Metabolic Syndrome Accompanied by Hypercholesterolemia Is Strongly Associated With Proinflammatory State and Impairment of Fibrinolysis in Patients With Type 2 Diabetes

Abstract

OBJECTIVE -To determine whether plasma concentrations of thrombin-activatable fibrinolysis inhibitor (TAFI) in patients with type 2 diabetes were associated with components of metabolic syndrome (MS), including high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor (PAI)-1, and LDL cholesterol.RESEARCH DESIGN AND METHODS -We studied 136 consecutive patients with type 2 diabetes. Diagnosis of MS was diagnosed by current criteria. Hypercholesterolemia (HC) was defined as serum LDL cholesterol Ͼ140 mg/dl (3.6 mmol/l) or treatment with a statin. For comparisons, diabetic patients were divided into four groups: those with no MS and no HC (n ϭ 38), with MS but not HC (n ϭ 39), with no MS but with HC (n ϭ 26), and with both MS and HC (n ϭ 33).RESULTS -Considering all patients with type 2 diabetes, plasma PAI-1 was strongly associated with MS components such as BMI, triglyceride, alanine aminotransferase, a homeostasis model assessment of insulin resistance, and hs-CRP. Plasma TAFI only correlated positively and independently with LDL cholesterol. Plasma concentrations of plasmin-␣2-antiplasmin complex (PAP), a measure of fibrinolytic activity in blood, showed a significant negative correlation with plasma PAI-1 but not TAFI. Diabetic patients with both MS and HC had the highest serum hs-CRP concentrations and the lowest plasma PAP concentrations.CONCLUSIONS -LDL cholesterol is a main determinant of plasma TAFI in patients with type 2 diabetes. Coexistence of MS and HC synergistically accelerates inflammation and impairment of fibrinolysis via elevated concentrations of both TAFI and PAI-1, which inhibit fibrinolysis. Diabetes Care 28:2211-2216, 2005M etabolic syndrome (MS), also known as insulin resistance syndrome, is defined by the clustering of several cardiovascular risk factors in an individual patient, including impaired glucose tolerance (diabetes), hypertension, dyslipidemia, and visceral obesity (1,2). Several studies have demonstrated that this syndrome strongly predicts cardiovascular disease (CVD), especially coronary heart disease (3,4), independently of LDL cholesterol. Recently, a close association of MS with hemostatic abnormalities has been reported. Among hemostatic abnormalities, an increase in plasma plasminogen activator inhibitor (PAI)-1, a strong inhibitor of fibrinolysis, is considered a core feature of MS (5). High plasma PAI-1 concentrations may be associated with thrombus formation, causing cardiovascular events (6).A new inhibitor of fibrinolysis has been recently identified in plasma. As this protein is activated by thrombin and then downregulates fibrinolysis, it has been named thrombin-activatable fibrinolysis inhibitor (TAFI) (7). TAFI proved to be identical with plasma procarboxypeptidase B, U, or R (8). TAFI removes COOHterminal lysine or arginine residues from partially degraded fibrin, decreasing plasminogen binding to the fibrin surface (9). Since TAFI is associated with coagulation/ fibrinolysis and inflammation, plasma TAFI may participate in arterial thromb...

Increased concentration of plasminogen activator inhibitor-1 and fibrinogen in individuals with metabolic syndrome

“…MS subjects in our study presented similar plasma levels of PAI-1 to those found in other studies: 42-50 ng/ml in subjects 30-75 years of age with MS (29)(30)(31). On the other hand, similar to our study, Pankow et al (32) found elevated levels of PAI-1 in men (33.2±38.9 ng/ml) compared to women (24.2±34.8 ng/ml) with MS, 40-69 years of age.…”

Elevated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Antigen Levels in Overt and Subclinical Hypothyroid Patients Were Reduced by Levothyroxine Replacement

“…Depletion of thyroid hormones leads to a reduced number of LDL receptors in the liver and to decreased biliary excretion of cholesterol resulting in elevated serum LDL. The relationship between LDL cholesterol and TAFI antigen levels have been reported in several studies [30][31][32]. Aso et al [32] found that serum LDL cholesterol is an independent predictor of plasma TAFI levels in type 2 diabetes.…”

Serum Proteomic Signature of Human Chagasic Patients for the Identification of Novel Potential Protein Biomarkers of Disease

“…A deficiency of, as well as up-regulation of, PLG and F2 beyond physiological levels can lead to multiple pathological outcomes, including thrombosis caused by partial or inadequate degradation of blood clots, defective wound healing, and excessive bleeding (55)(56)(57). Plasmin is postulated to influence the progression of cardiovascular diseases through activation of collagenases and matrix metalloproteinases and resultant degradation of matrix proteins (58) and has also been implicated in metabolic syndrome (59). PLG, F2, and their receptors are also closely linked to regulation of cardiovascular inflammatory responses and have been suggested by others to influence cell migration through regulation of growth factor and chemokine pathways and acute phase response signaling through activation of C3 component of complement system (60).…”