INTRODUCTION

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IT IS NOW OVER SEVEN YEARS since we drew together the then rather limited information linking vascular effects to metabolism in skeletal muscle (28). The major message emerging from that article was that muscle metabolism and contractile performance were markedly affected by vasomodulators that redistributed blood flow between nutritive and nonnutritive vascular routes. In the intervening period, there have been some notable developments in this field based largely on new techniques for measuring microvascular flow changes and particularly insulin's action to increase microvascular (nutritive) perfusion of muscle. It is thus timely to review these and related advances. This review also affords an opportunity to examine a significant previous omission concerning the effects of bulk flow change, particularly that evoked by insulin, on muscle metabolism.

	INSULIN-MEDIATED INCREASES IN BULK BLOOD FLOW TO SKELETAL MUSCLE

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Insulin-mediated vasodilation. Interest in this area was renewed in the 1990s by Baron and colleagues [Laakso et al. (93)], when they reported insulin's ability to increase total blood flow to skeletal muscle and suggested that this may, in fact, enhance insulin action by augmenting the delivery of insulin and glucose to muscle cells. Those studies were carried out in human subjects during a hyperinsulinemic euglycemic clamp to minimize the possible effects of counterregulatory hormones. A number of investigators have repeated these findings in both humans (2, 40, 133, 170, 180, 183, 190) and animals (101, 140); however, there is considerable variation between studies in the magnitude of the response, and in fact some groups have failed to observe changes in flow with insulin (46, 47, 80, 88, 145, 199) (see also Table 1). The discrepancies are not related to the method used to determine flow, since changes have been detected by thermodilution (40, 93), dye dilution (51), plethysmography (2, 180, 183, 190), positron emission tomography (PET) combined with [¹⁵O]H₂O (133), and ultrasound in animals (136). Systemic insulin (2, 40, 170, 183, 190) vs. local intra-arterial infusion (51, 116, 171, 180) also does not seem to explain the difference, as vasodilation has been reported in both situations. Interestingly, Ueda et al. (180) did report greater increases in flow when the local intra-arterial infusions in the forearm were combined with an infusion of a physiological concentration of glucose. Nevertheless, the magnitude of vasodilation was similar in forearm and calf during systemic insulin infusion (183).

Vascular resistance and cardiac output. Whereas insulin augments skeletal muscle flow, it does so with either no change (134) or a small decrease in mean arterial pressure (MAP) (10, 183). Accordingly, there is a fall in leg or forearm vascular resistance, calculated from MAP divided by limb blood flow (10, 134).

Sympathetic nervous system activation. There are several reports that insulin increases sympathetic nervous system (SNS) activity, as assessed by venous catecholamine levels (144) and forearm norepinephrine (NE) release (98) as well as by direct measurements of muscle sympathetic nerve activity (MSNA) (2, 190). These sympathoexcitatory effects of insulin appear to be centrally mediated, since they are apparent only during systemic insulin infusion but not following local infusion (98). As mentioned previously, during a hyperinsulinemic euglycemic clamp, there is generally no change in MAP. This is possibly due to the opposing effects of increased sympathetic vasoconstrictor action and a decrease in skeletal muscle vascular resistance (190). However, in patients with autonomic failure, a decrease in blood pressure is seen, since there is no sympathetic pressor effect (103). Although it was suggested that MSNA may be stimulated as a baroreflex to maintain blood pressure following vasodilation, this does not seem to be the case, since Spraul et al. (162) reported that MSNA increased before total flow and there was no correlation between the two. They also concluded that the increased MSNA did not cause the increased flow through sympathetic vasodilation. This is supported by the findings of Randin et al. (134) that insulin-mediated vasodilation was unaltered by the cholinergic blocker atropine and the -adrenergic blocker propranalol. Moreover, from experiments on patients with complete motoric lesion of the cervical spinal cord, Dela et al. (42) demonstrated that the central nervous system is not involved in insulin-mediated vasodilation, as the percentage of increase in leg blood flow was similar to that of healthy individuals. Comparisons of absolute increases in flow were complicated by the lower basal flows in the patients with spinal cord injury that are likely to be a result of decreased muscle mass, although this was not measured.

	INSULIN-MEDIATED CAPILLARY RECRUITMENT

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Although most studies have focused on increases in total flow to skeletal muscle, what may be more important is the distribution of flow within this tissue. Before this is discussed, it is necessary to give a brief description of the structure of the skeletal muscle vasculature and the possibility of two flow routes in this tissue.

Structure of skeletal muscle vasculature. Not all muscles are suitable for viewing the microvasculature in situ. Therefore, most studies have been performed on muscles such as the cremastor, hamster retractor, tenuissimus, or spinotrapezius muscle because of the thinness of the muscle and the ease in which vessels can be viewed. There do appear to be similarities in the structure of the microvasculature between different muscles; however, comparisons must be made with caution, because these are often very specialized muscles and may differ considerably from the structure found in load-bearing cylindrical muscles (112).

Evidence for two vascular flow routes in muscle. Work done in our laboratory using the perfused rat hindlimb supports earlier proposals by others that there are two flow routes in muscle: one in intimate contact with the myocytes and able to exchange nutrients and hormones freely and thus regarded as nutritive, and a second with essentially no contact with myocytes and regarded as nonnutritive [the history and background of this concept together with references can be found elsewhere (28)](29, 30). It is thought that the nutritive network consists of long, tortuous capillaries, which have large surface area for optimal exchange with the muscle cells. On the other hand, the nonnutritive network may be made up of shorter, possibly slightly larger capillaries, as judged by passage or failure of passage of different-size microspheres (188) of lower resistance. Some of the nonnutritive route may supply muscle connective tissue (septa and tendon) (121) and nourish associated adipocytes (32). Laser Doppler flowmetry (LDF) using impaled microprobes (200-µm diameter) indicates that the nonnutritive vessels may be distributed evenly throughout the load-bearing muscles but are relatively fewer than nutritive vessels (27). The data are consistent with the proposition that these nonnutritive vessels carry a flow reserve, which can redistribute to the nutritive route during periods of high metabolic demand, such as during exercise (30) or after a meal, to allow insulin-mediated glucose uptake into muscle. The balance between these two circuits is controlled by vasomodulators and neural input. In the constant flow pump-perfused hindlimb, we have classified vasoconstrictors according to whether they increase or decrease metabolism (type A and type B, respectively) (28). Examples of type A vasoconstrictors include low-dose NE, angiotensin II, vasopressin, and low-frequency SNS activation. These all redirect flow and increase oxygen consumption. Serotonin, high-dose NE, and high-frequency SNS activation are all type B vasoconstrictors, and these decrease oxygen consumption and metabolism generally (28). Changes in flow redistribution are suggested from vascular casts and changes to the pattern of red cell washout (119). There is evidence that oxygen uptake by resting muscle is a function of oxygen delivery (92), thus offering an explanation why the vasomodulator-mediated redistribution of flow within muscle has such profound effects on oxygen uptake. During type B vasoconstrictor action, a large proportion of the muscle very likely undergoes a physiological hypoxia. As indicated above, the constant vasomotion activity may allow the sharing of this over the entire muscle with time. Evidence to date shows that only the phosphocreatine-to-creatine ratio is compromised by a low ratio of nutritive to nonnutritive flow, and this is reversed when the nutritive-to-nonnutritive ratio is increased (187). For present considerations, the presence of this nonnutritive route in muscle may explain two phenomena that are developed further in sections below. These are 1) the ability of many systemic vasodilators to markedly increase limb blood flow without affecting insulin-mediated glucose uptake (114, 123) or ameliorating insulin resistance (115), and 2) the ability of insulin to increase capillary recruitment without either an increase in limb blood flow or a slowing in mean cell velocity in the capillaries (186). Other workers in the past have also invoked the notion of a nonnutritive route or functional shunt to explain the differences in clearance of intramuscular injected or infused markers due to exercise or vasodilators (see Ref. 30 and references therein).

Capillary recruitment: technical approaches for determining capillary recruitment in vivo. In an indirect approach, Bonadonna et al. (16) utilized a pulse injection into the brachial artery of L-[1-³H]glucose, an extracellular marker, that fills both blood vessels and the interstitial space. By analyzing the washout curve, the amount of tissue drained by the deep forearm vein was estimated. Although there was no change in the amount of muscle tissue drained when saline and a physiological dose of insulin (400 pM) were compared, there was an increase in the extracellular volume in response to supraphysiological levels of insulin (5,600 pM). This was interpreted by the authors to indicate capillary recruitment.

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	MECHANISMS FOR THE VASCULAR ACTIONS OF INSULIN

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Insulin effects in cultured cells and isolated vessels. To better understand the mechanisms of insulin-mediated increases in both total flow and capillary recruitment, it is useful to consider insulin's action in isolated vessels and cultured cells. However, studies in these in vitro systems must be interpreted with caution, because the conditions do not necessarily mimic those in vivo and insulin's actions appear to vary in different vascular beds. Also, because supraphysiological doses of insulin are often used in vitro, it is possible that the effects seen are due to insulin's interaction with insulin-like growth factor I (IGF-I) receptor rather than the insulin receptor (65). Nevertheless, these studies are valuable because they indicate insulin's effects on specific cell types in the absence of systemic effects.

Mechanisms of insulin-mediated increases in bulk flow: in vivo evidence. Increases in blood flow in response to insulin could result from either a direct vasodilator action of insulin via receptors on the vascular cells or indirectly from a signal generated from the stimulation of metabolism within skeletal muscle cells. The latter possibility is analogous to exercise-induced hyperemia, where muscle blood flow increases to provide sufficient oxygen and nutrients to support muscle contraction. Although the exact identities of the metabolic vasodilators have not been pinned down, there is evidence for the involvement of adenosine, potassium, NO, and/or lactate (153). It is conceivable that any one of these could mediate the increased flow in response to insulin. McKay and Hester (105) found evidence of a role for adenosine in the response to insulin (1,200 pM) applied topically to cremaster muscle of anesthetized hamsters. Dilation of second- and fourth-order arterioles by insulin was blocked by the adenosine receptor antagonist 1,3-dipropyl-8-(4-sulfophenyl)xanthine. They showed that the dilation was affected by opening of ATP-sensitive K⁺ channels, which have been implicated in adenosine-mediated vasodilation. Conversely, studies by Vollenweider et al. (190) have suggested that increased muscle cell glucose metabolism, to generate a putative metabolic vasodilator, fails to cause vasodilation in the absence of insulin. Whereas combined insulin and glucose infusion significantly increased calf blood flow, there was no such increase during fructose infusion in which insulin levels remained low, but a similar rise in carbohydrate oxidation was achieved. However, as pointed out by Baron (7), although the rates of whole body carbohydrate oxidation were equivalent, this is not necessarily true for skeletal muscle, as fructose oxidation may have taken place in other tissues.

Mechanism of capillary recruitment. At present, the mechanism of insulin-mediated capillary recruitment remains elusive. Although insulin's action to increase total flow is likely to involve first- and second-order arterioles, the capillary recruitment is probably mediated by third- to fifth-order arterioles. Certainly, small arterioles respond to insulin, either systemically or topically applied to the muscle. Iwashita et al. (78) observed dilation of fourth-order arterioles (10 µm diameter), viewed by intravital microscopy of rat cremaster muscle in response to subcutaneous insulin injection resulting in a serum insulin of 835 pM. Vasodilation resulting from epinephrine release due to the fall in blood glucose (from 6.7 to 5.8 mM) in these experiments cannot be ruled out, however. Porter et al. (131) established that third-order arterioles (20 µm diameter) were much more responsive to insulin than larger vessels in cremaster muscle in situ, albeit at very high concentrations of topically applied insulin (48 nM). A similar increase in sensitivity to insulin-mediated vasodilation with decreasing vessel size has been reported elsewhere (105, 125).

	INFLUENCE OF BLOOD FLOW ON GLUCOSE UPTAKE

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Whereas it is generally accepted that insulin can increase total blood flow, controversy still remains as to the physiological relevance of this, both in regulating normal glucose uptake and as a possible cause of insulin resistance. The notion that insulin-mediated glucose uptake is improved by increasing hormone and substrate delivery implies that flow is rate limiting, either in the bulk sense or at the level of the microvasculature.

Early studies using the perfused rat hindlimb showed that increasing glucose delivery with or without insulin raises glucose uptake (55, 151). Grubb and Snarr (55) demonstrated that increasing glucose concentration within the physiological range increased glucose uptake in a linear fashion. However, with a constant glucose level, the relationship between flow and glucose uptake was hyperbolic. They proposed that this saturation of glucose uptake might be due to flow being shunted into a parallel network with low nutrient exchange. Importantly, though, at physiological flow rates, glucose uptake was not maximal; thus further increases in flow would be expected to increase glucose uptake.

Limb glucose uptake can be calculated by using the Fick principle, which states that glucose uptake is equal to the product of the arteriovenous glucose difference and flow (205). Therefore, increasing either flow or cellular permeability to glucose will increase glucose uptake. When a simplified model of a single capillary of fixed surface area is considered, glucose uptake is limited by either permeability or flow. If the capillary is completely permeable to glucose, then, depending on metabolism, the extraction will be 100% and thus flow could become rate limiting; however, in a situation in which the extraction is low, an increase in flow will have no effect on the rate of glucose uptake (141). It has been reported that, in vivo, ~40% of glucose is extracted, so that, in fact, the situation is a combination of the two scenarios (7). As glucose is extracted from the capillary, its concentration drops, forming a gradient from the arterial to the venous end of the capillary. By increasing flow, this gradient is reduced, although it was estimated that, in vivo, this would increase glucose uptake only ~10% (7). However, if capillary recruitment also takes place, the capillary surface area will be increased, further enhancing glucose uptake.

To investigate this issue, Natali (113) compared experimental data with a model of gradient dilution and capillary recruitment. In the capillary recruitment model, as flow was increased, glucose uptake would be expected to increase in a linear fashion, whereas in the gradient dilution scenario increasing flow would cause a hyperbolic increase in glucose uptake. In the experiments (113), flow was altered during a hyperinsulinemic euglycemic clamp in healthy humans. It was found that the data fitted a model of capillary recruitment when flow was reduced by ouabain and fitted a model of gradient dilution after flow was increased with phentolamine and propranalol. Thus it was concluded that increasing flow would not have a large effect on glucose uptake. Accordingly, it was reasoned that vasodilators such as adenosine (114), bradykinin (123), sodium nitroprusside (115), and low doses of IGF-I (128), which increase total limb blood flow, would do little to influence glucose uptake in healthy subjects or improve insulin resistance. However, the reason that these vasodilators failed to influence glucose uptake may relate more to the fact that they preferentially increase flow into nonnutritive areas, where insulin-mediated glucose uptake is low (28, 118, 138). Indeed, all vasodilators may not act in the same way, and at least one other vasodilator may increase capillary recruitment. Thus, during a hyperinsulinemic euglycemic clamp, Baron et al. (14) used the endothelium-dependent vasodilator methacholine chloride to further increase flow and the NOS inhibitor L-NMMA to decrease flow. Whereas glucose uptake was increased by methacholine, it was reduced by L-NMMA. Taken together, the data indicated a significant deviation from the Renkin equation for a fixed capillary surface area (141), indicating capillary recruitment. Furthermore, they examined whether the importance of flow depends on the degree of insulin sensitivity. They found that subjects with a higher glucose disposal rate (GDR) demonstrated a greater increase in leg glucose uptake due to methacholine infusion during the hyperinsulinemic euglycemic clamp, indicating that, in more-insulin-sensitive subjects, flow is more rate limiting for glucose uptake than in less-insulin-sensitive subjects.

Mather et al. (102) recently investigated the dependence of glucose uptake on flow in a group composed of lean, obese, and obese type 2 diabetic subjects. They found that, in the basal state, there was no difference in either GDR or leg blood flow. Moreover, when a GDR of 2,000 µmol · m² · min¹ was achieved in both a euglycemic hyperinsulinemic clamp and a hyperglycemic hyperinsulinemic clamp, subjects exhibited leg blood flows of 0.4 l/min regardless of their insulin sensitivity. Thus these data demonstrate the close coupling between flow and glucose uptake.

As indicated above, we have found capillary recruitment and glucose uptake to be closely linked in rats in vivo. Bulk flow was not significantly correlated with glucose uptake (137), but bulk flow increase may lead to an increase in capillary recruitment. However, it is yet to be finally resolved whether changes in glucose uptake result exclusively from changes in the latter rather than the former. There are definite situations where total flow can be increased in limbs in vivo, as with the vasodilators discussed above (114, 115, 123, 128) and epinephrine (136), without an increase in glucose uptake.

	INSULIN RESISTANCE

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Impaired increases in total flow. Insulin resistance is the state in which normally insulin-sensitive cells exhibit a low response to insulin.

Impaired capillary recruitment. Using 1-MX metabolism as an indicator of capillary recruitment, we have demonstrated that insulin-mediated changes in this parameter in anesthetized rats are indeed impaired in three states of acute insulin resistance. First, insulin resistance was induced by infusion of -methylserotonin, a vasoconstrictor that has been shown to decrease nutritive capillary flow in the perfused rat hindlimb (117). In vivo, insulin's ability to increase total flow was abolished by -methylserotonin, and the insulin-stimulated increase in 1-MX metabolism was decreased by 71% (137). These hemodynamic alterations by -methylserotonin were associated with a 56% decrease in insulin-stimulated hindleg glucose uptake (Table 1). It has previously been shown that serotonin has no effect on glucose uptake in incubated muscles devoid of vascular involvement (138). Therefore, it was concluded that serotonin induced a hemodynamic insulin resistance by limiting insulin and glucose access to skeletal muscle. Because infusion of this vasoconstrictor maintained an increase in blood pressure, this represented the first experimental model where hypertension and muscle insulin resistance could be seen to result from a single cause.

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Endothelial dysfunction and vascular complications of type 2 diabetes. Endothelial cells produce a variety of vasodilator and vasoconstrictor molecules that act on VSMC, thereby controlling vessel tone. In addition, it is now recognized that the endothelium also plays an important role in the regulation of vessel permeability and proliferation as well as blood fluidity and the adhesion of blood cells to the vascular wall (reviewed in Refs. 20, 174). Therefore, a range of complications can potentially result from a dysfunctional endothelium. This is of consequence, because it is also believed that endothelial dysfunction plays a key role in the development of the microvascular complications of type 2 diabetes, which include retinopathy, nephropathy, and neuropathy (reviewed in Ref. 95). Likewise, endothelial dysfunction is also central to the macrovascular complications of atherosclerosis and thrombosis, which lead to coronary artery, cerebrovascular, and peripheral vascular disease (95). The frequent association between endothelial dysfunction and insulin resistance, as well as with many of the features of the insulin resistance syndrome, including dyslipidemia, hypertension, and hyperglycemia, has led to the proposal that endothelial dysfunction may be an important factor leading to insulin resistance (130, 174). Evidence in support of this theory comes from the fact that endothelial dysfunction precedes the development of type 2 diabetes (reviewed in Ref. 176). Furthermore, first-degree relatives of type 2 diabetics displayed alterations in micro- and macrocirculation despite normal glucose tolerance (19). One of the most important aspects of endothelial dysfunction is the impaired synthesis and/or increased degradation of NO (reviewed in Ref. 100), which has been suggested to result from increased oxidative stress (173). Because insulin is reported to increase flow and recruit capillaries through the production of NO (148, 165, 189), endothelial dysfunction is likely to contribute to the impaired vascular actions of insulin in states of insulin resistance.

Interstitial insulin levels. There is a delay in the onset of insulin action in vivo compared with that in vitro (129, 157, 196), which may be due to transendothelial insulin transport. In earlier in vitro studies, King and Johnson (91) demonstrated a receptor-mediated transport of insulin across endothelial cells. However, more recent studies conducted in vivo dispute these findings, claiming that insulin moves across the endothelium predominantly via diffusion, since the process did not become saturated (163).

	EXERCISE ENHANCEMENT OF INSULIN SENSITIVITY

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Muscle contraction increases total blood flow to muscle (74), recruits capillaries (70), and stimulates the translocation of GLUT4 to the plasma membrane, thereby increasing glucose uptake (44). Exercise-stimulated glucose uptake and maximal insulin-mediated glucose uptake are additive (142), and two distinct signaling pathways appear likely. Exercise-mediated glucose uptake, unlike insulin-mediated glucose uptake, is not inhibited by wortmannin and may involve AMP kinase rather than signaling through PI 3-kinase (146). NOS inhibition has been reported to inhibit exercise-mediated glucose uptake in humans (18) but not in mice (143). It remains to be tested whether blood flow redistribution occurs in muscle as a result of eNOS inhibition when exercise is the stimulus for glucose uptake. For insulin, the reported effect of NOS inhibition to partly inhibit insulin-mediated glucose uptake is attributed to vascular effects in both humans (8) and rats (189).

It is well established that prolonged exercise leads to enhanced insulin sensitivity and maximal insulin responsiveness (17). Evidence for this comes from comparisons of trained athletes with untrained subjects (46) as well as from training intervention studies. Glucose uptake measured during a hyperinsulinemic euglycemic clamp in individuals before and after 6 wk of endurance training revealed a 30% increase in glucose uptake (161). Endurance training leads to increased cardiac output and muscle oxygen extraction, resulting in a higher maximal oxygen uptake. In addition, a number of metabolic and structural changes occur in muscle. Skeletal muscle's ability to oxidize pyruvate, fatty acids, and ketones is increased as a result of elevated levels of mitochondrial citric acid cycle enzymes as well as enzymes involved in fatty acid breakdown and ketone utilization (reviewed in Ref. 67). Apart from hexokinase activity, which is significantly increased, changes in glycolytic enzymes are generally small. Specific alterations differ depending on the muscle fiber type, and often no differences are seen overall (reviewed in Ref. 67). It has also been reported that there is no change in glycogen synthase activity (24). In accordance with these changes in enzyme profiles, there is generally a shift from fast type II to slow type I fibers following exercise training (reviewed in Ref. 38).

The augmented insulin sensitivity may also be due to alterations in insulin-signaling molecules. In fact, raised mRNA levels of the insulin receptor, IRS-1, and MAP kinase (ERK1) have been reported in exercise-trained rats (90). In addition, other studies have found increases in IRS-1- and IRS-2-associated PI 3-kinase activity and Akt phosphorylation (24). Possibly one of the most important changes is the elevated GLUT4 protein content following exercise training in healthy humans (73).

It is also possible that hemodynamic factors may be involved in the elevated insulin sensitivity following exercise (77). As mentioned previously, acute exercise increases total flow and capillary recruitment. Moreover, some studies have found elevated basal blood flow in athletes compared with untrained individuals (46); however, this is not always significantly increased (59). Nevertheless, Hardin et al. (59) did report that insulin-stimulated blood flow was 31% higher in athletes than in controls. Furthermore, Dela et al. (41) found that the insulin-stimulated blood flow was increased after 10 wk of one-legged training in both healthy subjects and type 2 diabetic patients. Although there are studies that have not observed differences in capillarization (46), it has been reported by others that there are increases in capillary density in skeletal muscle following training in humans (1, 63) and in rats (57). If this is the case, the increased capillary surface area may provide a greater scope for insulin-mediated capillary recruitment. It is also possible that exercise training may enhance insulin's ability to increase total flow and/or capillary recruitment, thereby contributing to the enhanced glucose uptake.

Even though interpretation may be complicated by the effects of aging, exercise-stimulated glucose uptake is generally not impaired in type 2 diabetics (36, 52). Consequently, there are several reports that exercise is beneficial in both the prevention and treatment of type 2 diabetes (53, 87, 127). However, some studies showed either no or only minimal beneficial effects in the treatment of diabetes (17, 149). The reason for this may be due to the duration of the disease, the training protocol, or the method to determine insulin sensitivity. Nevertheless, there are studies that report weight loss and favorable effects on lipid metabolism, leading to increases in HDL cholesterol and decreases in LDL cholesterol (87).

At the experimental animal model level, voluntary exercise training was found to have a marked improvement in insulin responses under hyperinsulinemic euglycemic conditions. Whole body GIR, hindleg glucose uptake, and capillary recruitment (1-MX disappearance) were each increased compared with untrained animals as a result of the training period in which the animals had run an average of 18 km (139) (Table 1).

	CONCLUSION

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New methods have shown that a major hemodynamic effect of insulin is to increase nutritive capillary blood flow in muscle. Current evidence suggests that this effect is independent of an increase in bulk flow to muscle that often accompanies insulin's action. Insulin-mediated capillary recruitment may have similar beneficial effects to those of exercise relating to hormone and substrate delivery to the muscle cells. Interventions that impair capillary recruitment give rise to insulin resistance with decreased insulin-mediated glucose uptake in muscle. Conversely, exercise training enhances both insulin-mediated capillary recruitment and muscle glucose uptake.