Endocrine Abstracts

Development of type-2 diabetes (T2D) is critically affected by the loss of phenotypic flexibility. There is emerging evidence suggesting that, under adverse metabolic conditions, alternative mRNA splicing is markedly dysregulated at different levels. For this reason, we hypothesized that such dysregulation could contribute to loss of phenotypic flexibility. Consequently, we aimed to explore whether changes in the splicing machinery in peripheral blood mononuclear cells (PBMCs) may serve as early indicator of T2D development, and if dietary intervention could modulate the expression of these components in order to reduce the risk of T2D. Thus, the expression pattern of selected components of the major (n=13) and minor (n=4) spliceosomes, and splicing factors (SFs; n=28) was determined in PBMCs, isolated from basal and 4 h postprandial blood, from non-T2D patients with high-risk to develop T2D (individuals with cardiovascular event included in the CORDIOPREV study). Specifically, 107 patients developed T2D in a median follow-up of 5 years (incident-T2D) and 108 non-T2D patients were randomly selected as controls. This analysis indicated that PBMCs of incident-T2DM patients exhibited lower levels of certain spliceosome components and SFs compared to non-T2D controls, which were significantly associated to the risk of T2D development. Altogether, these results showed that incident-T2D patients had an altered expression pattern at the inclusion in the study, suggesting a potential predictive value for T2D development. As these patients were randomly assigned to one of two healthy diets (Mediterranean and low-fat diets) in order to prevent T2D development, we also analyzed the expression of the splicing machinery components in the PBMCs from basal and 4 h postprandial blood from incident-T2DM and non-T2D patients after 3 years of follow-up under the two diet conditions. Results revealed that the expression of a reduced number of spliceosome components and SFs may be influenced by diet in a different manner in incicent-T2D and non-T2D subjects, as several spliceosomal components (e.g. SPFQ and SKIP) showed an alteration in their expression level in incident-T2D patients under the different diet conditions. Interestingly, changes were most remarkable during the post-prandial phase (e.g. RNU4 and RNU11) and associated to clinical parameters. Taken together, these data revealed the existence of pre-T2D development-associated spliceosome alterations that could be modulated by the diet and could be associated to the loss of phenotypic flexibility, suggesting that these changes might help to predict the development of T2D in high-risk patients.