation, mediate production of insulin and lowering of HbA1c levels in vivo are reported.
Methods: SM15238 and SM15268 (DMSO and harmine as -ve & +ve controls) were investigated in the 3D InSight™ Human Islet Microtissue (spheroids) system to assess β-cell proliferation and function. In vivo studies were conducted in 5-week-old male db/db mice receiving daily oral dosing (35 days) of either molecule or vehicle for 5 weeks (n=8/group), measuring body weight (BW), fasted and non-fasted glucose (GLU), HbA1c levels, OGTT, CMP18, and histological analysis of pancreatic tissue.
Results: Spheroids treated for 4 days with SM15238 and SM15268 (1 or 5μM) demonstrated increased β-cell proliferation compared to DMSO, a significant increase in stimulated insulin secretion at 1μM SM15238 and a similar trend at both concentrations of SM15268 (Dunnett’s 1-way ANOVA) compared to controls. Oral dosing of both molecules at 45 mg/kg once daily in db/db mice resulted in sustained increased circulating 4-hr fasted insulin levels. Mice treated with SM15268 had significantly reduced non-fasted and 4-hr fasted GLU levels and those treated with SM15238 significantly reduced GLU during OGTT. Dosing with both molecules resulted in decreases in HbA1c levels after 21 days. Histological analysis showed β-cell proliferation but no significant increase in α-cells.
Conclusions: In this early proof of concept study, selective small molecule inhibitors of DYRK1A/B mediated β-cell proliferation and induced positive changes in in vitro and in vivo hyperglycemic settings. Further toxicology and dose optimization studies are planned.

Disclosure
G. Mittapalli: Employee; Biosplice Therapeutics. C. Mak: Employee; Biosplice Therapeutics, Inc. C. Bossard: Employee; Biosplice Therapeutics. R. Vakiti: Employee; Biosplice Therapeutics. E. Creger: Employee; Biosplice Therapeutics. E. Gutierrez: Employee; Biosplice Therapeutics. E.A. Horsley: None. C. Swearingen: Employee; Biosplice Therapeutics. J.S. Hill: Stock/Shareholder; AbbVie Inc., Amgen Inc., Pfizer Inc. Employee; Biosplice Therapeutics.
892-P: Potential for New Oral Insulin Sensitizers in Combination with GLP-1 Agonists
Authors: COLCA JERRY R. 
Published: June 2024

MSDC-0602K (azemiglitazone) is a second-generation insulin sensitizer that was designed based on the knowledge of the activity of active metabolites of the first-generation insulin sensitizer pioglitazone. This molecule was purposely designed not to bind to PPAR transcription factors but to maintain the interaction with the mitochondrial target of pioglitazone and its metabolites, namely the mitochondrial pyruvate carrier. A one-year dose-escalating phase 2b clinical trial in subjects with biopsy-proven NASH with and without diabetes was conducted from 2016-2019. This study demonstrated similar insulin sensitizing pharmacology as pioglitazone, but without dose-liming issues at up to two times the exposures that occur with the highest approved dose of pioglitazone (45 mg). Here we have looked specifically at the 23 subjects with NASH (MASH) and type 2 diabetes who had been enrolled in the trial while on a stable dose of a GLP1 agonist (11 liraglutide, 8 dulaglutide, and 4 exenatide). A further analysis of this subset showed that any dose of azemiglitazone was able to further lower fasting glucose, insulin and liver enzymes. On average there was a further decrease in HbA1 by 0.5% (from an average baseline of 7.2%) with several subjects showing more than a 2% decrease. Of particular interest with respect to the hepatic pathology, 5 of the 19 subjects who had been on both azemiglitazone and a GLP1 agonist had a reduction in the liver fibrosis scores in the post-treatment liver biopsies. GLP1 agonists are particularly useful in producing weight loss. Some subjects who had been on a GLP1 continued to lose weight while others did not. Given the major effects of his pharmacology to improve insulin sensitivity Iin skeletal muscle and based on some existing precedent with high dose pioglitazone, maintenance of lean mass could be a component of the overall pharmacology achieved with oral metabolic modulators.

Disclosure
J.R. Colca: Stock/Shareholder; Cirius Therapeutics, Inc.