Endocrine Abstracts (2017) 49 EP472 | DOI: 10.1530/endoabs.49.EP472

Dysregulation of the splicing machinery could represent an early, predictive event in the development of type 2 diabetes

Emilia Alors-Pérez1,2,3, Mercedes del Río-Moreno1,2,3, Sergio Pedraza-Arévalo1,2,3, Antonio Camargo4, Javier Delgado-Lista4, José López-Miranda4, Manuel D Gahete1,2,3, Justo P Castaño1,2,3 & Raúl M Luque1,2,3

1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; 2Reina Sofia University Hospital (HURS), Cordoba, Spain; 3Department of Cell Biology, Physiology and Immunology, University of Cordoba (UCO); CIBER Physi, Cordoba, Spain; 4Lipids and Atherosclerosis Unit, IMIBIC, HURS, UCO and CIBERobn, Cordoba, Spain.

Metabolic syndrome (MetS) and type-2 diabetes (T2D) development is critically affected by the loss of phenotypic flexibility (i.e. the difficulty to cope with stressors to maintain metabolic homeostasis). Thus, it is essential to identify key modifiers of phenotypic plasticity that define individual susceptibility to develop T2D. Particularly, there is emerging evidence that alternative mRNA splicing is dysregulated under adverse metabolic-conditions, such as T2D, in several tissues. Therefore, we hypothesized that, as gene expression pattern in PBMCs commonly reflects disease-characteristic expression patterns, changes in spliceosome components of PBMCs may serve as early indicator of MetS/T2D development. To explore this, the expression of selected components of the major (n=13) and minor spliceosome (n=4), and associated splicing factors (SFs; n=28) was evaluated in PBMCs of individuals with high risk to develop T2D due to a previously occurred cardiovascular event (CORDIOPREV study). Specifically, 87 patients that developed T2D during the first 3-year follow-up (43 during the first, 23 during the second and 21 during the third year) and 87 non-T2D matched controls were selected. PBMCs were isolated from basal and post-prandial blood at the inclusion in the study. Results revealed that the basal expression of certain splicing-machinery components was altered in PBMCs from patients who developed T2D (e.g. SRSF5, U2AF1) compared to controls, especially on those patients that developed T2D in a short-term (first year of study). The most remarkable changes were observed during the post-prandial response wherein expression of several SFs (e. g. PTB, Tra2beta) was drastically induced in T2D-developing individuals compared to controls, which might suggest that the alteration of these SFs precedes the development of T2D. Taken together, our results reveal the existence of pre-T2D development-associated spliceosome alterations, which could be related to the loss of phenotypic flexibility, and could help to predict development of T2D in high-risk patients.