Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients
Introduction
In 1988, Reaven postulated that insulin resistance and its compensatory hyperinsulinemia predisposed patients to hypertension, hyperlipidemia, and diabetes and it was underlying cause of cardiovascular disease (CVD), termed as “syndrome X” [1]. Kaplan emphasized the importance of abdominal obesity in the concept of deadly quartet in 1988 [2] and de Fronzo further shed light to insulin resistance in the syndrome in 1991 [3]. The term “metabolic syndrome” has now taken hold in the medical literature and it has been defined principally by the World Health Organization (WHO) in 1998 [4], the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) in 2001 [5]. Because the criteria are ambiguous or incomplete and rationale for thresholds are ill-defined, the International Diabetes Federation (IDF) has proposed a new definition of metabolic syndrome based on recommendations from a consensus workshop of its Epidemiology Task Force in April 2005 (http://www.idf.org/home/) to unify the definitions. This new definition intends to be a better predictor of types 2 diabetes mellitus, stroke, and CVD than either of the earlier definitions, but no study has assessed its performance compared with other definitions.
In WHO criteria, microalbuminuria is one of the components of the metabolic syndrome and it was based on the evidence that microalbuminuria predict the risk for CVD in the patients with type 2 diabetes as well as without type 2 diabetes [6], [7], [8], [9]. Especially, data from HOPE, LIFE, and Framingham, clearly suggest that the minute amount of increase in albumin excretion, above 2 mg/g of creatinine, is significantly associated with cardiovascular death, myocardial infarction, stroke and elevation of blood pressure. It has been considered that an increase in urinary albumin excretions reflect the alterations of permeability of the glomerular capillaries and it makes sense to determine minute alterations of vascular permeability particularly in an early stage of systemic diseases. In such a notion, the analysis of various urinary protein markers possibly predicts the risk of CVD besides the evaluation of metabolic syndrome. Lipocalin-type prostaglandin D synthase/(β-trace) (L-PGDS) was originally found in the central nervous system, and it is now recognized as an enzyme synthesizing prostaglandin D2 (PGD2) and a secretory protein of the lipocalin superfamily [10], [11]. It is synthesized in choroid plexus or leptomeninges in the brain and secreted steadily through cerebrospinal fluid into circulating blood. L-PGDS in blood is filtered through glomerular basement membranes, and part of it is probably reabsorbed/metabolized in the proximal tubules. A report suggested urinary L-PGDS excretions behave as a marker of glomerular damage in an early stage of systemic diseases and they are useful to predict a forthcoming of urinary albumin excretions in type 2 diabetes [12], [13]. Thus, we speculate that increased urinary PGDS might be an earlier predictor for CVD.
Both WHO criteria and NCEP ATP-III criteria have been shown to be predictors of cardiovascular morbidity and mortality in general population as well as in patients with type 2 diabetes [14], [15], [16], [17], [18], [19], [20], [21], [22]. However, type 2 diabetes itself is high risk for CVD, it is still questionable for including diabetes patients into the category of metabolic syndrome. Here, we aim to investigate the association of metabolic syndrome, using the new IDF and WHO definition, with CVD risk of the in type 2 diabetes patients in a cross-sectional clinical study. Furthermore, we investigated whether the measurement of urinary proteins, like urinary albumin, type IV collagen, β2-microglobulin (β2MG), N-acetyl-β-d-glucosaminidase (NAG) and PGDS, in type 2 diabetes might be a better predictor of CVD.
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Subjects
Japanese type 2 diabetes patients (n = 233, men = 124, women = 109), regularly attending six participating hospitals in Okayama, were enrolled into current study with informed consents. The participants were recruited years 2000–2001, this time we analyzed the data. The exclusion criteria were a serum creatinine level above 1.5 mg/dL and urinary albumin/creatinine ratio (ACR) >300 mg/g Cr. Diabetes was defined according to WHO criteria and a previous history of diabetes (treated with insulin and/or oral
Characteristics of subjects with and without metabolic syndrome
The overall prevalence of metabolic syndrome is 31.3% (73 patients) in 233 patients with type 2 diabetes. Patients with metabolic syndrome associated with significantly higher body mass index (BMI), waist circumference, blood pressure, uric acid, serum total cholesterol and triglyceride levels and with significantly lower serum high-density lipoprotein (HDL) cholesterol levels (Table 1). There were no differences in fasting plasma glucose and HbA1c levels between subjects with and without
Discussion
Many reports documented that the patients with metabolic syndrome, as defined by two definitions (WHO and NCEP ATP-III), have higher prevalence of CVD and are at greater risk of developing it. In these studies, the CVD risk in patients with the syndrome ranged from 30 to 400% [15], [19], [20], [26], this variation may be due to the size of population studied, the definition of metabolic syndrome, and the length of follow-up. Some reports concluded that ATPIII definition is a slightly better
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research (C), Ministry of Education, Science and Culture, Japan (14571025 and 17590829) to J. Wada.
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