Hormone-Induced Resistance to GLP-1 Receptor Agonists in Diabetes: Unraveling the Molecular Complexities

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of type 2 diabetes mellitus (T2DM). However, a subset of patients does not respond to these agents or develop treatment resistance, which poses a significant clinical challenge.

Background

Emerging evidence from our work in humans and mice shows that endogenous amidated hormones synergize with GLP-1RAs to reduce glycated hemoglobin, and their absence promotes GLP-1RA resistance. This proposal explores the intricate mechanisms by which endogenous amidated hormones affect endogenous GLP-1 secretion, modulate its function, and influence the effectiveness of GLP-1RAs.

Objectives

Furthermore, it will investigate which characteristics predict the GLP-1RA effectiveness in patients and test potential therapeutic approaches to prevent detrimental GLP-1 resistance mechanisms with the goal of ameliorating T2DM treatment and outcomes.

Methodology

A plethora of approaches will be used to elucidate amidated hormone-induced GLP-1 resistance:

1. We will study L-cell functions and GLP-1 endogenous secretion in vitro and in vivo in the absence of amidated hormones.
2. With tissue-specific genetically engineered mice, we will selectively deplete key amidated hormones that counteract the effects of GLP-1RAs and dissect their contribution in physiological readouts of GLP-1RA resistance.
3. Lastly, we will leverage machine learning approaches to clinical data analysis on large deeply phenotyped biomedical cohorts to select for patient characteristics that determine the likelihood of developing GLP-1RA resistance and to assess the combinatorial contribution of amidated hormones on T2DM susceptibility.

Conclusion

By combining experimental and computational approaches, this project aims to gain a deeper understanding of the complex interplay between endogenous hormones (and their combinatorial effects) and GLP-1 signaling, to develop more effective and personalized therapies, and ultimately to improve clinical outcomes in individuals with T2DM.