Endothelial Dysfunction Insulin Resistance And The Metabolic Syndrome

Insulin resistance usually precedes the development of type 2 diabetes and is often accompanied by a cluster of other risk factors (see above). The mechanisms underlying this clustering are still unclear, but all elements of the cluster share two important pathophysiological features, namely insulin resistance and endothelial dysfunction. A widely accepted theory states that insulin resistance is the primary abnormality that gives rise to type 2 diabetes, hypertension and dyslipidaemia, and that endothelial dysfunction merely represents the impact of hyperglycaemia and other features of the metabolic syndrome. An alternative concept is that endothelial dysfunction is at the heart of the metabolic syndrome. According to this concept, the endothelial dysfunction in large arteries that is an early and prominent event in atherothrombotic disease is parallelled by endothelial dysfunction in resistance vessels and metabolically important capillary beds that contributes to the development of the metabolic syndrome [50].

How can endothelial dysfunction impair insulin-induced glucose disposal? Firstly, insulin is a vasoactive hormone. Insulin increases muscle blood flow in a time- and concentration-dependent fashion through a mechanism that involves binding to the insulin receptor on the endothelial cell membrane and that can be abolished by inhibiting nitric oxide synthase. Nevertheless, insulin-induced increases in glucose uptake and total blood flow have different concentration-effect curves as well as time kinetics. Therefore, it is unlikely that a simple insulin-induced increase in total blood flow per se can increase glucose disposal. Secondly, however, in a process termed capillary recruitment, insulin can redirect blood flow in skeletal muscle from non-nutritive capillaries (those that are not coupled to muscle cells) to nutritive capillaries (those that are) and thus increase glucose disposal even without increasing total blood flow [51,52]. In this way, physical integrity and normal function of the arteriolar and capillary endothelium are prerequisites for normal metabolic insulin action. Indeed, insulin's vasodilator actions have been shown to be impaired in classic insulin-resistant states, notably type 2 diabetes, obesity and hypertension, and to be decreased by mediators closely associated with insulin resistance, namely tumour necrosis factor-a (TNF-a) and free fatty acids [53-55]. Taken together, these data suggest that endothelial dysfunction and impaired capillary recruitment can cause insulin resistance with respect to glucose disposal both when the microvascular endothelium is otherwise healthy but cannot react properly to insulin ('endothelial insulin resistance') and when the microvascular endothelium is injured through other mechanisms, such as age-related capillary drop-out ('rarefaction', i.e. reduced capillary density per volume of tissue).

Decreased capillary density and impaired capillary recruitment may in part explain why insulin resistance is associated with hypertension [56-58], as capillaries can contribute to control of peripheral vascular resistance by virtue of their narrow caliber and relative non-distensibility; by rarefaction (modelling indicates that for ~40% rarefaction, there is a ~20% increase in peripheral vascular resistance); and through active deformations, i.e. contractility [59]. In turn, the association of decreased capillary density and impaired recruitment with low birth weight [60,61] and increasing age may help explain the propensity of such individuals both to insulin resistance and hypertension.

Decreased capillary density and impaired capillary recruitment may also play a role in the development of atherogenic changes in lipoprotein concentrations, through impaired action of endothelium-bound lipoprotein lipase [50].

The molecular pathways through which insulin increases nitric oxide synthesis, endothelium-dependent vasodilation and capillary recruitment have not yet been fully elucidated, nor how TNF-a, free fatty acids and perhaps hyperinsulinaemia itself [62,63] impair these actions of insulin. Firstly, insulin can act on insulin receptors on endothelial cells to produce nitric oxide but also endothelin-1, a potent vasoconstrictor. Endothelial insulin resistance can thus be conceptualised as a shift in the balance between vasodilators and vasoconstrictors produced by insulin, with vasodilation as the normal response and impaired vasodilation or even net vasoconstriction as abnormal responses. Secondly, although insulin's endothelial actions have been shown to occur in cell culture and in isolated vessels, this does not exclude that, in vivo, insulin may act at insulin receptors on vascular smooth cells to cause vasodilation and (or) on skeletal muscle to activate glucose metabolism to produce a metabolite (e.g., adenosine) that then acts on local endothelial and (or) smooth muscle cells. Thirdly, regardless of the presence of diabetes, chronic, low-grade inflammation is closely associated with, and may link, endothelial dysfunction and metabolic insulin resistance [64-67]. These postulated pathways are summarised in Figure 2.

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