Amale Lteif

Obesity, Insulin Resistance, and the Metabolic Syndrome Determinants of Endothelial Dysfunction in Whites and Blacks

Background—Insulin resistance is strongly associated with obesity and other components of the metabolic syndrome (MS). The relative importance of these components in the determination of endothelial function is unknown. Furthermore, there is conflicting evidence about whether ethnic differences exist in the relative importance of these components in regard to other cardiovascular outcomes. We evaluated the contributions of insulin resistance, obesity, and the other components of the MS to impaired endothelial function. Methods and Results—The relationships of the MS components (as defined according the National Cholesterol Education Program) and insulin resistance (estimated using the homeostasis model) with endothelium-dependent vasodilation were examined in 42 white and 55 black subjects. Endothelium-dependent vasodilation was assessed as the increment in leg blood flow (measured by thermodilution) after exposure to methacholine chloride. Waist circumference, glucose, blood pressure, and insulin resistance distributions did not differ between ethnic groups; blacks in our sample had higher HDL cholesterol (1.31 versus 1.09 mmol/L; P<0.001) and lower triglyceride levels (1.01 versus 1.37 mmol/L; P=0.005) than white subjects. In the absence of the MS, black subjects exhibited reduced endothelium-dependent vasodilation compared with white subjects (P=0.005), and both groups demonstrated significantly worse endothelial function when the MS was present (maximal increase in leg blood flow: blacks: 107±9% MS absent, 53±16% MS present; whites: 163±16% MS absent, 54±18% MS absent; P=0.007, MS absent versus present; P=NS for interaction of ethnicity and MS). Multivariable regression analysis examining relationships of endothelial function with the 5 MS components (analyzed as continuous variables) revealed independent relationships only with waist circumference (P=0.01) and systolic blood pressure (P=0.02). Waist circumference was no longer independently associated after adding insulin resistance to the modeling (P=0.02 for log of homeostasis model index of insulin resistance, P=0.02 for systolic blood pressure). Ethnicity still exerted an independent effect on endothelial function after accounting for the above components (P=0.04 for an additional effect of ethnic status on endothelial function), with an ethnic difference in the effect of insulin resistance on endothelial function (P=0.046 for interaction of ethnicity and log of homeostasis model index of insulin resistance). Conclusions—These findings suggest that insulin resistance and systolic blood pressure are the principal determinants of endothelial dysfunction in the MS and that there are ethnic differences in the relative importance of these factors. These differences may imply different benefits from treatments targeting blood pressure or insulin resistance in different ethnic groups.

Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU · m−2 · min−1) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 μmol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 ± 5.7 vs. 107.4 ± 18.9 mg/min with BQ123), with no change in lean subjects (103.7 ± 11.4 vs. 88.9 ± 16.3, P = 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects.

Diabetes and heart disease: An evidence-driven guide to risk factors management in diabetes

Type 2 diabetes is a worldwide epidemic. Cardiovascular diseases remain the major cause of death in patients with diabetes, partly because of the association of diabetes and the metabolic syndrome. In this review, we will discuss the evidence for treatment and prevention of cardiovascular diseases in patients with diabetes. Aggressive treatment of hypertension and dyslipidemia is at the cornerstone in the management of heart disease in those patients. Despite its known benefit on the prevention of the microvascular complications of diabetes, intensive glycemic control may or may not have a significant effect on reducing macrovascular diseases. Finally, lifestyle changes and other cardiovascular therapies aimed at preventing heart disease may also prevent or delay the development of diabetes.

Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium‐dependent vasodilation in humans

Individual effects of hyperglycaemia and obesity to impair vascular health are recognized. However, the relative contributions of dysglycaemia versus other obesity‐related traits to vascular dysfunction have not been systematically evaluated.

Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans

Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU.m(-2).min(-1), respectively), with the goal of matching insulins nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-1 (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 +/- 10.2 pmol/l vs. 518.4 +/- 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction.

Insulin resistance as a therapeutic target for improved endothelial function: metformin.

Endothelial dysfunction is a feature of a variety of clinical states of insulin resistance, and increasingly it is recognized that pre-diabetic states of insulin resistance are associated not only with insulin resistance but with increased cardiovascular risk. The metabolic syndrome which typically accompanies insulin resistance brings aberrations in a number of classical cardiovascular risk factors, but it appears that insulin resistance itself represents an additional, non-classical risk factor. Therefore, the approach to treating the endothelium in patients with the metabolic syndrome might include therapies targeting insulin resistance. In this review, we provide a detailed overview of the current state of knowledge regarding the biguanide metformin and its effects on the endothelium. Its mode of action is reviewed, along with the available data from laboratory and experimental studies related to vascular function in animals and in humans. Metformin has beneficial effects on endothelial function which appear to be mediated through its effects to improve insulin resistance. Therapeutically targeting insulin resistance appears to be a viable route to improving endothelial function in clinical states of insulin resistance.

Effects of losartan on whole body, skeletal muscle and vascular insulin responses in obesity/insulin resistance without hypertension

Aims: Renin‐angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin‐mediated vasodilation, and thereby improve insulin‐stimulated glucose uptake in skeletal muscle of insulin‐resistant subjects.

Role of Endogenous ET‐1 in the Regulation of Myocardial Blood Flow in Lean and Obese Humans

Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH3]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine‐stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 µmol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123‐induced increase in resting myocardial perfusion of ∼40%, not different between lean and obese subjects (BQ123‐induced increase in flow: lean 0.12 ± 0.20, obese 0.32 ± 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123‐induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine‐stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity.

A cross-sectional evaluation of seasonality as a determinant of endothelial function.

Endothelium-dependent vasodilation is impaired in obese versus lean humans. We set out to evaluate whether agonist-mediated endothelium-dependent vasodilation varies by season in a cross-sectional dataset of lean and obese humans, and whether this effect differed by obesity status. All vascular studies performed in our laboratory over a 12 year period from 1997 to 2009 were evaluated. Endothelium-dependent vasodilation was measured invasively using thermodilution in the leg as the response to intra-arterially infused methacholine chloride. Resting blood pressure was measured concurrently by cuff and intra-arterially. The association of endothelium-dependent vasodilation and blood pressure measurements with season was evaluated, comparing responses in lean and obese subjects. Endothelium-dependent vasodilation differed between lean and obese subjects, and varied across seasons (p=0.02), but without an interaction between season effect and obesity status. The proportion of obese versus lean subjects differed significantly across seasons in our dataset, and after adjusting for this factor the apparent seasonal variation in endothelium-dependent vasodilation was lost (p=0.12), and was not present in either lean or obese subjects separately. Systolic arterial blood pressure varied across seasons, and this effect remained significant after adjusting obesity status (p=0.019 and p=0.043 for blood pressures measured intra-arterially and by cuff respectively). In our cross-sectional dataset, seasonal variations in blood pressure were seen but we did not observe an association between season and endothelium-dependent vasodilation in lean or obese subjects.

Endothelin contributes differently to peripheral vascular tone and blood pressure in human obesity and diabetes

Endothelin contributes to abnormalities in peripheral blood vessel function of subjects with obesity, with or without concurrent type 2 diabetes mellitus, but it is unknown if endothelin contributes specifically to obesity and diabetes-associated changes in blood pressure. We evaluated the effect of systemic endothelin antagonism on peripheral and central hemodynamics and peripheral vascular tone in lean, obese, and type 2 diabetic subjects without overt hypertension by cuff plethysmography. We measured the effects of acute systemic infusions of BQ123 (an antagonist of type A endothelin receptors) in seven lean (body mass index [BMI] 22.7 +/- 3.2 kg/m(2)), seven obese (BMI 35.8 +/- 4.6), and six diabetic subjects (BMI 38.2 +/- 5.0, glycosylated hemoglobin 8.1 +/- 2.2%). BQ123 was infused via antecubital vein sequentially at infusion rates from 0.1 to 1.0 mumol/min. Diastolic blood pressure was significantly lower than baseline across this dose range, but without a clear dose dependence and without differences in the dose response across groups. Obese and diabetic subjects exhibited progressive dilation of peripheral blood vessels (P </= .01), with 0.03 and 1.0 mumol/min BQ123 (P = .03 comparing integrated response across groups). No significant changes were observed in systolic blood pressure, cardiac index, or stroke index. These observations confirm the relevance of endothelin in the abnormal regulation of peripheral vascular tone in obesity and diabetes, but they argue against a specific effect of endothelin in diabetes- and obesity-associated blood pressure elevations.