**2. Physiopathological changes**

#### **2.1. Role of insulin**

countries. Although deaths from CVDs have declined in some developed countries with better healthcare interventions and systems and primary prevention, population growth and aging

Vascular diseases, including atherosclerosis, media calcification, macrovascular expression of diabetes vascular disease, and microangiopathy, are very prevalent in these patients and are

The nexus between microangiopathy and macroangiopathy is not yet fully explained, but it is much more important than a simple time line, although it could be said that microangiopathic pathology precedes macroangiopathy in 5–10 years in the natural history of the disease. Atherosclerosis occurs earlier in patients with diabetes, frequently with greater severity and a more diffuse distribution. Diabetes and metabolic syndrome are associated with vascular function abnormalities and ensuing morphological changes associated with vascular

One way to study vascular disease in diabetes mellitus is through experimental models in animals. One of them consists of feeding with carbohydrate-enriched diets to normal rats for induced metabolic syndrome [6, 7]. Fructose-fed rats (FFR) have been used to assess the pathophysiological mechanisms involved in the development of this syndrome [8]. This model has proven to be very interesting, since it allows the study of vascular changes, associated with

**Figure 1.** The evolution of vascular disease, with atherosclerosis being the final stage and vascular remodeling of the

primary causes of death and disability in these individuals (see **Figure 1**) [3].

metabolic syndrome, without the effects produced by hypercholesterolemia.

will drive up global CVDs in the coming decades [1, 2].

remodeling and atherosclerosis [4, 5].

78 Ultimate Guide to Insulin

vascular disease manifested as vascular insufficiency.

Recent studies have suggested that insulin and Ang II share a cross talk at multiple levels (**Figure 2**). Insulin signaling is initiated by binding to its receptor. The insulin receptor is a heterotetrameric tyrosine kinase that after binding insulin undergoes a rapid tyrosine autophosphorylation that activates the receptor kinase and allows transient interaction with IRS-1. Interaction of tyrosine-phosphorylated IRS-1 with PI3K results in PI3K activation and Akt phosphorylation, which stimulates translocation of Glut-4 to the sarcolemma to facilitate glucose uptake and NO production in the endothelium to induce vasorelaxation [9].

Ang II has been shown to inhibit the insulin-PI3K signaling pathway in both vascular and skeletal muscle cells. Ang II inhibits downstream signaling, including Akt phosphorylation, Glut-4 translocation to the sarcolemma, and NO production in the endothelium [9].

In the vasculature, insulin stimulates two major signaling transduction cascades: PI3K and MAPK. Insulin stimulation of NO production through activation of the PI3K pathway leads to vasodilation and increased blood flow and subsequent augmentation of glucose disposal in skeletal muscle. Insulin also stimulates the MAPK pathway, which mediates cellular growth and migration as well as production of prothrombotic and profibrotic factors [10].

**Figure 2.** Insulin-Ang II relationship. Insulin signaling is initiated by binding to its receptor. The insulin receptor is a heterotetrameric tyrosine kinase that after binding insulin undergoes a rapid tyrosine autophosphorylation that activates the receptor kinase and allows transient interaction with IRS-1. Interaction of tyrosine-phosphorylated IRS-1 with PI3K results in PI3K activation and Akt phosphorylation, which stimulates translocation of Glut-4 to the sarcolemma to facilitate glucose uptake and NO production in the endothelium to induce vasorelaxation.

Fasting plasma insulin levels in a normal insulin-sensitive individual are usually in the lowpicomolar range (50–150 pM). At this range, insulin constitutively stimulates the PI3K pathway, which participates in the regulation of the metabolic effects of insulin and maintenance of vascular tone [11].

disease, from initial injury until the final stage of thrombotic complications that compromise the bloodstream. Researchers now appreciate that the mere narrowing of the arterial lumen does not necessarily presage myocardial infarction and that simply treating narrowed blood vessels does not prolong life. Although invasive procedures such as angioplasty and coronary bypass will remain necessary in some cases, we now understand that medical treatment and lifestyle modification (diet and physical activity) produce benefits that may result from reduc-

Role of Insulin Resistance in Vascular Inflammation http://dx.doi.org/10.5772/intechopen.77287 81

It has been shown that atherosclerosis is not only a disease of lipid deposition but also a complex interaction between resident cells, inflammatory cells, and extracellular matrix, asso-

A key part of this interaction between the endothelium and the leukocytes is the vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 binds to monocytes and T lymphocytes; these leukocytes are found in early atherosclerotic plaques. The most important stimuli for the membrane docking of this molecule are the nuclear factor kB (NF-kB) as well as the interleukin-1β

Cell adhesion molecules (CAM) are essential in the mediation of adhesion and transendothelial migration of leukocytes. In several murine models, the absence of CAM reduces atherogenesis [17]. We have demonstrated the presence of VCAM-1 in the endothelium in an experimental model of metabolic syndrome, in which the expression of this protein is familiar with the AT1 receptor (AT1R) and the local inflammatory process. High levels of ICAM-1 are predictive of cardiac events and are also independent cardiovascular risk factors [18]. This relationship was examined by Pradhan et al. [19], who showed that men with and without prior ischemic heart

VCAM-1 is expressed in endothelial cells at sites predisposed to plaque formation [20]. By contrast, ICAM-1 is expressed throughout the plate; VCAM-1 is detected only in areas of rupture. In addition, VCAM-1 levels have a consistent association with atherosclerosis; high levels of VCAM-1 in the transcardiac gradient correlate with endothelial dysfunction and the

LCZ696 is the first of a new class of drugs that simultaneously block angiotensin 1 receptor blocker (ARB) and neprilysin or neutral endopeptidase protein (NEP); hence, they are

This complex system results in multiple effects on the cardiovascular system. In the first instance, according to different experiments, LCZ696 can increase the half-life of BNP through the initiation of NEP, managing to increase natriuresis and vasodilation through activation

disease, accelerated atherogenesis, are associated with elevated levels of ICAM-1.

ciated with a characteristic phenotypic change of macrophages to foam cells.

tions in the processes inflammatory [16].

(IL-1β) and the tumor necrosis factor (TNF-α) [10].

progression of coronary atherosclerosis [21].

referred to with the acronym ARNI [22].

**3.1. New drugs**

**3. Pharmacology on vascular remodeling**

**2.4. Initiation of atherosclerosis**

In insulin-resistant states, such as obesity and diabetes, fasting insulin levels may reach the nanomolar range and are often associated with activation of RAAS. In addition, insulin stimulation of the PI3K pathway is selectively impaired.
