The role of fibrinolysis in the development of prediabetes-associated coronary heart disease: a focus on the plasminogen activator inhibitor -1 and its potential use as a predictive marker in diet-induced prediabetes

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular diseases (CVD). However, the onset of T2DM is preceded by prediabetes, which is associated with sedentary lifestyles and consumption of high-calorie diets. Studies have shown that impaired glucose homeostasis creates an environment for developing T2DM-related complications. Using a high-fat-high-carbohydrate diet-induced prediabetes animal model, this study sought to assess the risk factors of coronary heart disease (CHD) in diet-induced prediabetes and identify biomarkers that can be used for early detection of prediabetes-associated CHD.

Methods: Male Sprague Dawley rats were randomly grouped into two groups and were kept on different diets for 20 weeks (n = 6 in each group). One group was fed standard rat chow to serve as a non-prediabetes (NPD) control, while the other group consumed a high-fat-high-carbohydrate diet to induce prediabetes (PD). Post induction, the homeostasis model assessment- insulin resistance (HOMA-IR) and glycated haemoglobin (HbA1c) was used to test for insulin resistance. Body weight, mean arterial pressure (MAP), resting heart rate (HR), inflammatory cytokines (C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6)), lipids (total cholesterol (TC), triglyceride (TG), lipoproteins (HDL, LDL, VLDL)), endothelial function (endothelial nitric oxide (eNOS), endothelin -1 (ET-1)), fibrinolysis (plasminogen activator inhibitor-1 (PAI-1)) were all measured to assess the risk of CHD. All data were expressed as means ± S.E.M. Statistical comparisons were performed with Graph Pad. Instat Software using Student's two-sided t-test. The Pearson correlation coefficient and linear regression were calculated to assess the association. The value of p < 0.05 was considered statistically significant.

Results: There was significant insulin resistance accompanied by significantly increased HbA1c and body weight in PD compared to NPD. Simultaneously, there was a significant increase in inflammatory cytokines in PD compared to NPD. This was accompanied by significantly increased TG and VLDL and endothelial dysfunction in PD. The association between HOMA-IR and PAI-1 was insignificantly positive in NPD, whereas a significantly strong positive association was observed in PD.

Conclusion: There is a positive correlation between insulin resistance and PAI-1 during prediabetes; therefore, suggesting that prediabetes increases the risk of developing vascular thrombosis. The current therefore study warrants further investigation on PAI-1 and other markers of fibrinolysis for the early detection of thrombosis and risk of CHD in prediabetes.

Keywords: C-reactive protein; biomarker; cardiovascular diseases; endothelin-1; high-fat-high-carbohydrate diet; plasminogen activator inhibitor-1; prediabetes.