Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes

Abstract

Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n ‫؍‬ 144) had higher baseline levels of fibrinogen (mean ؎ SD; 287. ). It has been hypothesized that atherosclerotic cardiovascular disease and type 2 diabetes arise from a "common soil" (2,3), and chronic inflammation may be such a candidate (4,5). Inflammatory markers, such as high white cell count, high fibrinogen, or low albumin (6), and markers of hemostasis, such as factor VIII (7), have been related to the development of type 2 diabetes. Adipose body mass may be an important mediator to explain these relations (6,7), but pathophysiological mechanisms remain elusive, and no data on the role of insulin resistance are available. This is of particular interest because decreased insulin sensitivity has been linked to incident type 2 diabetes (8), as well as increased levels of inflammatory proteins (9,10) and markers of hemostasis (11,12) and fibrinolysis (11,13).In the present study, we investigated the relation of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) to incident type 2 diabetes during a 5-year period in the Insulin Resistance Atherosclerosis Study (IRAS). Furthermore, we sought to clarify the role of insulin resistance, as directly measured using a frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODSThe Insulin Resistance Atherosclerosis Study (IRAS) is a multicenter, epidemiological study aiming to explore relationships among insulin resistance, cardiovascular risk factors, and disease across different ethnic groups and varying states of glucose tolerance. A full description of the design and methods of the IRAS has been published previously (14). The IRAS protocol was approved by local institutional review committees, and all subjects gave informed consent.A total of 1,625 individuals participated in the IRAS. This report includes data on 1,047 subjects, who were nondiabetic at the baseline examination and in whom CRP, PAI-1, and fibrinogen were measured. Subjects were investigated twice following the same protocol. The mean follow-up duration was 5.2 years (range 4.5-6.6). Each of the two IRAS examinations required two visits. Patients were asked before each visit to fast for 12 h, to abstain from heavy exercise and alcohol for 24 h, and to refrain from smoking on the morning of the examination. Race and ethnicity were assessed by self-report. Family history of type 2 diabetes and physical activity were assessed using standard interviewing procedures. A positive family history of diabetes was d...

Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome

“…4 However, prospective studies have shown that PAI-1 is a predictor for future cardiovascular events 28 and the onset of type 2 diabetes. 29 In contrast to hsCRP, the measurement of PAI-1 antigen or activity in routine clinical practice is limited by practical considerations such as the cost and standardization of blood sampling and assays, 26 making it difficult to define a cut point for abnormal PAI-1 values as a clinical criterion for the metabolic syndrome. However, the measurement of PAI-1 could provide additional information on the risk of the individual patient for future cardiovascular events and to decide who will benefit most from intensive lifestyle treatment.…”

CRP reduction following gastric bypass surgery is most pronounced in insulin-sensitive subjects

“…7,21 The levels correlate positively with body fat in nondiabetic Pima Indians 22 and are high in people with type 2 diabetes. [23][24][25] In a recent study of the polycystic ovary syndrome, obesity was reported to be the major determinant in driving the production of markers CRP, IL-6, and tumour necrosis factor. 9 Others found that CRP, in addition to BMI, 26 also correlated with the metabolic syndrome as indicated by insulin resistance, obesity, hypertension, impaired glucose tolerance, low HDL-cholesterol and hypertriglyceridaemia.…”

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…Indeed, high levels of many inflammatory factors at baseline in diverse human populations are correlated with incident T2DM, regardless of the initial degree of insulin resistance and obesity. Prospective studies have identified white blood cell count [12,15], pro-inflammatory cytokines [16], chemokines [17], and other several indirect markers of inflammation such as fibrinogen, sialic acid and PAI-1 [15,18] as predictors of T2DM. In contrast to all these inflammatory biomarkers, CRP measurement is less expensive, standardized and widely available.…”