Endothelial dysfunction in patients with type 2 diabetes and the effects of thiazolidinedione antidiabetic agents

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Abstract

Endothelial dysfunction is increasingly recognised as a key event in the pathogenesis of atherosclerosis, which occurs in association with insulin resistance early in the course of type 2 diabetes mellitus (T2DM). Thiazolidinediones (TZDs), such as rosiglitazone, are a class of oral antidiabetic agents that act primarily as insulin sensitisers, reducing insulin resistance with associated improvements in glycemic control. Available data indicate that thiozolidinediones also have beneficial effects on numerous markers of endothelial function and profound antiinflammatory activity, indicative of potential antiatherogenic activity. These effects may be of considerable clinical significance if sustained during long-term therapy, given the morbidity and mortality associated with atherosclerosis in T2DM patients.

Introduction

Diabetes mellitus comprises a group of diseases characterised by high levels of blood glucose resulting from defects in insulin secretion and insulin action (DeFronzo, Bonadonna, & Ferrannini, 1992). Diabetes is frequently associated with serious health complications and premature death. Risk factors for type 2 diabetes mellitus (T2DM) include increasing age, obesity, family history of diabetes, impaired glucose tolerance, and physical inactivity. Globally, there is an increasing prevalence of obesity combined with a sedentary lifestyle, and the incidence of T2DM is fast approaching epidemic proportions. Indeed, T2DM is currently estimated to affect 200 million people worldwide (Zimmet & McCarthy, 1995), with prevalence predicted to increase to 300 million by 2025 (De Courten, McCarty, & Zimmet, 1999).

Section snippets

Diabetes and coronary heart disease (CHD)

CHD is a major cause of morbidity and mortality in diabetes, with diabetic patients known to have a two- to fivefold increased risk of CHD Haffner et al., 1998, Manson et al., 1991. Patients with T2DM have been also shown to have as high a risk of myocardial infarction (MI) as nondiabetic patients who have suffered previous MT (Haffner et al., 1998). Overall, 80% of all deaths in patients with T2DM are due to cardiovascular complications Carr, 2001, National Diabetes Data Group, 1995.

The main

Thiazolidinediones (TZDs)

TZDs are a class of oral antidiabetic agents that act primarily as insulin sensitizers through actions at the peroxisome proliferator-activated receptor γ (PPARγ), enhancing the effects of endogenously secreted and exogenous insulin in the target tissues of the body, specifically skeletal muscle, liver, and fat, and thereby directly improving peripheral insulin resistance in the target tissues for insulin. PPARγ plays a regulatory role in the expression of genes involved in carbohydrate and

Evidence of effects related to PPARγ

Fig. 2 summarises the possible effects of TZDs, as PPARγ agonists, on markers of endothelial function. PPARγ is a ligand-activated nuclear receptor expressed in all major cell types found in atherosclerotic lesions: monocytes/macrophages, endothelial cells, and smooth muscle cells (Collins, Noh, Hsueh, & Law, 2001). PPARγ has been shown to be a novel regulator of gene expression of PAI-1 in endothelial cells (Marx, Bourcier, Sukhova, Libby, & Plutzky, 1999). The PPARγ agonists troglitazone and

Conclusions

Available data clearly indicate that treatment of T2DM with TZDs not only improves glycemic control and decreases insulin resistance but also improves many of the abnormalities of endothelial function associated with the metabolic syndrome of insulin resistance. While the exact relationship between insulin resistance and endothelial dysfunction remains to be clarified, evidence is increasing that insulin sensitisers such as rosiglitazone have profound antiinflammatory activity and beneficial

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