Glucose Insulin and Potential Mechanisms of Vascular Stiffening

Among patients with diabetes [15] or the metabolic syndrome, arterial stiffening is observed across all age groups. In children with severe obesity, arterial wall stiffness and endothelial dysfunction are accompanied by low plasma apolipoprotein A-I levels, insulin resistance, and android fat distribution, changes that may be the main risk factors for the early events leading to atheroma formation [16]. The positive correlation between insulin resistance and central arterial stiffness and the close relationship between the extent of metabolic changes and the degree of arterial stiffness suggest that insulin resistance is a primary underlying factor. In animal models of insulin-resistant diabetes, chronic hyperglycemia and hyperinsulinemia increase local angio-tensin II production and expression of vascular Ang II type I receptors via stimulation of TGF-^1, upregulate plasminogen activator inhibitor-1, and downregulate matrix metalloprotease activity, all of which play a critical role in coronary remodeling and vessel wall hypertrophy and fibrosis. The prolif-erative effects of insulin occur because insulin resistance impairs PI3-kinase-dependent signaling, while having little effect on the growth-promoting mito-

Fig. 1. Increased arterial stiffening is a hallmark ofboth type 1 and 2 diabetes. The accompanying dyslipidemia, hypertension, visceral obesity and sedentary lifestyle also contribute to structural changes in the arterial wall. Premenopausal women may also have increased arterial stiffening compared to men, suggesting a role for estrogens. Fracture of elastin fibers and increased deposition of collagen associated with aging leads to gradual widening and decreased distensibility of the aorta and the consequent loss of its buffering capacity. These clinical features act through a variety of mechanisms, including insulin resistance, oxidative stress, endothelial dysfunction, and formation of AGEs and pro-inflammatory cytokines, to increase arterial stiffening and increase the risk of CVD.

Fig. 1. Increased arterial stiffening is a hallmark ofboth type 1 and 2 diabetes. The accompanying dyslipidemia, hypertension, visceral obesity and sedentary lifestyle also contribute to structural changes in the arterial wall. Premenopausal women may also have increased arterial stiffening compared to men, suggesting a role for estrogens. Fracture of elastin fibers and increased deposition of collagen associated with aging leads to gradual widening and decreased distensibility of the aorta and the consequent loss of its buffering capacity. These clinical features act through a variety of mechanisms, including insulin resistance, oxidative stress, endothelial dysfunction, and formation of AGEs and pro-inflammatory cytokines, to increase arterial stiffening and increase the risk of CVD.

gen-activated kinase pathways. In addition, insulin resistance enhances non-enzymatic glycation of proteins with covalent cross-linking of collagen (AGEs). Other elements occurring early in the insulin-resistant state, such as elevated levels of LDL cholesterol, free fatty acids, and endothelin-1, or decreased levels of adiponectin and natriuretic peptides, may impair endothelial function and increase arterial stiffness as well. Hyperglycemia in DM-2 causes increased oxidative stress by generating reactive oxygen species, leading to increased gly-cosylation of functional proteins and glucose autooxidation with activation of the polyol pathway and generation of reactive oxygen species, including superoxide, hydrogen peroxide, and hydroxyl radicals. Elevated glucose levels may also reduce NO synthase activity by enhancing oxidation of tetrahydrobiop-terin (BH4), an essential cofactor for NO synthase. As a result, NO production from arginine and molecular oxygen is reduced and electrons are transferred to molecular oxygen to further increase superoxide and peroxynitrite levels.

Despite lower systolic blood pressure and pulse pressure and more favorable lipid levels, young women have greater small vessel stiffness than age-matched men [17], suggesting that estrogens may lack the vasculoprotective

Table 1. Treatment strategies to reduce arterial stiffening in DM-2

Blockade of renin-angiotensin system (ACEs, ARBs)

Reduced vascular smooth muscle tone (calcium channel blockers)

Aldosterone antagonist treatment (eplerenone)

Increased NO release from endothelial cells (HMG-CoA reductase inhibitors)

Administration of NO synthase cofactor (tetrahydrobiopterin)

Use of antioxidants (vitamin C)

Fish oil supplementation

Regular aerobic exercise

AGE cross-link breakers (alagebrium)

effects previously attributed to them. Increased small vessel stiffness in pre-menopausal women may provide a plausible explanation for the failure of postmenopausal estrogen treatment to prevent CHD in recent clinical trials.

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