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Postpartum (PP) maternal mortality remains alarmingly high, with a rate of 32.9 per 100,000 live births in 2021 in the United States. Cardiovascular diseases, including peripartum/postpartum cardiomyopathy (PPCM) and coronary heart disease, are among the leading causes of PP morbidity and mortality. Although socioeconomic status and the level of PP care can influence the mortality rate, the underlying mechanisms leading to PPCM are not well understood. PPCM is clinically defined as (1) the development of the disease in the last month of pregnancy or within 5 months of delivery, (2) absence of pre-existing heart disease prior to the last month of pregnancy, (3) unknown cause of heart failure, and (4) left ventricular systolic dysfunction. Prognosis remains poor, with full recovery reported in only 23% of affected individuals and 50% experiencing heart failure-related mortality due to limited therapeutic options. Limited studies in both humans and mouse models of PPCM have proposed several potential mechanisms, including inflammation, viral myocarditis, autoimmune reactions, oxidative stress, and apoptosis, resulting from environmental as well as genetic factors. Studying these mechanisms in animal models, particularly those involving genetic causes, has been difficult due to the lack of severity or relevance of existing mouse models of PPCM to the human disease.

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A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice

Jonathan D. Douros, Aaron Novikoff, Barent DuBois, Rebecca Rohlfs, ... Patrick J. Knerr

A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice

 

Objective

Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to modern obesity pharmacotherapies. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models.

Methods

We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss efficacy in diet induced obese (DIO) rodents than cAMP potency alone.

Results

Our data demonstrate that signaling bias significantly correlates to GLP-1R agonist mediated weight loss in diet-induced obese mice. We further characterized a protracted GLP-1 analogue (NNC5840) which exhibits a partial-Gsα, cAMP-biased GLP-1R signaling profile in vitro and demonstrates superior maximal body weight reduction compared to semaglutide in DIO mice. The NNC5840 weight loss profile is characterized by reduced in vivo potency but increased maximal efficacy.

Conclusion

The data demonstrate that biased agonism is a strong predictor of in vivo efficacy for GLP-1R agonists independent of factors like intrinsic cAMP potency or pharmacokinetics. These data suggest that drug discovery screening strategies which take a holistic approach to target receptor signaling may provide more efficacious candidate molecules. The interpretations of these studies are limited by unknowns including how structural modifications to the biased GLP-1R agonist effect physiochemical properties of the molecules.

 

 

Articles in Press

A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice

Jonathan D. Douros, Aaron Novikoff, Barent DuBois, Rebecca Rohlfs, ... Patrick J. Knerr

A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice

 

Objective

Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to modern obesity pharmacotherapies. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models.

Methods

We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss efficacy in diet induced obese (DIO) rodents than cAMP potency alone.

Results

Our data demonstrate that signaling bias significantly correlates to GLP-1R agonist mediated weight loss in diet-induced obese mice. We further characterized a protracted GLP-1 analogue (NNC5840) which exhibits a partial-Gsα, cAMP-biased GLP-1R signaling profile in vitro and demonstrates superior maximal body weight reduction compared to semaglutide in DIO mice. The NNC5840 weight loss profile is characterized by reduced in vivo potency but increased maximal efficacy.

Conclusion

The data demonstrate that biased agonism is a strong predictor of in vivo efficacy for GLP-1R agonists independent of factors like intrinsic cAMP potency or pharmacokinetics. These data suggest that drug discovery screening strategies which take a holistic approach to target receptor signaling may provide more efficacious candidate molecules. The interpretations of these studies are limited by unknowns including how structural modifications to the biased GLP-1R agonist effect physiochemical properties of the molecules.

 

 

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13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

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