0 2.5 5 7.5 10 12.5

Methacholine Chloride Infusion Rate (|Lig/min)

Fig. 5. Percent change (%A) from baseline in leg blood flow (LBF) in response to graded intrafemoral artery infusions of the endothelium dependent vasodilator methacholine chloride in groups of lean, obese, and obese type 2 diabetic subjects. (From ref. 11a.)

Other evidence for impaired vascular action of insulin in obesity comes from a recent study by Westerbacka (66). The authors studied the effect of obesity on insulin's ability to decrease arterial stiffness. In contrast to lean controls, arterial stiffness did not change in response to hyperinsulinemia with insulin levels of about 70 pU/mL, and decreased only slightly in response to insulin levels of about 160pU/mL.

Type 2 diabetes was associated with even more pronounced impairment of insulinmediated vasodilation. In our study (64), only supraphysiological hyperinsulinemia (~2000 pU/mL) achieved about a 33% rise in blood flow and the limitation in flow increments could not be overcome by higher insulin concentrations (Fig. 1).

Because insulin-mediated vasodilation, which depends on NO, is impaired in obesity and type 2 diabetes, we studied whether this impairment results from defective endothelial function or whether or defective NO activity. To this end, we generated dose-response curves for the leg blood-flow response to the endothelium-dependent vasodilator metha-choline chloride and to the endothelium-independent vasodilator sodium nitroprusside. Leg blood-flow in response to methacholine increased threefold in the lean but only twofold in both obese and type 2 diabetics (Fig. 5). In contrast, the leg blood-flow response to sodium nitroprusside did not differ between lean, obese and type 2 diabetics. Resistance to leg blood-flow increments in response to the endothelium-dependent vasodilator bradykinin has also been recently reported in obesity (67), thus supporting our data that NO production is impaired.

In addition to obesity and type 2 diabetes, elevated blood pressure levels are associated with impaired insulin-mediated vasodilation (68). Laine and associates (67) demonstrated that insulin-stimulated leg blood flow increased by 91% in the control subjects but only by 33% in the hypertensive subjects. This is important because hypertension has been shown by Forte and associates (69) to be associated with significantly decreased rates of NO production. Therefore, it is likely that in hypertension, impaired NO production is responsible for the blunted vasodilation in response to hyperinsulinemia.

Direct measurements of the effect of obesity and type 2 diabetes on NO production in skeletal muscle, however, have yielded conflicting data. In one preliminary study (70), we measured insulin-induced changes in NO flux rates in subjects exhibiting a wide range of insulin sensitivity. NO flux was calculated by multiplying the concentration of nitrite and nitrate times leg blood-flow rates before and after 4 hours of euglycemic hyperinsulinemia. In this study, NO flux rates more than doubled in athletes who exhibited high insulin sensitivity but did not change in diabetics who were insulin resistant. However, Avogarro and associates (71), who measured NO flux rates in the forearm in obese and type 2 diabetic subjects, were unable to detect a difference in NO flux between the two groups. The reason for the discrepant observations are not clear but further research will help to clarify this issue. More recently, measurements of whole-body NO production, using labeled l-arginine, the precursor of NO, revealed lower NO production rates in type 2 diabetics as compared to normal subjects (72), which provides more direct evidence for impaired NO production in type 2 diabetes.

Taking the data together, basal whole-body NO production is decreased in hypertensive and in type 2 diabetic patients, and it is highly likely that obesity, hypertension, and type 2 diabetes exhibit impaired NO production in response to euglycemic hyperinsulinemia. Because NO is not only a potent vasodilator but also possesses a number of antiatherogenic properties, this defect in NO production could theoretically contribute to the increased rate of CVD in insulin-resistant states such as obesity, hypertension, or type 2 diabetes.

The mechanism(s) of impaired insulin-mediated vasodilation in obesity or type 2 diabetes are not known. One of the metabolic abnormalities consistently observed in insulin resistance is elevated FFA levels. Elevation of FFA levels also induces insulin resistance, which may be mediated, in part, via impairment of insulin-mediated vasodilation. Therefore, we studied the effect of FFA elevation on endothelial function in lean, insulin-sensitive subjects. The results of this study indicated that moderate two- or threefold elevation of FFA levels sustained for 2 hours and achieved by systemic infusion of Intralipid plus heparin blunted the response to the endothelium-dependent vasodilator methacholine chloride (Fig. 6) but not to the endothelium-independent vasodilator sodium nitroprusside (73). Similar results were reported by de Kreutzenberg and colleagues, who measured forearm vascular responses to before and after elevation of FFA

(74). Interestingly, the postischemic flow response was also impaired by FFA elevation

(75). Importantly, elevation of triglyceride levels alone in our studies did not cause endothelial dysfunction. This notion is supported by studies from patients with low lipoprotein lipase activity who exhibit normal endothelial function (76) despite markedly elevated triglyceride levels.

To further investigate the relation among elevated FFA levels, insulin sensitivity, and insulin-induced vasodilation, we investigated the time-course effect of FFA elevation on insulin-mediated increments in blood flow. Four to 8 but not 2 hours of FFA elevation reduced insulin-mediated vasodilation (77). Furthermore, increments in NO flux in response to euglycemic hyperinsulinemia was nearly completely abrogated by superimposed FFA elevation. This effect on insulin-induced vasodilation was only observed when FFA elevation also caused insulin resistance. These data indicate that insulinmediated vasodilation is coupled to insulin's effect on glucose uptake. In contrast, muscarinergic agonist-induced endothelium-dependent vasodilation appears to be regulated by other mechanisms as this signaling pathway can be disrupted by FFA elevations as short as 2 hours (73). Indirect evidence for this proposed effect of FFA elevation on

Fig. 6. Leg blood flow (LBF) increments (A% ) in response to graded intrafemoral artery infusions of methacholine chloride during infusion of saline (open squares) or during 20% fat intralipid emulsion (closed squares) combined with heparin designed to increase systemic circulating free fatty acid levels two- or threefold. (From ref. 11a.)

Fig. 6. Leg blood flow (LBF) increments (A% ) in response to graded intrafemoral artery infusions of methacholine chloride during infusion of saline (open squares) or during 20% fat intralipid emulsion (closed squares) combined with heparin designed to increase systemic circulating free fatty acid levels two- or threefold. (From ref. 11a.)

insulin-mediated vasodilation comes from muscle biopsy studies in response to hyperinsulinemic euglycemia with and without superimposed FFA elevation (78). Dresner and colleagues (78) demonstrated that insulin resistance induced by FFA elevation was associated with decreased PI3K activity in skeletal muscle. Therefore, if insulin-signaling pathways are shared in endothelial cells and skeletal muscle, one may expect impaired insulin signaling in the endothelial cells in response to euglycemic hyperinsulinemia with superimposed FFA elevation.

Other evidence for the effect of elevated FFA levels to reduce endothelial NO production come from in vitro studies. Davda (79) and co-workers demonstrated a dose-dependent effect of oleic acid to impair NO release from cultured endothelial cells. Niu (80) and colleagues demonstrated that elevation of oleic acid attenuated the aortic strip relaxation in response to acetylcholine. Taken together, these findings from in vivo and in vitro studies strongly suggest a causal role of elevated FFA levels to impair endothelial function and decrease the rates of NO release.

Different mechanisms by which FFA may impair endothelial function could be via increased plasma levels of asymmetric dimethyl-L-arginine (ADMA) and/or via increased endothelin action. Lundman and associates (81) demonstrated that acute elevation of triglyceride (and likely elevated FFA) levels achieved by systemic infusion of a triglyceride emulsion was associated with elevation of ADMA levels and decreased flow-mediated vasodilation. Similarly, Fard and associates (82) showed that a high fat meal given to diabetic subjects resulted in increased plasma ADMA levels and impaired flow-mediated vasodilation.

Endothelin levels have been shown to increase in response to FFA elevation. Because elevated FFA levels are a hallmark of obesity and type 2 diabetes mellitus, Cardillo and associates (83) and Mather and associates (84) infused an inhibitor of endothelin, BQ 123 (specific inhibitor of the endothelin 1A receptor) directly into the brachial and femoral artery respectively. Both studies revealed more pronounced vasodilation in response to BQ123 in the obese and diabetic subjects, indicating an increased endothelin-dependent tone in the insulin-resistant subjects. Increased endothelin secretion in response to hyperinsulinemia may also contribute to the impaired vasodilation observed in insulin-resistant states (85).

The Metabolic Syndrome and Insulin's Effects on the Heart

Before discussing the effect of insulin on heart rate in insulin-resistant obese and diabetic subjects, two points should be made. First, basal heart rate and cardiac output (86) in obese and diabetic subjects is almost always increased as compared to lean subjects. Second, heart function in diabetes may be abnormal as a result of autonomic neuropathy. Thus, the data have to be interpreted with caution especially when comparing relative (A%) changes between insulin-sensitive and insulin-resistant groups.

The effect of insulin resistance on insulin-induced change in stroke volume has received little attention. Stroke volume did not change in our group of obese subjects (Fig. 3A) exposed to insulin concentrations of about 90 pU/mL. However, we may have failed to detect a small, less than 5% increase in stroke volume because of small group size. Muscelli and associates (87) however, report a near 10% rise in stroke volume at insulin concentrations of about 120 pU/mL. The reason for the different results is not clear. Groups were comparable in regards to body mass index or blood pressure. However, Muscelli and associates (87) used two-dimensional echocardiography whereas we used dye dilution technique to determine stroke volume. Thus, the discrepant results may be explained, at least in part, by different sensitivities of the methods by which cardiac output was determined.

We did not observe a change in heart rate in response to hyperinsulinemia about 90 pU/ mL in our obese subjects (Fig. 3B). In contrast to our findings, Vollenweider and associates detected about a 10% increase in heart rate in obese subjects with insulin levels comparable to our study (~100 pU/mL). Heart rate was also found to rise in a dose-dependent fashion in response to hyperinsulinemia (88) in type 2 diabetics.

Because stroke volume and heart rate did not change in our obese group (Fig. 3C), cardiac output did not change either. However, other studies report a significant 15% increment in obesity (87). In type 2 diabetes, data on changes in cardiac output in response to hyperinsulinemia are not available. Nevertheless, because heart rate has been reported to increase in diabetics in response to hyperinsulinemia, it is reasonable to assume that cardiac output may increase as well. Taken together, the observations suggest that insulin's stimulatory effect on stroke volume, heart rate, and cardiac output may be intact in obese and type 2 diabetic subjects.

Insulin's action on the heart may extend well beyond modulation of hemodynamics. Cardiomyocytes possess insulin receptors which are important in postnatal development of the heart (89). It is not known whether impaired insulin receptor signaling in the cardiomyocyte plays a role in the increased incidence of left ventricular hypertrophy and congestive heart failure observed in obesity and diabetes.

The Metabolic Syndrome and Insulin's Effects on the Sympathetic/ Parasympathetic Nervous System

When assessing the SNSA by measuring NE no differences were detected between lean and obese subjects (29,90,91). Tack and colleagues used tritiated NE combined with forearm blood-flow measurements to assess the effect of hyperinsulinemia on SNSA in the forearm of lean type 2 diabetic and controls. The results of the study were that insulin increased arterial and venous NE concentrations in both groups. For example, 45 minutes of hyperinsulinemia caused arterial NE levels to increase by 63.8 ± 14% and 41.3 ± 9.1% in diabetic and control subjects respectively. In both groups, the rise in NE concentration was as a result of higher rates of total body and forearm NE spillover. The changes in NE concentration and spillover were comparable between the diabetic and controls. Unfortunately, no obese subjects were studied which would have allowed to distinguish the effects of diabetes (hyperglycemia) from those of obesity.

When measured by micro-neurography, basal skeletal muscle SNSA was found to be elevated more than twofold in obesity (90-92). In diabetes, no microneurography data are available. In response to euglycemic hyperinsulinemia, SNSA increased significantly (29). Although the relative rise in SNSA was blunted in the obese subjects, the absolute levels of SNSA achieved during hyperinsulinemia were comparable between lean and obese subjects. These data suggest that SNSA is nearly maximally stimulated in obese insulin-resistant subjects and that added hyperinsulinemia is unable to increase SNSA above levels achieved in lean controls.

Only two groups have thus far studied the effect of the metabolic syndrome on PNSA. Unfortunately, the data are somewhat contradictory. Muscelli and associates (93) report an increase in the low-frequency/high-frequency (LF/HF) ratio in response to euglycemic hyperinsulinemia in lean normal subjects but not in obese insulin-resistant subjects. The authors conclude that insulin alters cardiac control by enhancing sympathetic outflow and withdrawal parasympathetic tone. On the other hand, Laitinen and associates (94) demonstrate the opposite, an increase in the LF/HF in obese insulin-resistant subjects but not in the normal controls. Certainly, these opposite findings require clarification. Nevertheless, both studies suggest that the effect of hyperinsulinemia on PNSA is modulated by the presence of the metabolic syndrome.

The Metabolic Syndrome and Insulin's Effect on the Kidney

The effect of euglycemic hyperinsulinemia on renal hemodynamics in obesity has not been studied. In one study assessing the effect of euglycemic hyperinsulinemia on renal function in type 2 diabetes, no differences in estimated renal plasma flow were observed. Thus, the scarce data suggest that insulin's effect on renal blood flow is intact in obesity and type 2 diabetes.

Insulin's effect on electrolyte handling has been well studied in type 2 diabetes but data on obesity are not available. The antinatriuretic effect of insulin is well preserved in type 2 diabetes. Gans and associates (88) report a fall in fractional sodium excretion fell by 43 ± 6% and 57 ± 9% in response to euglycemic hyperinsulinemia with insulin levels of 64 ± 12 and 1113 ± 218 pU/mL, respectively. Because no control group was available in this study, it is not possible to determine whether the antinatriuretic response was normal or exaggerated in type 2 diabetes. Exaggerated antinatriuresis could lead to volume retention and contribute to the development of hypertension.

The Metabolic Syndrome and Insulin's Effect on Blood Pressure

Insulin's effect on the heart, the SNS, and the kidneys appear to be intact in subjects with the metabolic syndrome. This is in contrast to the impairment of insulin's effect to vasodilate skeletal muscle vasculature, which contributes to the decrease in peripheral vascular resistance during euglycemic hyperinsulinemia. Therefore, because the product of cardiac output and vascular resistance determine blood pressure, one might expect euglycemic hyperinsulinemia to result in blood pressure elevation. In our study, euglcycemic hyperinsulinemia did not alter blood pressure in the obese subjects (Fig. 3D). Other groups have reported that blood pressure in response to euglycemic hyperinsulinemia increased (29), decreased (95), or remained unchanged (96) in obese and diabetic subjects. Thus, the current data do not support the idea that hyperinsulinemia per se is causally related to the blood pressure elevation associated with the metabolic syndrome.

The Metabolic Syndrome and Interactions Between Insulin and Norepinephrine

Although there is great interest in the effect of the metabolic syndrome on the vascular responses to vasopressors such as NE or angiotensin II, few data are available in humans. We have demonstrated that the pressure response to systemic infusion of NE is augmented in obesity (47). At similar NE concentrations, the obese subjects exhibited a nearly 50% more pronounced blood pressure rise than the lean controls. Furthermore, insulin's effect to attenuate the pressure response to NE was abolished by obesity.

The effect of insulin resistance on the pressure response to angiotensin II was evaluated by Gaboury and associates (97) in normotensive and hypertensive subjects. In nor-motensive subjects, no relationship between insulin sensitivity and the blood pressure response to angiotensin II was detected. However, insulin sensitivity correlated inversely with the blood pressure response to angiotensin II in the hypertensive subjects.

Taken together, these data suggest that vascular responses to pressors may be increased in insulin resistance, which could contribute to the development of hypertension. The data also indicate that the relationship between insulin resistance and pressure responsiveness is not linear and may be modulated by additional factors that are poorly understood.

Interventions to Ameliorate the Effects of the Metabolic Syndrome on the Vascular System

If the increased rate of CVD associated with metabolic syndrome is partially mediated via the effects of insulin resistance on the vascular system, amelioration of insulin resistance should improve the abnormalities of the vascular system, which have been described above. In other words, maneuvers that improve insulin sensitivity should result in lower blood pressure, decreased heart rate, reduced SNSA, and improved endothelial function. Unfortunately, only a few studies have assessed the effect of improved insulin sensitivity on insulin-mediated vasodilation and endothelial function.

Weight loss is known to improve insulin sensitivity and to lower blood pressure (98). Weight loss also decreases heart rate and reduces the heightened SNSA (99,100). Although no studies have yet examined the effect of weight loss on endothelial function one would predict that endothelial function improves as well (101). However, it is unclear whether endothelial function would return to completely normal levels.

Troglitazone, a thiozolidenedione derivative, has been described to improve insulin sensitivity (102) and lower blood pressure in obese subjects. Furthermore, troglitazone decreased peripheral vascular resistance in diabetics (103), and pioglitazone decreased blood pressure in diabetic subjects (104). These data suggest that improvement of insulin sensitivity without changes in body fat content ameliorates cardiovascular abnormalities observed with the metabolic syndrome.

Our own findings (105) using 600 mg of troglitazone per day for 3 months in obese females suffering from polycystic ovary syndrome suggest a beneficial effect of troglitazone on both insulin-mediated vasodilation and the blood-flow responses to the endothelium-dependent vasodilator methacholine chloride. In contrast to our study, Tack and co-workers (106) found no effect of troglitazone (400 mg per day for 8 weeks) on insulin-induced blood-flow increments in obese insulin-resistant subjects despite a 20% improvement in insulin sensitivity. Thus, given the sparse and somewhat contradictory literature about the effect of increased insulin sensitivity on insulin-mediated increments in blood flow and endothelial function, further studies are required. Nevertheless, reduction of insulin resistance leading to improved endothelial and vascular system function may result in decreased cardiovascular morbidity and mortality in obese, hypertensive, and diabetic subjects.

5 Ways To Get Rid Of The Baby Fat

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