Search Results (3)

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), a progressive liver disease frequently associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity, has the potential to progress symptomatically to liver cirrhosis and, in some cases, hepatocellular carcinoma. Hence, an urgent need arises to identify and approve new therapeutic options to improve patient outcomes. Research efforts have focused on either developing dedicated molecules or repurposing drugs already approved for other conditions, such as metabolic diseases. Among the latter, antidiabetic and anti-obesity agents have received the most extensive attention, with pivotal trial results anticipated shortly. However, the primary focus underlying successful regulatory approvals is demonstrating a substantial efficacy in improving liver fibrosis and preventing or ameliorating cirrhosis, the key advanced outcomes within MASLD progression. Besides liver steatosis, the ideal therapeutic candidate should reduce inflammation and fibrosis effectively. Although some agents have shown promise in lowering MASLD-related parameters, evidence of their impact on fibrosis and cirrhosis remains limited. This review aims to evaluate whether antidiabetic and anti-obesity drugs can be safely and effectively used in MASLD-related advanced fibrosis or cirrhosis in patients with T2DM. Our paper discusses the molecules closest to regulatory approval and the expectation that they can address the unmet needs of this increasingly prevalent disease. Full article

Glucagon exerts pleiotropic actions on energy balance and has emerged as an attractive target for the treatment of diabetes and obesity in the last few years. Glucagon reduces body weight and adiposity by suppression of appetite and by modulation of lipid metabolism. Moreover, this hormone promotes weight loss by activation of energy expenditure and thermogenesis. In this review, we cover these metabolic actions elicited by glucagon beyond its canonical regulation of glucose metabolism. In addition, we discuss recent developments of therapeutic approaches in the treatment of obesity and diabetes by dual- and tri-agonist molecules based on combinations of glucagon with other peptides. New strategies using these unimolecular polyagonists targeting the glucagon receptor (GCGR), have become successful approaches to evaluate the multifaceted nature of glucagon signaling in energy balance and metabolic syndrome. Full article