Endothelial function measures as predictors of diabetes or in prediabetes

There is a wealth of data suggesting a potential role for endothelial dysfunction in insulin resistance (Fonseca and Jawa, 2005). Although the direction of causality remains somewhat debated, circulating elevations in several endothelial-derived factors, cell adhesion molecules and t-PA, have been shown to predict risk for type 2 diabetes independently of other predictors (Meigs etal., 2006). Similar results have been seen with physiological tests of endothelial function. For example, Steinberg etal. (1996) showed that severely obese (mean body mass index = 34kg/m2) insulin-resistant individuals with normal glucose tolerance have the same degree of impairment in blood flow and vascular reactivity as those people with established type 2 diabetes. Similarly, when Caballero etal. examined endothelial function and vascular reactivity in two groups at risk for developing type 2 diabetes, subjects with impaired glucose tolerance and subjects with normal glucose tolerance but with a parental history of type 2 diabetes, they noted that both micro- and macrovascular reactivities were reduced in these two groups compared with healthy controls but were at a better level than in those with type 2 diabetes (Caballero etal., 1999) (Figure 2.4). These findings suggest that vascular dysfunction may be an early feature of the insulin resistance syndrome.

Figure 2.4 Impaired endothelium-dependent vasodilation in people at risk for type 2 diabetes. The brachial artery diameter change in response to reactive hyperaemia also known as flow-mediated dilation (endothelium-dependent vasodilation), is reduced in relatives of type 2 diabetic patients (Relatives), subjects with impaired glucose tolerance (IGT), and type 2 diabetic patients compared with healthy controls. Results are presented as mean percentage increase in diameter over baseline. *P < 0.05 vs. control; **one or both parents with diabetes. Reproduced with permission from Caballero AE (2003). Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obesity Research 11: 1278-89.

Figure 2.4 Impaired endothelium-dependent vasodilation in people at risk for type 2 diabetes. The brachial artery diameter change in response to reactive hyperaemia also known as flow-mediated dilation (endothelium-dependent vasodilation), is reduced in relatives of type 2 diabetic patients (Relatives), subjects with impaired glucose tolerance (IGT), and type 2 diabetic patients compared with healthy controls. Results are presented as mean percentage increase in diameter over baseline. *P < 0.05 vs. control; **one or both parents with diabetes. Reproduced with permission from Caballero AE (2003). Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obesity Research 11: 1278-89.

Endothelial dysfunction in diabetes

There is now ample evidence from studies employing a variety of techniques in patients with type 2 diabetes for vascular endothelial dysfunction and impaired arterial stiffness at several sites including coronary vessels, brachial arteries and subcutaneous vessels (Tooke and Goh, 1999; Hink etal., 2001). Many aspects of the insulin resistance syndrome may contribute to this dysfunction in patients with diabetes, including elevations in FFAs, characteristic lipid changes, obesity and hypertension, as well as the low-grade inflammation. Additionally, raised glucose concentrations can further damage vascular function. Finally, there is recent evidence that although insulin itself can stimulate both vasoconstrictor and vasodilator influences on the endothelium, the latter effects are likely diminished by factors common in diabetic individuals (Muis etal., 2005) - discussed in greater detail below. It is clear that multiple risk factor pathways in diabetes adversely influence endothelial function, an observation once again emphasising multiple linkages between risk factor pathways.

Microalbuminuria as a clinical marker of endothelial dysfunction in diabetes?

There is considerable evidence to suggest that the presence of microalbuminuria signals a greater risk of CVD events in patients with and without diabetes. Microalbuminuria is defined as low levels of urinary albumin excretion of 30-300 mg/day.

Microalbuminuria is highly prevalent; in hypertensive and diabetic populations, its prevalence varies from 10 to 40%. It is interesting that microalbuminuria also is found frequently in seemingly healthy individuals (5-7%). Dysfunction of the vascular endothelium is regarded as an important factor in the pathogenesis of diabetic micro- and macroangiopathy (Basi and Lewis, 2006). The close linkage between microalbuminuria and endothelial dysfunction in diabetes has been used to explain the fact that microalbuminuria is a risk marker for atherothrombosis, and this topic has been widely reviewed by others (Schalkwijk and Stehouwer, 2005).

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