RG7697 / Roche - LARVOL DELTA

GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells. (PubMed, Cell Mol Life Sci) - "For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Experimental colonization with H. hepaticus, S. aureus and R. pneumotropicus does not influence the metabolic response to high-fat diet or incretin-analogues in wildtype SOPF mice. (PubMed, Mol Metab) - "We conclude that the occurrence of Helicobacter hepaticus, Rodentibacter pneumotropicus and Staphylococcus aureus does neither affect the development of diet-induced obesity or type 2 diabetes, nor the efficacy of GLP-1-based drugs to decrease body weight and to improve glucose control in mice."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Single-Cell Multiomic Analysis of the Effect of GIP and GIP-1 Mono- and Multi-agonism on the Hypothalamus and Hindbrain (ADA 2024) - "The aim of this study is to identify mechanisms of action in the hypothalamus and hindbrain of GLP-1 and GIP agonists.Adult, diet-induced obese male CL57BL/6-J mice were injected IP with vehicle, GLP-1R agonist, GIPR agonist, GIPR antagonist, and MAR709, a mouse and human GLP-1R/GIPR dual-agonist, n=6...Differences in intercellular communication were identified using a novel atlas-informed cell-cell communication method.We have generated the largest single-cell multiome dataset in the hindbrain and hypothalamus to date and identified gene expression and gene regulatory changes by which GIP and GLP-1 mimetics act to exert their anti-obesity effects. These data and analysis identified candidate mechanisms of action of incretin-mediated weight loss."

Omic analysis • Diabetes • Metabolic Disorders • Obesity

Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice. (PubMed, Mol Metab) - "GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • LEP • LEPR

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice. (PubMed, Nat Metab) - "Whereas the GIPR-GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Spatiotemporal GLP-1 and GIPR receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. (PubMed, Mol Metab) - "Our data indicate that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking and recycling dynamics relative to the native peptides, semaglutide and matched mono-agonist controls. These findings support the hypothesis that the structure of the GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking."

Journal • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders