Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction–associated fatty liv...

Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction–associated fatty liv...

Early drivers of T2D include ectopic fat accumulation that impairs insulin sensitivity. Here, the authors show that GLP1/GCGR dual agonism provides multimodal benefits in obese male mice by reducing l...

Our findings indicate that mazdutide, via its dual GLP-1/GCGR activation effects, exerts multifactorial improvements in cognitive function in the context of obesity and T2DM. These results suggest tha...

Glucagon receptor (GCGR)-mediated thermogenesis is a key component for the next-generation of obesity therapeutics. Herein, we investigated the central and peripheral mechanism by which activation of the GCGR augments metabolic rate to promote weight loss. Chronic treatment of obese mice with a long …

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ALT: Simpsons Old Man Yells at Cloud

The glucagon receptor (GCGR) antagonism is a potential target for diabetes therapy but side effects such as α-cell hyperplasia and hyperglucagonemia limit therapeutic development. Here the authors rep...

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YouTube video by 란페이*蘭平*Ranpei

NNC-0640 is an effective negative allosteric modulator (NAM) of the human glucagon receptor (GCGR), with an IC50 value of 69.2 nM. NNC-0640 holds potential for research in the field of diabetes. - Mec...

YouTube video by 란페이*蘭平*Ranpei

Peptide hormone-receptor interactions serve as critical regulators of metabolic homeostasis, a paradigm exemplified by the clinical efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists. Building upon this framework, strategic design has yielded unimolecular dual and triple agonists targeting GLP-1R, glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GcgR), leveraging the sequence homology within the cognate native ligands of the class B G protein-coupled receptor (GPCR) family. However, the integration of Y2 receptor (Y2R) agonism─engaged by peptide YY (PYY) and belonging to the structurally divergent class A GPCR family─has remained an unaddressed challenge due to the topological and sequence disparities between these receptor classes. Y2R activation plays a pivotal role in appetite suppression, potentiating the metabolic benefits conferred by GLP-1R, GIPR, and GcgR agonism. Here, we report first-in-class, unprecedented tetra-agonists with high potency at GLP-1R, GIPR, GcgR, and Y2R. The chimeric peptides overcome the intrinsic sequence constraints imposed by class A and class B GPCR divergence, demonstrating the feasibility of rationally designed agonism mediated by single agents across receptor families. Lipidation of this template is well tolerated enhancing the promise of therapeutic viability. Furthermore, we show that biased agonism at GLP-1R selectively boosts cyclic AMP (cAMP) signaling while minimizing β-arrestin recruitment, thereby decoupling receptor desensitization from metabolic efficacy. Additionally, we introduce a tunable framework to modulate β-arrestin engagement without compromising cAMP potency, providing insight into the fine-tuning of GPCR-mediated signaling for next-generation peptide therapeutics.

Combination therapy with retatrutide and cagrilintide lowers body weight and improves markers of metabolic health in obese, male rats more efficiently than equimolar monotherapies and matched-dose com...

Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction–associated fatty liv...