OBJETIVOS DEL CONTROL AUTOMÁTICO DE GENERACIÓN

1.2.4.2. The ‘haemodynamic’ origin of insulin resistance Insulin as a vasodilator

The concept that attenuation o f insulin-mediated vasodilatation and decreased capillary recruitment are important in the pathophysiology o f insulin resistance has been named the “haemodynamic hypothesis o f insulin resistance”.

M ost groups have reported a vasodilatory effect o f systemically or locally infused insulin (83-88). Baron et al observed that systemic insulin infusion with maintenance o f

euglycaemia is associated with peripheral vasodilatation (89). These studies generally used pharmacological doses o f insulin. However, investigators who have examined the direct effect on vascular tone o f more physiological local hyperinsulinaemia have reported different findings. A number o f groups reported the absence o f any effect o f local insulin infusion on vasodilation (88;90-94) or only a weak effect (95).

Furthermore, some authors reported that insulin-mediated vasodilatation in vitro appears to be dependent on local glucose uptake (96). In contrast. Tack et al reported that

vasodilatory response to insulin was preceded by an increase in glucose uptake, but that the glucose uptake did not determine the vascular response to insulin (87). Cleland et al performed a ‘ forearm clamp’ by locally infusing glucose and insulin, thus avoiding any confounding effects o f sympathetic stimulation on peripheral blood flow, in 18 healthy volunteers. Whole body insulin sensitivity was correlated with change in forearm blood flow, but not with body mass index (BMI), or mean arterial pressure. The authors state that these data support the concept o f a significant functional relationship between insulin's metabolic and vascular actions, possibly at an endothelial level (97).

Overall, it appears that insulin has not only systemically-mediated but also locally-acting effects. It is plausible that impairment o f either o f these functions could lead to

decreasing access o f insulin to receptors in target tissues. Assuming that insulin has a physiological vasodilator action, it is conceivable that impairment o f this response might result in increased vascular resistance. This could link insulin resistance with

hypertension independent o f hyperinsulinaemia (98).

Using the leg-perfusion technique during systemic hyperinsulinaemia Baron et al have extensively studied the relative contributions o f decreased glucose delivery and decreased glucose extraction to insulin-sensitive tissues in insulin resistant states. The finding o f these studies have been consistent in type 1 and type 2 diabetes mellitus and obesity showing that ‘conventional’ insulin resistance in these subjects is paralleled by a

decreased ability o f insulin to stimulate skeletal muscle blood flow (99-101). In support o f this, sensitivity to insulin-mediated vasodilatation is highly correlated with whole- body insulin-mediated glucose uptake in healthy subjects (102).

Effect o f increased blood flo w on glucose uptake

It has been widely debated if insulin’s effect on vasculature or its effect on glucose metabolism is more essential to the development o f insulin resistance. Normalisation o f blood flow response to insulin in type 2 diabetes mellitus leads to an improvement o f insulin-stimulated glucose by up to 40% (84). Intra-arterial infusion o f methacholine

during hyperinsulinaemia has been reported to increase glucose uptake in normal subjects (103). It has also been reported that an increase in forearm blood flow p er se mediated by exogenous bradykinin results in increased glucose uptake (104). However, not all groups have demonstrated an increase in insulin-mediated glucose uptake simply by increasing blood flow (105; 106). Yki-Jarvinen et al, using PET scanning, recently reported that whilst bradykinin significantly increased blood flow, glucose uptake in the bradykinin- treated muscles was unchanged, even in insulin resistant subjects (107). Sarabi et al observed that changes in forearm blood flow in response to metacholine, but not SNP, increased glucose uptake (108). Some studies in hypertension have demonstrated reduced glucose uptake in the absence o f any differences in insulin-stimulated blood flow

(93; 109). However, in several studies Clark et al have demonstrated that important differences exist between perfused and incubated skeletal muscle preparations with regard to their metabolism and control. In the constant- flow perfused rat hindlimb preparation, a group o f vasoconstrictors has been identified that enhance muscle

metabolism and aerobic contractility. Another group o f vasoconstrictors decreases muscle metabolism and aerobic contractility even though perfusate flow remains constant. All effects o f both groups o f vasoconstrictors are opposed by vasodilators. Because none o f the vasoconstrictor effects is evident when isolated muscles are incubated or perfused, involvement o f an active vascular system is indicated. Several mechanisms to account for vascular control o f perfused skeletal muscle metabolism have been suggested 1)

functional vascular shunts, regulated by site-specific vasomodulators, 2) a direct response to a change in the rate o f supply o f nutrients and removal o f products, and 3) a signal substance released by vascular tissue in association with vasoconstriction that interacts with surrounding skeletal muscle cells. Hindlimb perfusion experiments, where perfusion rate is fixed, suggest that changes in distribution o f microcirculatory perfusion can

modulate substrate uptake (110-112).

Insulin-mediated increase in muscle perfusion may account for approximately 30% o f insulin's overall action to stimulate muscle glucose uptake, suggesting a role for insulin and glucose delivery as a determinant o f insulin action. Thus the haemodynamic

hypothesis o f insulin resistance implies that in insulin resistant states the proportion o f insulin-mediated glucose uptake, which is under normal conditions facilitated by insulin- mediated vasodilatation, is diminished.