**Conflict of interest**

**3.2. Gliptin on vascular inflammation**

84 Ultimate Guide to Insulin

increasing endothelial production of NO [34].

activation of the inflammatory process.

**4. Conclusion**

Renna et al. suggest that incretin system dysfunction, as happens in patients with diabetes mellitus or metabolic syndrome, allows activation of inflammatory response in different levels. The consequence is the creation of a vascular microenvironment that is conducive to the creation, perpetuation, progression, and destabilization of vascular injury, with either a simple eutrophic mechanism of vascular remodeling or the generation of an atherosclerotic lesion [32]. Several mechanisms may underlie these results: (1) increase the circulating levels of GLP-1 [33]. The cardiovascular actions of GLP-1 may occur either directly through the GLP-1 receptor or through a GLP-1 receptor-independent effect of the degradation product of GLP-1 [38]; (2) DPP-IV also degrades GIP and potentially cytokines and certain chemokines (including stromal-derived factor 1-α). Thus, other substrates of DPP-IV may be responsible for the improvement in endothelial function. Alternatively, DDP-IV inhibition might improve endothelial function by influencing insulin and glucose levels. Insulin causes vasodilation by

The improvement in endothelial function and oxidative stress could result in a decrease in

Other authors have suggested that the DDP-IV inhibitors may have anti-inflammatory effects,

There is sufficient evidence to show that insulin resistance and hyperinsulinism produce significant changes at the vascular level [7, 25, 32, 36, 37]. The proposed mechanisms are (1) the IGF-1 receptor, (2) through the coactivation between IG-1 and AT1R, (3) by activating nuclear transcription factors such as NF-KB or AP-1, (4) by dimerization of IL-6R, and (5) from the activation of oxidative cascades such as NADP (H) oxidase, peroxynitrites, or superoxide dismutase (SOD). However, the effects of hyperglycemia are more erratic: moderate hyperglycemia is sufficient to induce adverse structural changes in the mesenteric vasculature, but

It is more interesting that the blocking of these pathways has significant effects on the activation/deactivation of vascular remodeling, independent of the correction or not, of hyperinsulinism or insulin resistance. This shows that intracellular cascades, in most of these

On the other hand, it is likely that the vascular remodeling associated with insulin resistance, due to the stimulation of growth factors, from the pathways, is due to changes in vascular hemodynamics or to the increase in peripheral resistances, as in the case of arterial hypertension.

The new drugs, which modify the inflammatory modulating response, such as tocilizumab (anti-IL-6R alpha) and canakinumab (anti-IL-1b), will be drugs that could further modify the cardiovascular risk of these patients in the future, since it could modify the vascular inflammatory

such as reduced activation of TNF-alpha during macrophage activation [33, 35].

more severe hyperglycemia is essential to cause endothelial dysfunction.

mechanisms, have no feedback from insulin or glucose receptors.

The authors have no "conflict of interest" to declare.
