Abstract
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality that is seen in both hypertensive and normotensive populations. Insulin resistance (IR) strongly correlates with SSBP and affects nearly 50% of salt sensitive people. While the precise mechanism by which IR and SSBP relate remains elusive, several common pathways are involved in the genesis of both processes, including vascular dysfunction and immune activation. Vascular dysfunction associated with insulin resistance is characterized by loss of nitric oxide (NO)-mediated vasodilation and heightened endothelin-1 induced vasoconstriction, as well as capillary rarefaction. It manifests with increased blood pressure (BP) in salt sensitive murine models. Another common denominator in the pathogenesis of insulin resistance, hypertension, and salt sensitivity (SS) is immune activation involving pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, IL-1β, and IL-6. In the last decade, a new understanding of interstitial sodium storage in tissues such as skin and muscle has revolutionized traditional concepts of body sodium handling and pathogenesis of SS. We have shown that interstitial Na+ can trigger a T cell mediated inflammatory response through formation of isolevuglandin protein adducts in antigen presenting cells (APCs), and that this response is implicated in salt sensitive hypertension. The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that modulates both insulin sensitivity and BP. PPARγ agonists increase insulin sensitivity and ameliorate salt sensitivity, whereas deficiency of PPARγ results in severe insulin resistance and hypertension. These findings suggest that PPARγ plays a role in the common pathogenesis of insulin sensitivity and salt sensitivity, perhaps via effects on the immune system and vascular function. The goal of this review is to discuss those mechanisms that may play a role in both SSBP and in insulin resistance.
Highlights
Salt sensitivity (SS) of blood pressure (BP) is a phenotype characterized by changes of BP that parallel changes in dietary salt intake
By examining T cell receptor (TCR) usage, we showed that accumulation of an oligoclonal CD8+ T cell population in the kidney contributes to hypertension by inducing endothelial dysfunction and vascular rarefaction as well as sodium and volume retention (Trott et al, 2014)
Methylglyoxal (MGO), a metabolite of the glycolysis pathway that is increased in diabetes, has been proposed to contribute to the development of salt sensitivity as well as insulin resistance through oxidative stress and advanced glycation endproducts (AGE; Guo et al, 2009)
Summary
Salt sensitivity (SS) of blood pressure (BP) is a phenotype characterized by changes of BP that parallel changes in dietary salt intake. Salt-Sensitivity and Insulin Resistance populations, SS is well-known to be associated with insulin resistance (IR; Zavaroni et al, 1995; Fuenmayor et al, 1998; Suzuki et al, 2000; Giner et al, 2001). Epidemiological studies suggest that approximately 50% of salt sensitive individuals are insulin resistant (Reaven, 2003), independent of confounding factors such as age, obesity, and glucose intolerance (Galletti et al, 1997). The degree of salt sensitivity seems to correlate with the severity of IR (Zavaroni et al, 1995; Giner et al, 2001), suggesting a causal relationship between the two states. This article reviews the existing evidence on the interplay between salt sensitivity and insulin resistance and propose mechanisms to explain their relationship
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