Vascular Effects of Insulin

Peripheral Vasodilatation

Insulin is a slow vasodilator of peripheral resistance arteries in skeletal muscle [13]. This action of insulin is slow and requires prolonged exposure to supraphysiological doses. In normal subjects, infusion of a high physiological dose of insulin (1 mU/kg • min) increases peripheral blood flow slowly on average by 20% (range 10-90%) within approximately 2 h in normal subjects [13-15]. Factors which contribute to interindividual variation in blood flow responses to insulin include limb muscularity [14], the number of capillaries surrounding muscle fibers [16] and possibly endothelial function [17].

Regarding the mechanism responsible for insulin-induced vasodilatation of resistance vessels in vivo, stimulation of endothelial NO synthesis by insulin seems to be involved. Both Scherrer et al. [18] and Steinberg et al. [19] demonstrated that the insulin-induced increase in blood flow can be abolished by inhibiting NO-dependent vasodilatation with L-NMMA, but not by other vasoconstrictors such as norepinephrine [18], In vitro studies support these observations. Insulin increases NO production in human vascular endothelial cells in vitro [ 20], and both removal of the endothelium and inhibition of eNOS using L-NNMA abolish insulin-induced vasodilatation in isolated rat skeletal muscle arterioles [21]. Insulin induces NO-mediated endothelium-de-pendent vasodilatation in arterioles from red and white gastrocnemius muscles [22], After removal of functional endothelium in these arteries, insulin paradoxically evokes vasoconstriction. Insulin also increases eNOS gene expression in microvessels in lean but not insulin-resistant obese hyperglycemic rats [23]. Studies in humans have shown that insulin enhances blood flow responses to the endothelium-dependent agonist acetylcholine but not to the endothelium-independent agonist sodium nitroprusside [24-26], Although these data would suggest that insulin is an endothelium-dependent vasodilator, the time course for insulin action on peripheral blood flow is markedly slower than that of classic endothelium-dependent vasodilators such as acetyl-choline, which increases blood flow fivefold within a minute in the human forearm [27]. The reason for the slow vasodilatory effect of insulin on peripheral resistance vessels is unknown. One possibility is that insulin rapidly activates the sympathetic nervous system, and that this counteracts the vasodila-tory effects of insulin as discussed below.

Autonomic Nervous Tone

Under normoglycemic conditions, physiological concentrations of insulin increase the activity of the sympathetic nervous system, as determined from increases in plasma norepinephrine but not epinephrine concentrations [28,

29]. Physiological insulin concentrations, lower than those needed for peripheral vasodilatation, also increase muscle sympathetic nerve activity, as measured directly in the peroneal nerve with microneurography [28, 30, 31]. In studies which used power spectral analysis of heart rate variation to assess effects of insulin on autonomic nervous function, insulin has been found to acutely increase the low frequency component of heart rate variation, a measure of predominantly sympathetic nervous system activity in lean insulinsensitive subjects [32-34] and to decrease the high-frequency component, which reflects vagal control of heart rate variation [32-34]. Insulin-induced sympathetic activation leading to vasoconstriction has been suggested to counteract insulin-induced vasodilatation [28].

Large Arteries

In studies measuring changes in the augmentation index using pulse wave analysis (for methods, see chapter by Safar, pp 1-18) during euglycemic hyper-insulinemic conditions in vivo in normal subjects, insulin decreases central pressure augmentation and the augmentation index [35-37] (fig. 1). This effect is observed within 30-60 min at physiological insulin concentrations in normal lean men [35]. It clearly precedes insulin-induced increases in blood flow (fig. 2) and its magnitude correlates with whole-body insulin sensitivity of glucose uptake [38]. Changes in the augmentation index provide a measure of changes in stiffness, or alternatively of arterial muscular tone, provided both heart rate and peripheral vascular resistance remain unchanged [39, 40]. These conditions were met in the above-mentioned studies during the lower dose insulin infusion.

The discovery that insulin acutely decreases the augmentation index initiated studies examining whether this action is blunted in insulin-resistant subjects. This was the case in both obese men [36], and type 1 [41] and type 2 [37] diabetic patients. In these insulin-resistant groups, in contrast to the normal subjects, the decrease in the augmentation index required supraphysiological insulin concentrations and was not observed until 1.5-2.5 h after start of the insulin infusion. These findings demonstrate that insulin resistance extends to insulin action on large arteries. Consistent with these findings, insulin therapy, which improves insulin sensitivity, has also been shown to decrease the augmentation index in poorly controlled type 2 diabetic patients [42]. In a larger study of 50 non-diabetic men searching for factors associated with insulin action on the augmentation index, none of the most important correlates of the basal augmentation index (age, LDL cholesterol, blood pressure) were significantly associated with insulin action on the augmentation index [38]. The change in the augmentation index was, however, significantly correlated with several features of insulin resistance. These included directly measured

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