Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients

https://doi.org/10.1016/j.diabres.2006.09.004Get rights and content

Abstract

Background

The presence of metabolic syndrome has been shown to be predictors of cardiovascular morbidity and mortality in patients with type 2 diabetes. In a cross-sectional clinical study, we investigated the association of metabolic syndrome with asymptomatic lacunar strokes and cardiovascular disease (CVD) and we compared its significance with urinary protein markers.

Methods

We studied Japanese type 2 diabetes patients (n = 233, men = 124, women = 109). The diagnosis of metabolic syndrome was made according to WHO and International Diabetes Federation (IDF) criteria. Cardiovascular events were recorded and asymptomatic lacunar lesions were evaluated with magnetic resonance imaging (MRI). We also measured urinary levels of albumin, type IV collagen, β2-microglobulin (β2MG), N-acetyl-β-d-glucosaminidase (NAG) and lipocalin-type prostaglandin D synthase (PGDS).

Results

The prevalence of metabolic syndrome is 31.3% (IDF) and 52% (WHO) in 233 patients and microalbuminuria was present in 62 subjects (26.6%). Metabolic syndrome (WHO) significantly associated with asymptomatic lacunar lesions (p = 0.035, OR = 2.854, CI 1.075–7.579), while metabolic syndrome (IDF) or urinary markers failed to associate with presence of asymptomatic lacunar lesions. The presence of metabolic syndrome or microalbuminuria did not show significant association with CVD; however, the elevation of β2MG, NAG and PGDS showed significant association with CVD. By a logistic regression analysis using urinary proteins as independent variables, the presence of higher PGDS excretion independently associated with history of CVD (p = 0.025, OR = 3.847, CI 1.180–12.545).

Conclusions

In type 2 diabetes patients, the elevation of urinary PGDS secretion closely associated with cardiovascular events and may be a supplemental or additional marker to the criteria of metabolic syndrome.

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.

Section snippets

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.

References (38)

  • Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection,...
  • H.C. Gerstein et al.

    Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals

    JAMA

    (2001)
  • H.L. Hillege et al.

    Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population

    Circulation

    (2002)
  • K. Borch-Johnsen et al.

    Urinary albumin excretion. An independent predictor of ischemic heart disease

    Arteriosc. Thromb. Vasc. Biol.

    (1999)
  • M. Roest et al.

    Excessive urinary albumin levels are associated with future cardiovascular mortality in postmenopausal women

    Circulation

    (2001)
  • N. Hirawa et al.

    Urinary prostaglandin D synthase (beta-trace) excretion increases in the early stage of diabetes mellitus

    Nephron

    (2001)
  • K. Hamano et al.

    Blood sugar control reverses the increase in urinary excretion of prostaglandin D synthase in diabetic patients

    Nephron

    (2002)
  • J.B. Meigs et al.

    Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies

    Diabetes

    (2003)
  • B. Isomaa et al.

    Cardiovascular morbidity and mortality associated with the metabolic syndrome

    Diab. Care

    (2001)
  • Cited by (0)

    View full text