Guanine and pregnenolone sulfate are associated with incident type 2 diabetes in two independent populations.
Maria Barranco-Altirriba, Minerva Granado-Casas, Oscar Yanes, Jordi Capellades, Alexandra Junza, Josep Franch-Nadal, Joan Vendrell, Gemma Llauradó, Sergio Valdés, Eva García-Escobar, Marcelino Bermúdez-López, José Manuel Valdivielso, Victor-Miguel López-Lifante, Cecilia Herrero-Alonso, Mireia Falguera, Maria Belén Vilanova, Ingrid Arteaga, Pere Torán-Monserrat, Alexandre Perera-Lluna, Esmeralda Castelblanco, Didac Mauricio
Journal: Frontiers in endocrinology
2025;16():1706886
PMID: 41416067
Abstract
BACKGROUND
Type 2 diabetes (T2D) is increasing its burden worldwide; therefore, research focused on its prediction and prevention is essential.
METHODS
We performed an untargeted metabolomics analysis using ultra high-performance liquid chromatography-mass spectrometry to discover metabolic biomarkers and biological pathways associated with incident T2D with a nested case-control design, followed by validation with targeted metabolomics in an independent cohort. In the discovery phase, plasma samples from 352 subjects (209 controls and 143 incident cases) were analyzed, collected with a mean (standard deviation) of 7.40 (0.76) years before they acquired the condition. Using this discovery phase cohort, six metabolites were identified using standards and were subsequently quantified in an independent validation phase cohort of 2,044 subjects (167 incident cases). Additionally, pathway enrichment was conducted in the discovery cohort.
RESULTS
Guanine, ecgonine, adenine, pregnenolone sulfate, phenyl sulfate, and citrulline were significantly associated with incident T2D in at least one of the analyses performed in the discovery phase. Among these, guanine, pregnenolone sulfate, and citrulline maintained their significant associations with incident T2D in the validation cohort. Additionally, several pathways were significantly altered, with nucleotide metabolism and ABC transporter pathways among the most consistently affected.
CONCLUSION
We identified significant associations of guanine, pregnenolone sulfate, and citrulline with incident T2D.
Copyright © 2025 Barranco-Altirriba, Granado-Casas, Yanes, Capellades, Junza, Franch-Nadal, Vendrell, Llauradó, Valdés, García-Escobar, Bermúdez-López, Valdivielso, López-Lifante, Herrero-Alonso, Falguera, Vilanova, Arteaga, Torán-Monserrat, Perera-Lluna, Castelblanco and Mauricio.
Address:
Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.; Bioinformatics and Biomedical Signals Laboratory (B2SLab), Institut de Recerca i Innovació en Salut (IRIS), Universitat Politècnica de Catalunya, Barcelona, Spain.; Networking Biomedical Research Centre in the Subject Area of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.; Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; DAP-Cat Group, Research Support Unit, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Barcelona, Spain.; GESEC Group, Department of Nursing and Physiotherapy, Faculty of Nursing and Physiotherapy, University of Lleida, Lleida, Spain.; Healthcare Research Group (GRECS), Institute of Biomedical Research in Lleida (IRBLleida), Lleida, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; Department of Electronic Engineering, Institute of Health Research Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; Institute of Health Research Pere Virgili (IISPV), Tarragona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; Scientific and Technical Resources Services, Universitat Rovira i Virgili, Tarragona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; DAP-Cat Group, Research Support Unit, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Barcelona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; Department of Endocrinology and Nutrition, Research Unit, Institut d'Investigació Sanitària Pere Virgili (IISPV) - Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; Department of Endocrinology and Nutrition, Hospital del Mar, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; UGC Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, IBIMA-Plataforma BIONAND, Málaga, Spain.; Experimental Medicine Department, University of Lleida, Lleida, Spain.; Vascular and Renal Translational Research Group, Institut de Recerca Biomédica IRBLleida, Lleida, Spain.; Vascular and Renal Translational Research Group, Institut de Recerca Biomédica IRBLleida, Lleida, Spain.; Faculty of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; Unitat de Suport a la Recerca Metropolitana Nord, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Mataró, Spain.; Primary Healthcare Palau-Solità i Plegamans, Gerència d'Àmbit d'Atenció Primària Metropolitana Nord, Institut Català de la Salut, Barcelona, Spain.; Unitat de Suport a la Recerca Metropolitana Nord, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Mataró, Spain.; DAP-Cat Group, Research Support Unit, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Barcelona, Spain.; Institute for Biomedical Research Dr. Pifarré Foundation IRB Lleida, University of Lleida and Primary Health Care Centre Tàrrega, Gerència d'Atenció Primaria, Institut Català de la Salut, Lleida, Spain.; DAP-Cat Group, Research Support Unit, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Barcelona, Spain.; Primary Health Care Centre Igualada Nord, Consorci Sanitari de l'Anoia, Igualada, Spain.; Unitat de Suport a la Recerca Metropolitana Nord, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Mataró, Spain.; Primary Healthcare Center Vall del Tenes, Gerència d'Àmbit d'Atenció Primària Metropolitana Nord, Institut Català de la Salut, Barcelona, Spain.; Unitat de Suport a la Recerca Metropolitana Nord, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Mataró, Spain.; Department of Medicine, Faculty of Medicine, Universitat de Girona, Girona, Spain.; Multidisciplinary Research Group in Health and Society (GREMSAS), Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAPJGol), Barcelona, Spain.; Bioinformatics and Biomedical Signals Laboratory (B2SLab), Institut de Recerca i Innovació en Salut (IRIS), Universitat Politècnica de Catalunya, Barcelona, Spain.; Networking Biomedical Research Centre in the Subject Area of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.; Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.; Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.; Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.; Centro de Investigación Biomédica en red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.; Institut d'Investigació Biomèdica Sant Pau (IR-Sant Pau), Barcelona, Spain.; Faculty of Medicine, University of Vic - Central University of Catalonia, Vic, Spain.
MeSH Terms:
Humans,
Diabetes Mellitus, Type 2,
Female,
Male,
Middle Aged,
Case-Control Studies,
Pregnenolone,
Biomarkers,
Guanine,
Metabolomics,
Incidence,
Aged,
Cohort Studies,
Adult
