Dietary Intervention Modulates the Expression of Splicing Machinery in Cardiovascular Patients at High Risk of Type 2 Diabetes Development: From the CORDIOPREV Study.

Mercedes Del Río-Moreno,Irene Roncero-Ramos,José López-Miranda,Justo P Castaño,Antonio Camargo,Oriol A Rangel-Zúñiga,Raúl M Luque,Juan F Alcalá-Diaz,Emilia Alors-Pérez,Manuel D Gahete

doi:10.3390/nu12113528

Abstract

Type-2 diabetes mellitus (T2DM) has become a major health problem worldwide. T2DM risk can be reduced with healthy dietary interventions, but the precise molecular underpinnings behind this association are still incompletely understood. We recently discovered that the expression profile of the splicing machinery is associated with the risk of T2DM development. Thus, the aim of this work was to evaluate the influence of 3-year dietary intervention in the expression pattern of the splicing machinery components in peripheral blood mononuclear cells (PBMCs) from patients within the CORDIOPREV study. Expression of splicing machinery components was determined in PBMCs, at baseline and after 3 years of follow-up, from all patients who developed T2DM (Incident-T2DM, n = 107) and 108 randomly selected non-T2DM subjects, who were randomly enrolled in two healthy dietary patterns (Mediterranean or low-fat diets). Dietary intervention modulated the expression of key splicing machinery components (i.e., up-regulation of SPFQ/RMB45/RNU6, etc., down-regulation of RNU2/SRSF6) after three years, independently of the type of healthy diet. Some of these changes (SPFQ/RMB45/SRSF6) were associated with key clinical features and were differentially induced in Incident-T2DM patients and non-T2DM subjects. This study reveals that splicing machinery can be modulated by long-term dietary intervention, and could become a valuable tool to screen the progression of T2DM.

Highlights

Type 2 diabetes mellitus (T2DM) has become a major global health problem in recent decades due to its rising incidence, prevalence, and its tight causal association with diverse comorbidities, Nutrients 2020, 12, 3528; doi:10.3390/nu12113528 www.mdpi.com/journal/nutrientsNutrients 2020, 12, 3528 including cardiovascular disease (CVD) [1,2]
The effect of dietary intervention on the expression pattern of splicing machinery components was evaluated in peripheral blood mononuclear cells (PBMCs) from 215 CVD patients at high risk of Type-2 diabetes mellitus (T2DM) development included in the CORDIOPREV study
Further analysis indicated that the increase in the expression of SPFQ during the 3 years of follow-up observed was inversely correlated with the evolution of the homeostatic model assessment-insulin resistance (HOMA-IR) and hepatic insulin resistance index (HIRI) indexes (Table 1), which decreased during the follow-up in the study population (Supplementary Table S1)

Summary

Introduction

Type 2 diabetes mellitus (T2DM) has become a major global health problem in recent decades due to its rising incidence, prevalence, and its tight causal association with diverse comorbidities, Nutrients 2020, 12, 3528; doi:10.3390/nu12113528 www.mdpi.com/journal/nutrientsNutrients 2020, 12, 3528 including cardiovascular disease (CVD) [1,2]. Prevention (CORDIOPREV) study, a prospective, randomized, controlled trial that includes CVD patients at high-risk of T2DM development [6], long-term consumption of a Med diet rich in olive oil and a LF diet have beneficial effects on the patients, improving insulin sensitivity and beta-cell function [7]. In this context, early identification of patients at higher risk of T2DM development is critical for prevention of new cardiovascular events [8,9]. In searching for novel associated molecular mechanisms and predictive markers, we recently discovered that the expression pattern of certain splicing machinery elements in the peripheral blood mononuclear cells (PBMCs) of patients is tightly associated with the risk of T2DM and could accurately predict T2DM development in those individuals from the CORDIOPREV study, outperforming the capacity of classical predictors of T2DM development, such as glycated hemoglobin (HbA1c) or predictive scores (FINDRISK) [10], two established strategies that have limitations and cannot precisely predict an individual’s risk of developing T2DM [11,12]

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