Review article
Thiazolidinediones—improving endothelial function and potential long-term benefits on cardiovascular disease in subjects with type 2 diabetes

https://doi.org/10.1016/j.jdiacomp.2006.10.009Get rights and content

Abstract

Endothelial dysfunction, which leads to impaired vasodilation, is an early event in the development of atherosclerosis. A number of mechanisms involving, for example, cell adhesion molecules, chemokines, and cytokines, contribute to this inflammatory disease, and insulin resistance plays a cardinal role in accelerating these processes. Hyperglycemia and other metabolic abnormalities that are commonly associated with insulin resistance also contribute to impaired endothelial function. In addition, the important role of the endothelium in damage repair following a cardiovascular event is emerging. The combination of proatherogenic factors in patients with type 2 diabetes results in blunted endothelial function and an increased risk of cardiovascular disease. Insulin-sensitizing agents such as thiazolidinediones have demonstrated a number of clinical benefits, including anti-inflammatory and antithrombotic properties, which may impact on the course of atherosclerosis. Recent studies have demonstrated that thiazolidinediones improve endothelial function in subjects with and without type 2 diabetes.

Introduction

Atherosclerotic cardiovascular disease (CVD) accounts for up to 75% of mortality in subjects with type 2 diabetes (Carr, 2001). The elevated risk of CVD in this population, combined with the poor prognosis for patients (Granger et al., 1993, Haffner et al., 1998), highlights the need for aggressive management of cardiovascular (CV) risk factors (Hu et al., 2002). Moreover, the common observation of vascular complications in newly diagnosed patients (UK Prospective Diabetes Study (UKPDS) Group, 1990, UK Prospective Diabetes Study (UKPDS) Group, 1998) indicates that CV damage is an early event during the development of type 2 diabetes. Atherosclerosis is an inflammatory disease that originates in endothelial dysfunction (Ross, 1999), markers of which have been observed in prediabetic individuals (Meigs, Hu, Rifai, & Manson, 2004). Insulin resistance, which underlies type 2 diabetes, is an independent risk factor for CVD (Bonora et al., 2002) and is closely associated with other metabolic abnormalities and oxidative and inflammatory stress that all play an important role in atherosclerotic disease (Dandona et al., 2004, Zimmet, 2002).

The link between chronic hyperglycemia and atherosclerosis has recently been demonstrated by analysis of data from the Atherosclerosis Risk in Communities Study, which identified a positive association between HbA1c levels and carotid intima-media thickness (IMT) in patients with type 2 diabetes (Selvin et al., 2005). Such intima-media thickening is common in individuals with type 2 diabetes, even in the absence of clinical coronary artery disease (Haffner et al., 2000). In addition, the Hoorn Study observed that type 2 diabetes was associated with impaired endothelium-dependent vasodilation and suggested that this could partially explain the increased risk of CVD in this population (Henry et al., 2004). Impaired endothelium-mediated vasodilation is related to increased reactive oxygen species (ROS) generation and inflammation. Obesity, hyperglycemia, and excessive macronutrient intake, which result in increased ROS generation and inflammation, are therefore associated with impaired endothelial function. These findings underscore the importance of good glycemic control and effective management of other metabolic factors such as plasma free fatty acids (FFAs) for patients with type 2 diabetes and obesity (Dandona et al., 2004).

Abnormalities in endothelial function also play an important role in promoting the development of microvascular disease in subjects with type 2 diabetes. This review, however, focuses on the contribution of insulin resistance to endothelial dysfunction in relation to atherosclerosis. The potential for the insulin-sensitizing thiazolidinediones to improve endothelial function, oxidative stress, and inflammation and impact on the course of atherosclerotic CVD is also discussed.

Section snippets

Function and regulation of the endothelium

The vascular endothelium, which is a single layer of cells within the inner lining of blood vessels, provides a dynamic interface and signaling channel between circulating plasma and vascular smooth muscle cells (VSMCs). The integrity of the endothelium is crucial to maintaining CV health. The healthy endothelium releases a range of vasoactive substances, which preserve a balance between vasodilator and vasoconstrictor forces, thus sustaining vascular tone and preserving luminal diameter, to

Measuring endothelial function

The vasodilatory response to either a pharmacological or mechanical stimulus is the most widely used measurement of endothelial function. Stimulation of ECs to provoke endothelium-dependent release of NO, and thus endothelium-dependent vasodilation, is performed by the use of shear stress or by agonists such as acetylcholine (ACh) and bradykinin. Endothelium-independent vasodilation is induced by agents that provide a source of NO and thus act directly on VSMCs, for example, sodium

Early events following endothelial dysfunction

Loss of vasodilatory response is a sign of endothelial dysfunction, but what are the processes that precipitate endothelial damage? A number of mechanisms are involved, some of which are outlined in Fig. 2. It is now widely recognized that inflammatory mechanisms are responsible for the events that signal the earliest changes in endothelial integrity. The inflammatory response is triggered by a number of factors, including dyslipidemia, shear stress, and chronic hypertension, while, in turn,

The role of the endothelium in damage repair

Endothelial cells have an important role to play in repairing damage after plaque rupture, which can lead to thrombus formation and, in the absence of adequate fibrinolysis, MI (Ross, 1999). Raised levels of the predominant inhibitor of fibrinolysis, PAI-1, which is released from the endothelium, is a sign of impaired endothelial response in insulin-resistant states (Kohler & Grant, 2000). IRAS demonstrated clearly that a stepwise increase in PAI-1 levels occurs through the progression from

The impact of thiazolidinediones on mechanisms of endothelial dysfunction

Many studies have now shown the benefits of thiazolidinediones on CV risk factors, including hypertension (Gerber et al., 2003, Hirose et al., 2002, Sarafidis et al., 2004, St John Sutton et al., 2002, Yosefy et al., 2004) and dyslipidemia (Freed et al., 2002, Parhofer et al., 2005), and in reducing microalbuminuria (Bakris et al., 2003, Nakamura et al., 2000, Nakamura et al., 2001). As activators of peroxisome proliferator-activated receptor γ (PPARγ) (Smith, 2002), thiazolidinediones may

Conclusions

Major progress has been made in improving the prognosis for individuals with CVD, and current research continues to unravel the complex mechanisms underlying endothelial dysfunction, monocyte to macrophage to foam cell formation, and atherosclerosis. The detrimental effects of insulin resistance, its relationship with inflammatory mediators and associated comorbidities on many of the intricate interrelationships governing endothelial integrity offer some explanations for the accelerated

Acknowledgments

Development of this manuscript was supported by GlaxoSmithKline plc. The authors wish to acknowledge the editorial assistance of Ann Parkin, PhD, in the development of this manuscript. P.D. is supported by NIDDK Grant R01-DK069805-02, GlaxoSmithKline, Takeda, Sanofi-Aventis, Solvay, Sankyo, and Abbott Pharmaceuticals.

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