Guanine and pregnenolone sulfate are associated with incident type 2 diabetes in two independent populations

Abstract

Type 2 diabetes (T2D) is increasing its burden worldwide; therefore, research focused on its prediction and prevention is essential.

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.

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.

We identified significant associations of guanine, pregnenolone sulfate, and citrulline with incident T2D.

The author(s) declare that financial support was received for the research and/or publication of this article. This work was funded by Spanish Ministry of Health, Instituto de Salud Carlos III (Madrid, Spain) grants PI15/0625 (to DM and EC), PI18/0328 (to DM). This work was supported by the Grant PID2021-122952OB-I00 funded by AEI 10.13039/501100011033 and by ERDF A way of making Europe (to APL). The authors acknowledge the financial support provided through the grants PI20/00312 (GL) and PI20/00338 and PI23/01133 (to JV), funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, as well as through the project “XII Ayudas SED a Proyectos de Investigación Clı́nica en Diabetes dirigidos por jóvenes investigadores,” funded by the Sociedad Española de Diabetes (GL). This research was supported by Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM -CB15/00071) and Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), initiatives of Instituto de Investigación Carlos III (ISCIII); ISCIII (grant AC22/ 00035) (to APL); and the CERCA Programme/Generalitat de Catalunya. Additional financial support was provided by the CIBER-Consorcio Centro de Investigación Biomédica en Red (CB07708/0012), ISCIII, Ministerio de Ciencia e Innovación. JV also acknowledge acknowledges support from the Agency for Management of University Research Grants of the Generalitat de Catalunya (2021 SGR 00829). B2SLab is certified as 2021 SGR 01052. Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau is accredited by the Generalitat de Catalunya as Centre de Recerca de Catalunya (CERCA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.