Stephan Sachs1,2,3, Lili Niu4,5, Philipp Geyer4,5, Sigrid Jall2,3, Maximilian Kleinert2,6, Annette Feuchtinger7, Kerstin Stemmer2,8, Markus Brielmeier9, Brian Finan10, Richard D DiMarchi10,11, Matthias H Tschöp2,3,8, Nicolai Wewer Albrechtsen4,12, Matthias Mann4,5, Timo D Müller2,8,13, Susanna M Hofmann1,8,14. 1. Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Centre Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. 2. Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Centre Munich, Neuherberg, Germany. 3. Division of Metabolic Diseases, Technische Universität München, Munich, Germany. 4. Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. 6. Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark. 7. Research Unit Analytical Pathology, Helmholtz Center Munich, Neuherberg, Germany. 8. German Center for Diabetes Research (DZD), Neuherberg, Germany. 9. Helmholtz Zentrum München-German Research Center for Environmental Health, Research Unit Comparative Medicine, Neuherberg, Germany. 10. Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana. 11. Department of Chemistry, Indiana University, Bloomington, Indiana. 12. Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 13. Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany. 14. Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Munich, Germany.
Abstract
AIMS: Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (GLP-1/GIP co-agonist) have been shown to outperform each single peptide in the treatment of obesity and cardiometabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomarkers to advance non-invasive metabolic monitoring of compound treatment success and exploration of ulterior treatment effects on an individual basis. MATERIALS AND METHODS: We performed metabolic phenotyping along with PPP in body weight-matched male and female diet-induced obese (DIO) mice treated for 21 days with phosphate-buffered saline, single GIP and GLP-1 mono-agonists, or a GLP-1/GIP co-agonist. RESULTS: GLP-1R/GIPR co-agonism improved obesity, glucose intolerance, non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia with superior efficacy in both male and female mice compared with mono-agonist treatments. PPP revealed broader changes of plasma proteins after GLP-1/GIP co-agonist compared with mono-agonist treatments in both sexes, including established and potential novel biomarkers for systemic inflammation, NAFLD and atherosclerosis. Subtle sex-specific differences have been observed in metabolic phenotyping and PPP. CONCLUSIONS: We herein show that a recently developed unimolecular GLP-1/GIP co-agonist is more efficient in improving metabolic disease than either mono-agonist in both sexes. PPP led to the identification of a sex-independent protein panel with the potential to monitor non-invasively the treatment efficacies on metabolic function of this clinically advancing GLP-1/GIP co-agonist.
AIMS: Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (GLP-1/GIP co-agonist) have been shown to outperform each single peptide in the treatment of obesity and cardiometabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomarkers to advance non-invasive metabolic monitoring of compound treatment success and exploration of ulterior treatment effects on an individual basis. MATERIALS AND METHODS: We performed metabolic phenotyping along with PPP in body weight-matched male and female diet-induced obese (DIO) mice treated for 21 days with phosphate-buffered saline, single GIP and GLP-1 mono-agonists, or a GLP-1/GIP co-agonist. RESULTS:GLP-1R/GIPR co-agonism improved obesity, glucose intolerance, non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia with superior efficacy in both male and female mice compared with mono-agonist treatments. PPP revealed broader changes of plasma proteins after GLP-1/GIP co-agonist compared with mono-agonist treatments in both sexes, including established and potential novel biomarkers for systemic inflammation, NAFLD and atherosclerosis. Subtle sex-specific differences have been observed in metabolic phenotyping and PPP. CONCLUSIONS: We herein show that a recently developed unimolecular GLP-1/GIP co-agonist is more efficient in improving metabolic disease than either mono-agonist in both sexes. PPP led to the identification of a sex-independent protein panel with the potential to monitor non-invasively the treatment efficacies on metabolic function of this clinically advancing GLP-1/GIP co-agonist.