Changes in Splicing Machinery Components Influence, Precede, and Early Predict the Development of Type 2 Diabetes: From the CORDIOPREV StudyResearch in context
Manuel D. Gahete,
Mercedes del Rio-Moreno,
Antonio Camargo,
Juan F. Alcala-Diaz,
Emilia Alors-Perez,
Javier Delgado-Lista,
Oscar Reyes,
Sebastian Ventura,
Pablo Perez-Martínez,
Justo P. Castaño,
José Lopez-Miranda,
Raul M. Luque
Affiliations
Manuel D. Gahete
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.
Mercedes del Rio-Moreno
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.
Antonio Camargo
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Lipid and Atherosclerosis Unit, Department of Medicine, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.
Juan F. Alcala-Diaz
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Lipid and Atherosclerosis Unit, Department of Medicine, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.
Emilia Alors-Perez
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.
Javier Delgado-Lista
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Lipid and Atherosclerosis Unit, Department of Medicine, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.
Oscar Reyes
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Department of Computer Sciences, University of Cordoba, Córdoba, Spain
Sebastian Ventura
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Department of Computer Sciences, University of Cordoba, Córdoba, Spain
Pablo Perez-Martínez
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Lipid and Atherosclerosis Unit, Department of Medicine, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.
Justo P. Castaño
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.
José Lopez-Miranda
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Lipid and Atherosclerosis Unit, Department of Medicine, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.
Raul M. Luque
Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.; Universidad de Córdoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain.; Corresponding author at: Lipid and Atherosclerosis Unit, Department of Medicine, Reina Sofia University Hospital, University of Córdoba, Córdoba 14004, Spain.
Background: Type-2 diabetes mellitus (T2DM) is a major health problem with increasing incidence, which severely impacts cardiovascular disease. Because T2DM is associated with altered gene expression and aberrant splicing, we hypothesized that dysregulations in splicing machinery could precede, contribute to, and predict T2DM development. Methods: A cohort of patients with cardiovascular disease (CORDIOPREV study) and without T2DM at baseline (at the inclusion of the study) was used (n = 215). We determined the expression of selected splicing machinery components in fasting and 4 h-postprandial peripheral blood mononuclear cells (PBMCs, obtained at baseline) from all the patients who developed T2DM during 5-years of follow-up (n = 107 incident-T2DM cases) and 108 randomly selected non-T2DM patients (controls). Serum from incident-T2DM and control patients was used to analyze in vitro the modulation of splicing machinery expression in control PBMCs from an independent cohort of healthy subjects. Findings: Expression of key splicing machinery components (e.g. RNU2, RNU4 or RNU12) from fasting and 4 h-postprandial PBMCs of incident-T2DM patients was markedly altered compared to non-T2DM controls. Moreover, in vitro treatment of healthy individuals PBMCs with serum from incident-T2DM patients (compared to non-T2DM controls) reduced the expression of splicing machinery elements found down-regulated in incident-T2DM patients PBMCs. Finally, fasting/postprandial levels of several splicing machinery components in the PBMCs of CORDIOPREV patients were associated to higher risk of T2DM (Odds Ratio > 4) and could accurately predict (AUC > 0.85) T2DM development. Interpretation: Our results reveal the existence of splicing machinery alterations that precede and predict T2DM development in patients with cardiovascular disease. Fund: ISCIII, MINECO, CIBERObn. Keywords: Peripheral blood mononuclear cells (PBMCs), Postprandial state, Spliceosome, OGTT, RNUs
