On endothelial function in type 2 diabetic patients with coronary artery disease

Abstract

Patients with type 2 diabetes have a poor outcome suffering a myocardial infarction (MI). Endothelial dysfunction may play a role in this poor prognosis. In type 2 diabetes, endothelial dysfunction is a salient feature coexisting with obesity and insulin resistance and may be linked by the same pathophysiology, i.e. low-grade inflammation. The aim of this work was to investigate endothelial function, i.e. flow-mediated vasodilation (FMD) and nitroglycerin induced vasodilation (NTG), in type 2 diabetic patients suffering a recent MI, in different working models.

Study I: In this prospective cohort study, we investigated temporal changes in endothelial function and inflammatory activity (C-reactive protein [CRP] and adiponectin) in type 2 diabetic and nondiabetic patients suffering an MI. Type 2 diabetic patients demonstrated a persistent endothelial dysfunction, which coincided with a persistent low-grade inflammation as reflected by elevated CRP levels. Changes in CRP negatively correlated with changes in FMD. Adiponectin levels were also lower in type 2 diabetic patients but showed no correlation to endothelial function.

Study II: This cross-sectional study comprised 20 type 2 diabetic and 20 non-diabetic patients with a recent MI. We investigated the association between lipids, CRP, interleukin-6 (IL-6), tumor necrosis factor-a (TNF-alpha), insulin sensitivity (SI) and adipokines (adiponectin and resistin) and endothelial function. FMD and NTG were both impaired in type 2 diabetic patients concomitant with increased TNF-alpha and IL-6 levels and decreased levels of adiponectin. TNF-alpha concentrations and brachial artery diameter were negatively, whereas SI was positively associated with FMD.

Study III: This was a cross-over study, where we compared the acute effects of the endothelial nitric oxide synthase cofactor, tetrahydrobiopterin (BH4), between groups of 12 type 2 diabetic and 10 nondiabetic patients with a recent MI. Subjects were tested twice, one week apart, regarding FMD/NTG and SI during infusion of BH4 or placebo. BH4 improved glucose disposal in type 2 diabetic patients, without any effects in other groups. This beneficial effect of BH4 occurred without any discernable changes in FMD.

Study IV: Twenty-two male subjects, of whom 12 were type 2 diabetic patients with a recent MI and the remaining 10 were unmatched healthy subjects, took part in this randomized cross-over study. Subjects were tested twice, one week apart, regarding FMD/NTG and SI during short-term infusion of the emerging antidiabetic drug glucagon-like peptide- 1 (GLP-1) or placebo. Also, we investigated whether GLP-1 receptors are expressed on endothelial cells. GLP-1 improved FMD in type 2 diabetic patients, without any effects in healthy subjects and the receptor for GLP-1 on endothelial cells was demonstrated. No effects on SI were noted after short-term GLP-1 infusion.

Study V: This study was conducted to investigate whether GLP-1 directly relaxes conduit vessels. It was found that GLP-1 relaxed femoral artery rings from male Sprague-Dawley rats ex vivo in a dose-response manner, via an endothelium-independent mechanism. The GLP-1 relaxation effect was completely attenuated by the specific GLP-1 receptor antagonist exendin(9-39), indicating the requirement for specific GLP-1 receptor occupancy.

Conclusions: In type 2 diabetic patients with a recent MI, prolonged endothelial dysfunction, proinflammatory activity and low plasma adiponectin concentrations coexist. FMD seems to be inversely associated with CRP and TNF-alpha and to some extent SI. BH4 enhances glucose disposal in type 2 diabetic patients, which may be due to a capillary recruitment mechanism. GLP-1 ameliorates endothelial dysfunction in type 2 diabetic patients with a recent MI and dose-dependently relaxes rat conduit vessels ex vivo. Improvement of insulin resistance and endothelial dysfunction may translate into beneficial effects on many cardiovascular risk factors and may thus have important clinical implications in preventing macroangiopathy in type 2 diabetes.