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(Circulation. 1997;96:4104-4113.)
© 1997 American Heart Association, Inc.

Articles

Insulin as a Vascular and Sympathoexcitatory Hormone

Implications for Blood Pressure Regulation, Insulin Sensitivity, and Cardiovascular Morbidity

Urs Scherrer, MD; ; Claudio Sartori, MD

From the Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Correspondence to Dr Urs Scherrer, Department of Internal Medicine, BH 10.642, CHUV, CH-1011 Lausanne, Switzerland. E-mail Urs.Scherrer{at}chuv.hospvd.ch

	Abstract

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Abstract The past several years have witnessed a major surge of interest in the cardiovascular actions of insulin. This interest has stemmed on the one hand from epidemiological studies that demonstrated an association between obesity, insulin resistance, and hypertension, leading to the so-called insulin hypothesis of hypertension. On the other hand, this interest has been stimulated by experimental evidence suggesting that the vascular actions of insulin may play a role in its main action, namely the promotion of glucose uptake in skeletal muscle tissue. Two tenets have emerged about how insulin may exert its cardiovascular actions. First, it is now firmly established that acute insulin administration stimulates sympathetic nerve activity in both animals and humans. Second, there is increasing evidence that insulin stimulates muscle blood flow, an effect that appears to be mediated at least in part by an endothelium-dependent mechanism. This review summarizes the current understanding and gaps in knowledge on cardiovascular actions of insulin in humans and pathophysiological consequences of derangements of such actions.

Key Words: insulin • nervous system, autonomic • nitric oxide • hypertension • vasodilation

	Introduction

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Insulin, apart from its effects on intermediary metabolism, also has effects on the heart and the vasculature. Even though the cardiovascular actions of insulin were first described shortly after the introduction of insulin into clinical practice,¹ over the following decades research in this area remained dormant and focused mainly on the metabolic actions of this hormone. The past several years, however, have witnessed a major surge of interest in this field. This interest has been stimulated by epidemiological evidence suggesting a potential link between insulin and cardiovascular morbidity^2–4 and by experimental studies suggesting a direct relationship between vascular and metabolic actions of insulin in skeletal muscle tissue.⁵ The sympathetic nervous system and the L-arginine–nitric oxide pathway have emerged as major players in the mediation of the cardiovascular actions of insulin. The present review summarizes the current understanding and gaps in knowledge on the cardiovascular actions of insulin in humans, with particular emphasis on the role played by these two systems and pathophysiological consequences of derangements of such actions.

	Effects of Short-term Hyperinsulinemia

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Sympathetic Actions of Insulin
It is now firmly established that in both animals and humans, acute, short-term insulin infusion^6–16 and carbohydrate ingestion^17–19 stimulate sympathetic-nerve activity. In humans, acute physiological and pharmacological euglycemic hyperinsulinemia²⁰ increases sympathetic nerve activity as determined by measurements of venous plasma catecholamine concentration,^9–12,21 plasma norepinephrine spillover,¹³ or direct microneurographic recordings of sympathetic nerve action potentials targeted at the skeletal muscle vasculature.^{10,12,14–16} With the use of direct microelectrode recordings, it has been demonstrated that in humans, insulin selectively stimulates sympathetic outflow to skeletal muscle but not to skin.^10,19 The concept that insulin exerts highly differential sympathetic effects is further supported by observations in rats, indicating that insulin stimulates lumbar but not adrenal or renal sympathetic outflow.²²

To examine whether the primary stimulus that triggers sympathetic activation during insulin/glucose infusion is insulin itself or insulin-induced stimulation of carbohydrate metabolism, Vollenweider and colleagues¹⁶ performed microelectrode recordings of sympathetic nerve discharge to calf muscles during three experimental interventions in which the plasma insulin concentration was altered whereas the stimulation of the carbohydrate metabolism was held constant. These studies established the concept that sympathetic activation is related primarily to hyperinsulinemia itself rather than to stimulation of carbohydrate metabolism.

Mechanism(s) of Insulin-Induced Sympathetic Activation
In some studies^14,23 insulin infusion was accompanied by small decreases in blood pressure, raising the possibility that baroreceptor reflex mechanisms could contribute to sympathetic activation. It is likely, however, that other mechanisms also play a role, and several lines of evidence suggest that insulin sympathoexcitatory effects are mediated at least in part by a central neural action.²⁴ Insulin crosses the blood-brain barrier,²⁵ and insulin receptors have been demonstrated in several distinct regions of the central nervous system such as the median hypothalamus.²⁶ In anesthetized dogs, insulin injection into the carotid artery, at a dose without effect on plasma glucose concentration, increases arterial pressure; this effect is sympathetically mediated because it is abolished by ganglionic blockade.⁶ In rats, when administered intracerebroventricularly at a dose that did not have any systemic action, insulin stimulates sympathetic nerve activity,⁸ an effect that is abolished by anterolateral third ventricle lesions.²⁷ In humans, systemic insulin infusion stimulates norepinephrine spillover in skeletal muscle vasculature, whereas local insulin infusion into the forearm has no such stimulatory effect,¹³ indicating that insulin sympathoexcitatory actions are not mediated by a local mechanism. During euglycemic clamp studies, there exists a marked time lag between peak increases in plasma insulin concentration and sympathetic nerve activity suggesting that insulin may have to reach the interstitial space to exert its excitatory effects.^11,12,14,16 Consistent with this hypothesis, during insulin infusion in humans, the kinetics of the increase in lymph insulin concentration,²⁸ (a marker of the interstitial insulin concentration) mimic those of the increase in muscle sympathetic nerve activity,^{10,12,14–16} and the sympathetic activation persists after insulin infusion has been stopped and plasma insulin concentration starts to decline.¹⁴ Finally, in rats, the centrally mediated effects of insulin on food intake are modulated by glucocorticoids,²⁹ presumably by altering central neural release of peptides such as corticotropin-releasing hormone and neuropeptide Y. Interestingly, these peptides also play a role in the neural regulation of the cardiovascular system.^30,31 On the basis of this evidence, effects of dexamethasone on insulin-induced sympathetic activation have been examined in humans.¹² Dexamethasone was found to dramatically and specifically impair the ability of insulin to stimulate sympathetic nerve activity. This drug could exert its effects either by inhibition of the transport of insulin from the plasma to the central nervous system (as evidenced by studies in dogs³²) and/or by altering central neural peptide release.³³ These observations are consistent with the concept that the sympathoexcitatory effects of insulin are centrally mediated and may involve the release of specific neuropeptides.

Insulin-Induced Sympathetic Neural Activation Is Impaired in Obese Humans
In lean subjects, insulin infusion at a rate that elevates plasma insulin concentration twofold to threefold above fasting levels causes sympathetic activation that is comparable to the one observed during elevation to high physiological levels.^11,12,34 Thus it appears that even very small increases in plasma insulin concentration have marked sympathetic effects. This observation could be of importance in pathophysiological states that are characterized by sustained hyperinsulinemia such as obesity. A recent study compared the sympathetic responses in skeletal muscle between lean and obese subjects.¹¹ The main findings were that in the fasting state, obese subjects had more than twofold higher rates of sympathetic nerve firing than did lean subjects, and insulin infusion that more than doubled sympathetic nerve activity in lean subjects had only barely detectable sympathetic effects in obese subjects. The inability of insulin to stimulate sympathetic nerve activity does not appear to be related to impaired stimulation of carbohydrate metabolism because in lean subjects, induction of resistance to the stimulatory effects of insulin on carbohydrate metabolism by fat emulsion infusion does not attenuate the sympathetic response evoked by acute hyperinsulinemia,³⁵ and attenuated stimulation of glucose uptake during low-dose insulin is not accompanied by attenuated stimulation sympathetic-nerve activity.^11,34 The impairment in sympathetic responsiveness in obese subjects is specific for insulin, because the responses during a Valsalva maneuver and immersion of the hand in ice water are preserved.¹¹ Two possible explanations can be considered. First, the attenuated sympathetic responsiveness to insulin infusion in obese subjects may be related to a resistance to the sympathoexcitatory effects of insulin and thus represent another feature of insulin resistance in obesity. Alternatively, preserved sensitivity to the sympathoexcitatory effects of insulin could cause the sustained sympathetic activation found in chronically hyperinsulinemic obese subjects^15,36,37 and preclude the demonstration of any additional sympathoexcitation during acute short-term insulin infusion.

Impaired sympathetic activation in obese subjects during short-term hyperinsulinemia may not be generalized. For example, insulin-induced increases in heart rate, which are sympathetically mediated because they are abolished by propranolol infusion, are preserved in obese subjects.¹¹ Similarly, insulin-induced stimulation of sodium retention (and presumably stimulation of renal nerve traffic) is preserved in obese adolescents.³⁸

Finally, there may exist interethnic differences in the effects of obesity on sympathetic responsiveness. In obese Pima Indians, baseline sympathetic nerve activity has been reported to be diminished rather than augmented, and sympathetic responsiveness to insulin infusion appears to be preserved.³⁶ Thus one has to be careful not to extrapolate from findings in Caucasians, and studies in other ethnic groups are needed.

Vascular Actions of Insulin
Even though insulin-induced sympathetic activation is thought to be, at least in part, sympathetic vasoconstrictor,¹³ there is abundant evidence that insulin stimulates blood flow and decreases vascular resistance in skeletal muscle. Insulin-induced vasodilation was first reported, shortly after its introduction into clinical practice.¹ These early studies used injection of large doses of insulin, and the vasodilation was thought to be mediated at least in part by hypoglycemia-induced stimulation of epinephrine release.³⁹ Subsequently, it has been shown that insulin-induced stimulation of muscle blood flow is not dependent on epinephrine release because it occurs in adrenalectomized humans⁴⁰ and during euglycemic hyperinsulinemia,^{5,12,14,16,41–44} situations in which there is no stimulation of epinephrine release. At the beginning of the present decade, independent findings by Laasko and colleagues,^5,45–47 and Anderson and colleagues,¹⁴ firmly established the concept that in lean subjects, euglycemic hyperinsulinemia at high physiological concentrations stimulates blood flow in skeletal muscle tissue. Such stimulation is related primarily to insulin itself rather than to stimulation of carbohydrate metabolism.¹⁶ Insulin-induced increases in blood flow are comparable in the upper and the lower limbs⁴³ and have been demonstrated with the use of both invasive measurement techniques such as thermodilution^5,45–47 and dye dilution⁴⁸ and noninvasive techniques such as plethysmography,^{11,12,16,42,43,49–52} positron emission tomography,^53,54 and B-mode ultrasound.⁴³ Insulin-induced stimulation of limb blood flow occurs selectively in skeletal muscle tissue but not in skin.^43,54 The relative limb muscle content is an important determinant of the interindividual variation in the blood flow response to insulin in normal subjects.⁴³

Mechanism(s) of Insulin-Induced Vasodilation
In 1994, two independent reports have provided conclusive evidence that in lean subjects, inhibition of nitric oxide release by the stereospecific inhibitor of nitric oxide synthase N^G-monomethyl-L-arginine (L-NMMA) abolishes insulin-induced vasodilation.^50,55 Consistent with these observations in vivo, insulin increases cyclic guanosine monophosphate content by a nitric oxide–dependent mechanism⁵⁶ and activates L-arginine transport and nitric oxide synthase⁵⁷ in human vascular smooth muscle cells and stimulates nitric oxide release in cultured vascular endothelial cells in vitro.⁵⁸ While these studies establish the major role played by nitric oxide in the mediation of insulin-induced vasodilation, two important questions remain to be answered. Does insulin stimulate nitric oxide release by a local (vascular) or a systemic (ie, stimulation of neuronal vasodilation) action? Do other mechanisms contribute to insulin-induced vasodilation?

Regarding the former question, comparison of insulin-induced vasodilation during local, intra-arterial, and systemic intravenous insulin infusion should provide some clues. Although this approach appears compelling, the evidence is conflicting. Indeed, while insulin-induced vasodilation has been a consistent finding in the large majority^{5,12,14,16,42,43,46,54,59} but not all^13,60,61 of the studies using systemic insulin infusion at both physiological^{12,14,16,43,59} and pharmacological^5,43,54 concentrations, during local insulin infusion many studies did not find a vasodilation^62–69 but others did.^51,52,70,71 The observations that insulin infusion produces hypotension in patients with autonomic failure⁷² and vasodilation in patients having undergone regional sympathectomy for hyperhydrosis⁷³ argue against sympathetic neural vasodilation as the only mechanism. We find it interesting that vasodilation occurs much more rapidly in the denervated than in the innervated limb, which suggests that in innervated limbs, sympathetic vasoconstrictor tone may mask the local vasodilator action of insulin.⁷³

Earlier reports had suggested that ß-adrenergic mechanisms could contribute to insulin-induced vasodilation.^41,74 Interpretation of these studies was difficult, however, because of potential confounding effects of hypoglycemia-induced stimulation of epinephrine release. Recent observations in humans indicate that in the absence of hypoglycemia, ß-adrenergic mechanisms do not appear to contribute importantly to insulin-induced vasodilation.⁴² Similarly, cholinergic vasodilator mechanisms do not appear to play a role because atropine infusion did not alter insulin-induced stimulation of blood flow.⁴²

A final unresolved issue relates to the prolonged time course of insulin-induced vasodilation. During insulin infusion at stepwise increasing rates over several hours, muscle blood flow increases progressively throughout the infusion, an observation that has been used to indicate that stimulation of blood flow is both time dependent and dose dependent.⁴³ This experimental approach, however, does not allow determination of the respective roles of time and dose on insulin-induced vasodilation. Recent observations are consistent with the hypothesis that within the physiological range, infusion time rather than infusion rate is the main determinant of the vasodilator response to insulin. In lean subjects, when compared at the same time point, vasodilator responses were comparable during low and high physiological hyperinsulinemia,¹¹ and during insulin infusion at a constant rate over a prolonged 3- to 6-hour period, muscle blood flow continued to increase roughly linearly throughout the entire infusion.^42,49 It is possible, however, that in subjects who are resistant to the vasodilator action of insulin and/or when insulin is infused at pharmacological concentrations, dose may be an important determinant of the response, as evidenced by the stimulation of blood flow by pharmacological but not by physiological hyperinsulinemia in insulin-resistant obese subjects.⁵

In summary, in healthy subjects, insulin-induced vasodilation is mediated chiefly by stimulation of nitric oxide release. Further studies are needed to determine whether additional mechanisms contribute to insulin-induced vasodilation in vivo.

Does Insulin-Induced Vasodilation Play a Role in the Regulation of Blood Pressure During Short-term Hyperinsulinemia?
Studies in both animals and humans suggest that this is the case. In dogs, increases in plasma insulin levels to high physiological concentrations do not increase blood pressure because increases in cardiac output are offset by decreases in peripheral vascular resistance⁷⁵ that can be attributed at least in part to vasodilation in skeletal muscle.^41,75 Similarly, in humans, short-term insulin infusion, even though it is accompanied by marked sympathetic activation, does not increase arterial pressure,^{10,12,14,16,76} because the sympathetic pressor effects are offset by vasodilation.⁵⁰ In the clinical setting, the importance for blood pressure regulation of this balance between pressor and depressor actions of insulin is further evidenced by the observation that in patients with autonomic failure, unopposed insulin-induced vasodilaton is associated with marked hypotension.⁷²

On the basis of such observations, potential underlying mechanisms by which insulin may alter vascular responsiveness have been examined in many studies.

Does Insulin Alter the Vascular Responsiveness to Vasoactive Agents?
In vitro, insulin stimulates calcium efflux from vascular smooth muscle cells by activating the plasma membrane Ca-ATPase,⁷⁷ it induces hyperpolarization and relaxation of the vasculature by stimulating the sodium/potassium pump,⁷⁸ and it attenuates agonist-induced increases in intracellular free Ca²⁺ in vascular smooth muscle cells.^78–80 It is not clear, however, whether such mechanisms play a role in the attenuation by insulin of the vasoconstrictor responses to angiotensin II, serotonin, and potassium chloride in rat and rabbit arteries^81–83 in vitro and the attenuation of the angiotensin II–induced pressor response reported in some^66,84,85 but not all⁸⁶ studies in humans.

Effects of insulin on noradrenergic vasoconstriction also have been studied. In vitro, insulin stimulates ₁-adrenergic receptor expression in rat vascular smooth muscle cells⁸⁷ and it modulates the glucose-induced stimulation of protein kinase C and diacylglycerol in endothelial cells, a mechanism that appears to play a role in the potentiation by insulin of the norepinephrine-induced constriction in vascular ring preparations.⁸⁸ On the other hand, insulin attenuates norepinephrine release⁸⁹ and enhances its uptake⁹⁰ from sympathetic nerve endings and has been reported to attenuate noradrenergic vasoconstrictor responses in vitro.^81–83

In vivo, there is increasing evidence that insulin attenuates the reflex forearm vasoconstriction evoked by simulated orthostatic stress.^67,68,91 This effect, however, does not appear to be related to inhibition by insulin of forearm norepinephrine spillover (and/or stimulation of its reuptake) but to attenuation of ₂-adrenergic vasoconstriction.⁶⁸ Finally, vasoconstrictor responses to local^51,66,69 or systemic^50,86,92 noradrenaline infusion in humans were found to be either attenuated,^66,69,92 unaltered,^50,51 or augmented.⁸⁶

In addition to its own vasodilator action, in humans, insulin has been found to potentiate the vasodilator responses evoked by isoproterenol⁹³ and the endothelium-dependent vasodilator acetylcholine,⁹⁴ but did not alter the response evoked by the endothelium-independent vasodilator sodium nitroprusside.⁹³

In summary, there is evidence that insulin attenuates reflex sympathetic vasoconstriction and may potentiate endothelium-dependent vasodilation. While in vitro studies suggest numerous potential underlying mechanisms for these actions, their role in vivo remains to be determined.

Insulin-Induced Vasodilation Is Impaired in Obese Insulin-Resistant Subjects
In obese insulin-resistant subjects, the ability of insulin to stimulate muscle blood flow is impaired,^5,11,46 but the underlying defect is unclear. Because in healthy subjects, insulin-induced vasodilation is mediated by nitric oxide, endothelial dysfunction must be considered. In obese subjects, the vasodilator response to intra-arterial infusion of the endothelium-dependent vasodilator methacholine but not to sodium nitroprusside (an endothelium-independent vasodilator) is impaired, and insulin looses its ability to potentiate methacholine-induced vasodilation.⁹⁵ Factors that could contribute to endothelial dysfunction in obesity may include the following: In vitro, insulin stimulation of nitric oxide production and glucose transport appears to share common signaling pathways in endothelial cells, suggesting that insulin resistance with respect to glucose metabolism and nitric oxide production may be coupled.⁵⁸ Free fatty acids that are often elevated in obesity have been reported to inhibit endothelial nitric oxide synthase in vitro.⁹⁶ There is, however, no evidence that fatty acid infusion impairs insulin-induced stimulation of calf blood flow in vivo.³⁵

Conversely, augmented stimulation of vasoconstrictor mechanisms needs to be considered but has received little attention so far. Insulin infusion does not appear to evoke exaggerated -adrenergic stimulation in obese subjects.¹¹ The sympathetic overactivation found in obese subjects,^11,15,37 by stimulating the phosphoinositide system, could increase intracellular free calcium, an important determinant of vascular smooth muscle tone and contractility. The endothelium, in addition to relaxing factors, also synthesizes contracting factors, and among them endothelin-1 (ET-1) has recently received much attention. In vitro, insulin stimulates ET-1 gene expression⁹⁷ and ET-1 release in cultured porcine endothelial cells⁹⁸ and human vascular smooth muscle cells.⁹⁹ While there is evidence in vivo that both platelet-free cytosolic calcium¹⁰⁰ and plasma ET-1 concentration may be elevated in obese subjects,¹⁰¹ their role in the regulation of vascular responsiveness to insulin remains elusive. Finally, impaired insulin-induced stimulation of neural vasodilator pathways¹⁰² could also contribute to attenuated vasodilation in obesity.

In summary, there is some evidence that in obese subjects, endothelial dysfunction could contribute to the impairment in insulin-induced stimulation of muscle blood flow, but the exact underlying defect remains unknown, and alternative mechanisms such as augmented stimulation of vasoconstrictor mechanisms also must be explored.

Cardiovascular Effects of Short-term Hyperinsulinemia in Insulin-Resistant States Other Than Obesity
Insulin resistance is a common feature of essential hypertension,¹⁰³ and insulin-induced vasodilation has been reported to be either normal^51,104 or impaired^76,105 in such patients. The underlying mechanism is not clear but could include augmented stimulation of -adrenergic vasoconstriction¹³ and/or endothelial dysfunction, as reported by some^94,106 but not all¹⁰⁷ studies. A few studies examined sympathetic and vascular effects of insulin infusion in patients with non–insulin-dependent diabetes mellitus (NIDDM). In obese NIDDM subjects, insulin infusion failed to stimulate leg blood flow even at pharmacological concentrations in one study,⁴⁶ whereas blood flow responses were found to be normal in another report¹⁰⁸ In lean NIDDM subjects, insulin-induced stimulation of both sympathetic nerve activity (as determined by measurements of total-body norepinephrine spillover) and muscle blood flow has been reported to be normal.⁵⁹ Thus findings on vascular effects of insulin in patients with hypertension and NIDDM are sparse and conflicting.

	Pathophysiological Consequences of the Sympathetic and Vascular Actions of Insulin

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Cardiovascular Consequences of Sympathetic Overactivity
Epidemiological studies indicate that there exists an association between obesity, insulin resistance, and hypertension^2,3 and that insulin is an independent predictor of coronary artery disease.⁴ The underlying mechanism relating these disorders is not known, but insulin resistance is thought to play an important pathogenic role because it often persists during antihypertensive treatment¹⁰⁹ (and is not found in secondary hypertension^110,111) and is present in offspring of hypertensive parents (who are prone to develop hypertension later in their life) at a time while they are still normotensive.¹¹²

Over the past two decades, evidence has accumulated indicating that insulin resistance is associated with sympathetic activation. In rats, increased caloric intake and induction of insulin resistance by sucrose or fructose feeding augment sympathetic nerve activity and arterial pressure,^17,18 whereas caloric restriction and weight loss decrease sympathetic nerve activity, blood pressure, and plasma insulin concentration in both animals¹¹³ and humans.^100,114 In humans, sympathetic nerve activity is closely related to body fat ^15,36,37 and regional vascular resistance.¹⁵ Sympathetic activation could augment systemic vascular resistance and arterial pressure by stimulation of -adrenergic vasoconstriction and activation of the renin-angiotensin system.¹¹⁵ Such vasoconstriction could be reinforced by sympathetically mediated trophic effects on the vasculature.¹¹⁶ Finally, sympathetic activation promotes atherosclerosis and could trigger acute cardiovascular events by increasing platelet number and aggregability.¹¹⁷

The evidence of whether chronic hyperinsulinemia contributes to such sympathetic activation is conflicting. In dogs, insulin infusion for several weeks did not have any detectable effect on blood pressure (and presumably sympathetic nerve activity).¹¹⁸ Conversely, in Dahl salt-sensitive rats but not in the salt-resistant strain, chronic hyperinsulinemia increases arterial pressure by sympathetic activation.⁷ These observations suggest that species differences and genetic factors could be important determinants of the sympathetic (and blood pressure) response to chronic hyperinsulinemia. Consistent with this hypothesis, Pima Indians, who have a high incidence of insulin resistance, have normal sympathetic-nerve activity³⁶ and no augmented incidence of hypertension, whereas insulin-resistant Caucasians have increased sympathetic nerve activity^15,37 and a high frequency of hypertension. Recent observations in a patient of Caucasian origin with an insulinoma indicate that sustained hyperinsulinemia is not always associated with sympathetic activation.¹¹⁹ In this patient, before surgery, despite a roughly fourfold elevation of the plasma insulin concentration, the rate of sympathetic nerve firing was comparable to the rate observed several weeks after the removal of the insulinoma when plasma insulin concentration was normal. The lack of sympathetic activation before surgery could be related to downregulation of central insulin sensitive receptors in the face of sustained hyperinsulinemia. Interestingly, in patients with insulinoma the incidence of hypertension is not augmented, and blood pressure remains unchanged after removal of the tumor.^119,120

With regard to chronically hyperinsulinemic obese subjects, these findings may suggest that the augmented rate of sympathetic-nerve firing could be related to some (as yet unidentified) factor other than hyperinsulinemia itself. Possible candidates could include free fatty acids and the recently described antiobesity hormone leptin. Free fatty acids are often elevated in the plasma of obese subjects,¹²¹ and when infused into the hepatic circulation of rats, stimulate sympathetic nerve activity and increase blood pressure.¹²² Leptin levels are elevated in human obesity.¹²³ In rodents, this hormone stimulates sympathetic outflow¹²⁴ and potentiates sympathetically mediated pressor responses.¹²⁵ Finally, it is possible that in contrast to patients with an insulinoma, obese subjects may not develop resistance to the sympathoexcitatory effects of insulin.

A reduced sensitivity to the metabolic actions of insulin may be acquired or inherited. With regard to the latter, offspring (as yet normal) of parents with NIDDM¹²⁶ and parents with essential hypertension¹¹² already have insulin resistance and may offer a model to examine sympathetic nerve activity before the development of hypertension. In offspring of hypertensive subjects, resting sympathetic nerve activity was found to be normal, whereas sympathetic responsiveness to stress appeared to be augmented.¹²⁷

In summary, there is mounting evidence that in animal species and human populations in whom insulin resistance is associated with a high incidence of cardiovascular complications, sympathetic nerve activity is augmented and could play an important pathogenic role. The underlying triggering mechanism is unclear, but there is little evidence so far that chronic hyperinsulinemia per se contributes importantly to sympathetic overactivation.

Metabolic Consequences of Sympathetic Overactivity
Earlier studies using systemic exogenous norepinephrine infusion to examine the metabolic consequences of sympathetic activation have produced conflicting results and shown decreased,¹²⁸ unaltered,¹²⁹ or augmented⁹² insulin sensitivity. Systemic norepinephrine infusion, however, only very imperfectly mimics physiological sympathetic activation that may be highly selective and where only a small proportion of the norepinephrine released at sympathetic nerve terminals reaches the circulation. Recent studies, overcoming these limitations, have provided conclusive evidence that in healthy subjects, acute sympathetic activation modulates insulin stimulation of glucose metabolism. For example, unloading of cardiopulmonary receptors, a maneuver that evokes selective reflex sympathetic activation in skeletal muscle tissue, reduces the insulin-induced stimulation of muscle glucose uptake by 15% to 25%.^{52,91,130,131} The underlying mechanisms could include both vascular (a reduction in muscle perfusion and in turn, substrate delivery) and/or cellular (direct action of norepinephrine at the skeletal muscle cell) actions. Recent observations suggest that -adrenergic blockade with phentolamine infusion markedly attenuates the reduction of muscle glucose uptake evoked by unloading of cardiopulmonary baroreceptors, whereas ß-adrenergic blockade had no detectable effect.⁹¹ -Adrenergic blockade could exert its beneficial effects either by a direct action on the skeletal muscle cell or indirectly by augmenting blood flow to skeletal muscle tissue. Consistent with these acute studies, long-term treatment with -adrenergic antagonists increases insulin sensitivity in spontaneously hypertensive rats¹³² and obese patients with hypertension.¹³³

The inhibition of the insulin-stimulated muscle glucose uptake is seen only with the sympathetic overactivation evoked by the superposition of cardiopulmonary baroreceptor unloading and insulin/glucose infusion¹³⁰ but not with the normal activation evoked by insulin/glucose infusion alone.⁴² Consistent with these findings in humans, in the perfused rat hindlimb preparation, norepinephrine, when infused at a high rate (approximating the one predicted to occur at activated sympathetic vasoconstrictor synapses) inhibits insulin-induced muscle glucose uptake, whereas when infused at a low rate it has no inhibitory effect.¹³⁴ In the clinical setting, pathological states associated with sympathetic overactivation in skeletal muscle such as obesity,^15,36,37 heart failure,¹³⁵ and cirrhosis¹³⁶ are characterized by insulin resistance. The underlying mechanism is not clear, but in both experimental animals and humans, insulin sensitivity is determined at least in part by skeletal muscle capillary density and fiber type.¹³⁷ Skeletal muscle consists of slow-twitch fibers, characterized by high insulin binding and sensitivity, and fast-twitch fibers that have the opposite characteristics.¹³⁸ In rats, sustained sympathetic stimulation causes a slow- to fast-twitch fiber transition.¹³⁹ Taken together, these observations could be consistent with the concept put forward by Julius and Gudbrandsson¹⁴⁰ that sustained sympathetic activation, possibly by increasing the proportion of insulin-resistant slow-twitch muscle fibers and in turn decreasing muscle capillary density, contributes to insulin resistance.

There is preliminary evidence that not only sympathetic overactivity but also sympathetic denervation could be associated with insulin resistance. It is well established that muscle denervation results in insulin resistance,¹⁴¹ an effect that is not related to impaired insulin binding to its receptor or impaired activation of tyrosine kinase.¹⁴² In rats, sympathetic denervation abolishes the increase in muscle¹⁴³ and brown adipose tissue¹⁴⁴ glucose uptake evoked by stimulation of the ventromedial hypothalamus. In humans, local insulin infusion causes less stimulation of muscle glucose uptake (and no increase in forearm oxygen metabolism)¹⁴⁵ than systemic insulin infusion,⁶⁵ a difference that could be related to the lack of sympathoexcitation during local insulin infusion.¹³

In summary, these observations could be consistent with the hypothesis that the sympathetic nervous system plays a pivotal role in the regulation of insulin-stimulated muscle glucose uptake, with both excessive and absent sympathetic nerve activity being associated with metabolic insulin resistance.

Cardiovascular Consequences of Impaired Insulin Stimulation of Blood Flow
As shown earlier in this review, there is preliminary evidence that insulin-resistant states may be associated with endothelial dysfunction.^{94,95,106,146} The underlying mechanism is not clear but could include concomitant hypercholesterolemia-induced,¹⁴⁷ and/or free fatty acid–induced⁹⁶ endothelial dysfunction. Interestingly, the vasodilator response to acetylcholine has recently been found to be impaired in yet normotensive offspring of hypertensive parents, suggesting that genetic factors that may predispose to insulin resistance and hypertension also are associated with endothelial dysfunction.¹⁴⁸ In this regard, recent findings in vitro suggest that in endothelial cells, insulin stimulation of nitric oxide production and glucose transport may share common signaling pathways.⁵⁸ Conceivably, an acquired and/or inherited defect of this common signaling pathway could provide a scientific basis for both vascular and metabolic insulin resistance. The resulting endothelial dysfunction may tip the balance between pressor and depressor actions of insulin in favor of the former and ultimately result in hypertension and augmented cardiovascular morbidity.

Metabolic Consequences of Impaired Insulin Stimulation of Blood Flow
Since insulin increases muscle blood flow, the obvious question arises whether this effect plays a role in its main action, namely the promotion of glucose disposal in skeletal muscle tissue. Stimulated by the pioneering report of Laakso and colleagues⁵ providing evidence consistent with this hypothesis and the ensuing speculation that insulin may stimulate capillary flow,¹⁴⁹ several studies have examined the effects of an acute augmentation or inhibition of blood flow on insulin-stimulated muscle glucose uptake. The results are conflicting. In humans, one-legged physical training improves muscle glucose uptake, an effect that appears to be related in part to augmented insulin-induced stimulation of muscle blood flow after training.¹⁵⁰ In healthy subjects, angiotensin II infusion has been found to potentiate insulin-induced stimulation of leg glucose uptake, possibly by redistributing blood flow away from the insulin-insensitive kidney toward insulin-sensitive leg muscle.⁸⁵ On the other hand, in patients with NIDDM, angiotensin II infusion increases insulin sensitivity in the absence of a detectable hemodynamic effect, which suggests that hemodynamic actions may not be the sole underlying mechanism.¹⁵¹ In lean subjects, stimulation of blood flow by methacholine infusion into the femoral artery has been reported to potentiate insulin-induced stimulation of regional glucose uptake,²³ whereas acute reduction of femoral blood flow by intra-arterial L-NMMA infusion had the opposite effects.¹⁵² Conversely, others reported that prevention of vasodilation by L-NMMA during insulin/glucose infusion did not alter stimulation of whole body glucose uptake and glucose oxidation in healthy subjects.^50,153 Infusion of bradykinin into the femoral artery that increased femoral blood flow by roughly 70% did not have any detectable effect on insulin-stimulated muscle glucose uptake, as it resulted in a proportionally equal decrease in leg glucose extraction.⁵³ Finally, in patients with essential hypertension, doubling of the forearm blood flow by superimposing an intra-arterial adenosine infusion on a systemic insulin/glucose infusion did not further stimulate glucose uptake as compared with the control forearm, because the increase in flow was offset by a decrease in glucose extraction.¹⁴⁵

In summary, findings regarding the role of blood flow as an independent determinant of muscle glucose uptake are conflicting. This may be related at least in part to differences in study design, dose, and pharmacology of vasoactive agents used, confounding effects of vasoactive agents on other systems known to modulate glucose metabolism, and limitations of the measurement methods for muscle microcirculation.

	Conclusions and Future Directions for Research

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Many questions remain open to further investigation of the underlying mechanisms relating the cardiovascular and metabolic actions of insulin. What is now clear, however, is that the sympathetic nervous system and the L-arginine–nitric oxide pathway are emerging as central players in the mediation of these actions. During short-term hyperinsulinemia, insulin-induced sympathoexcitation helps to maintain blood pressure, and both sympathetic overactivation and denervation are associated with metabolic insulin resistance. Sympathetic overactivation characterizes several insulin-resistant states and could contribute to augmented cardiovascular morbidity and impaired insulin sensitivity in such patients. A primary goal of future work would be to identify the stimulus triggering sympathetic overactivation in insulin-resistant patients and to determine how genetic factors may modulate this response. It will also be important to explore the mechanism(s) by which sympathetic overactivation may contribute to metabolic insulin resistance.

Stimulation of nitric oxide release plays an important role in the mediation of the vasodilator action of insulin, which is impaired in obesity. It will now be important to explore the mechanisms that may result in impaired vasodilation in obesity, and factors that may impair nitric oxide release or stimulate vasoconstrictor mechanisms should be looked for. Another much-disputed area that needs further study is the potential role of muscle blood flow as an independent determinant of insulin-stimulated muscle glucose uptake. This will require more adequate measurements of capillary recruitment and flow in skeletal muscle tissue. These are only a few of the challenges that need to be overcome for a better understanding of the cross-talk between insulin, the sympathetic nervous and cardiovascular systems, and glucose metabolism and ultimately the development of new therapies for vascular and metabolic diseases.

	Acknowledgments

 
The authors' research was supported by grants from the Swiss National Science Foundation (32 to 28668.90, 32 to 36280.92, and 32 to 046 797), the International Olympic Committee, the Emma Muschamp Foundation, and the Placide Nicod Foundation. We would like to thank Drs Peter Vollenweider, Denis Randin, Laurent Vollenweider, Reza Owlya, Lionel Trueb, Mattia Lepori, and Luc Tappy for their invaluable contributions to this work. We are indebted to Dr Pascal Nicod for his superb support and many stimulating discussions and to Drs Peter Vollenweider and Pascal Nicod for their critical review of the manuscript.

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