Does microvascular dysfunction link obesity with insulin resistance and hypertension?

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Publisher: Expert Reviews Ltd.
Document Type: Article
Length: 4,899 words

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Author(s): Renate T de Jongh [[dagger]] 1 , Erik H Serné 2 , Etto C Eringa 3 , Richard G IJzerman 4 , Coen DA Stehouwer 5

Keywords:

adipokines; hypertension; insulin resistance; microcirculation; obesity

Obesity is becoming an increasing public health burden. Obesity, but even more its associated clinical disorders such as hypertension and insulin resistance, contribute to an increase in cardiovascular morbidity and mortality. In order to develop interventions to postpone or, preferably, prevent the development of obesity-associated insulin resistance and hypertension, a better understanding of the primary mechanisms involved is necessary. In this perspective, we postulate that impairment of microvascular function links obesity with insulin resistance and hypertension. Furthermore, we hypothesize that obesity-associated microvascular dysfunction precedes the development of insulin resistance and hypertension. Finally, we will discuss possible explanatory mechanisms and therapeutic targets.

Microvascular function is impaired in obesity

Obese individuals are characterized by microvascular defects in different tissues. First, in rat muscle, obesity is associated with impaired insulin-induced capillary recruitment [1] and diminished arteriolar reactivity to reactive hyperemia [2] . In addition, in human muscle, obesity is characterized by decreased capillary density, so-called rarefaction [3,4] . Second, in coronary arteries, obesity is associated with coronary endothelial dysfunction [5] . Third, in skin, it has been demonstrated that obese individuals have impaired increases in capillary recruitment or laser Doppler flow to different stimuli [6,7] . In addition, measures of obesity in lean individuals are related strongly to skin microvascular function [8-10] . Taken together, a clear association between obesity and microvascular dysfunction in different tissues has been established. Therefore, microvascular dysfunction is likely to represent a generalized characteristic of obesity.

Insulin resistance as a result of microvascular dysfunction

Clark and colleagues have introduced the concept that insulin switches blood flow from non-nutritive to nutritive capillary beds, thereby enhancing access of glucose and insulin to muscle tissue independently of changes in total flow [11] . In a constant-flow rat hindlimb model, vasoconstriction leads to decreases in nutritive flow and impairs insulin-induced muscle glucose uptake [12] . In rat muscle in vivo , insulin increases nutritive flow as measured by the metabolism of 1-methylxanthine, laser Doppler flow or contrast-enhanced ultrasound [13-15] . In humans, insulin has been shown to enhance the distribution volume of glucose [16-18] , skin capillary recruitment [19] and skin microvascular vasomotion, indicating increased endothelial and possibly neurogenic activity [20] . Furthermore, insulin recruits microvascular elements and increases muscle glucose uptake before it increases total blood flow [15,18,21] . A physiological link between insulin-mediated microvascular effects and glucose uptake is further suggested by a concomitant impairment of insulin-mediated glucose uptake and insulin-mediated effects on microvascular function in obesity [1,7,22] . These data underline that insulin, by reducing prearteriolar tone or altering arteriolar vasomotion, redirects blood flow from non-nutritive to nutritive capillary beds and, thereby, contributes to the regulation of glucose uptake.

The hypothesis that microvascular dysfunction may precede and even predict the development of insulin resistance is supported by the presence of microvascular dysfunction in normoglycemic individuals with a genetic predisposition to develop diabetes mellitus Type 2 [23] . In addition, retinal arteriolar narrowing prospectively increases the risk...

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Gale Document Number: GALE|A223154432