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.
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.
EBioMedicine. 2018 Nov;37:356-365. doi: 10.1016/j.ebiom.2018.10.056. Epub 2018 Nov 13.
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.
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.
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.
Our results reveal the existence of splicing machinery alterations that precede and predict T2DM development in patients with cardiovascular disease. FUND: ISCIII, MINECO, CIBERObn.
2 型糖尿病（T2DM）是一种发病率不断增加的主要健康问题，严重影响心血管疾病。由于 T2DM 与基因表达改变和异常剪接有关，我们假设剪接机制的失调可能先于、有助于和预测 T2DM 的发展。
我们使用了一个心血管疾病患者队列（CORDIOPREV 研究），这些患者在基线时（研究纳入时）没有 T2DM（n=215）。我们测定了所有在 5 年随访期间发生 T2DM 的患者（n=107 例 T2DM 事件）和 108 例随机选择的非 T2DM 患者（对照组）空腹和 4 小时餐后外周血单核细胞（PBMC）中选定剪接机制成分的表达。使用 T2DM 事件和对照患者的血清分析来自独立健康个体队列的对照 PBMC 中剪接机制表达的体外调节。
与非 T2DM 对照组相比，T2DM 事件患者空腹和 4 小时餐后 PBMC 中的关键剪接机制成分（如 RNU2、RNU4 或 RNU12）的表达明显改变。此外，与非 T2DM 对照组相比，T2DM 事件患者的血清体外处理健康个体的 PBMC 降低了在 T2DM 事件患者 PBMC 中下调的剪接机制元件的表达。最后，CORDIOPREV 患者 PBMC 中的空腹/餐后几种剪接机制成分的水平与 T2DM 的更高风险相关（优势比>4），并且可以准确预测（AUC>0.85）T2DM 的发展。
我们的结果揭示了在心血管疾病患者中，剪接机制改变先于和预测 T2DM 的发展。
ISCIII、MINECO、CIBERObn。
