In adipose tissue, insulin inhibits fat breakdown, or lipolysis, and stimulates glucose uptake. The net effect of all of these changes is to increase glucose uptake, reduce circulating glucose levels and increase the conversion of glucose into the storage molecules, glycogen or fat Kim et al. In insulin resistance, adipose, muscle and liver cells do not respond appropriately to insulin, and circulating glucose levels remain high, which leads to pathology. This is exacerbated by the deregulation of feedback mechanisms.
Insulin-mediated glucose disposal rates vary in the population by over six-fold. Some of this variation is because of adiposity and fitness, and some is the result of genetic origin. Insulin resistance occurs when there is a decrease in the responsiveness of peripheral tissues skeletal muscle, fat and liver to the effects of insulin. Insulin resistance is a powerful predictor of T2D, and hyperinsulinemia is a surrogate marker for insulin resistance.
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Physiological insulin signaling occurs following the binding of insulin to the insulin receptor, a ligand-activated tyrosine kinase. Binding of insulin results in tyrosine phosphorylation of downstream substrates and activation of two parallel pathways: the phosphoinositide 3-kinase PI3K pathway and the mitogen-activated protein MAP kinase pathway. The PI3K-Akt pathway is responsible for many of the downstream metabolic effects of insulin.
In vascular endothelial cells, Akt kinase phosphorylates and activates endothelial nitric oxide synthase eNOS. In skeletal muscle and adipose tissue, Akt kinase stimulates translocation of the insulin-responsive glucose transporter GLUT4 to the cell surface, leading to increased glucose uptake. The MAP kinase pathway mediates endothelin-1 ET-1 production, leading to vasoconstriction; expression of the vascular cell adhesion molecules VCAM-1 and E-selectin, leading to more leukocyte-endothelial interactions; and growth and mitogenesis effects on vascular smooth muscle cells.
This leads to a change in the balance between these two parallel pathways. Inhibition of the PI3K-Akt pathway leads to a reduction in endothelial nitric oxide NO production, resulting in endothelial dysfunction, and a reduction in GLUT4 translocation, leading to decreased skeletal muscle and fat glucose uptake. By contrast, the MAP kinase pathway is unaffected, so there is continued ET-1 production, expression of vascular cell adhesion molecules and mitogenic stimulus to vascular smooth muscle cells. In these ways, insulin resistance leads to vascular abnormalities that predispose to atherosclerosis.
Insulin increases local blood flow in tissues through the activation of eNOS, leading to two separable effects Kim et al. Capillary recruitment occurs within minutes, whereas dilation of the larger-resistance vessels increases overall perfusion between 30 minutes and 2 hours. Both of these effects contribute to vasodilation and increased delivery of glucose and insulin to tissues.
The vascular effects of insulin couple glucose homeostasis with blood flow and contribute to glucose metabolism at physiological concentrations of insulin.
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Thus, insulin signaling coordinately affects peripheral glucose use, vascular tone and blood flow. Common mechanisms that contribute to insulin resistance can, therefore, also affect vascular function, including hyperglycemia, advanced glycation products, toxicity from FFAs, obesity, dyslipidemia and other proinflammatory conditions.
Visceral obesity causes a decrease in insulin-mediated glucose uptake, and is clearly related to insulin resistance. The mechanisms for this probably involve adipokines, which are made by adipose tissue, that modulate crosstalk between metabolism and vascular function Kershaw and Flier, The renin angiotensin system is also activated in adipose tissue, leading to hypertension and insulin resistance.
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By contrast, adiponectin is a protective adipokine that couples insulin sensitivity with energy metabolism. Adiponectin levels are decreased in obesity, T2D and metabolic syndrome. In addition to these adipokines, FFAs, which are released from visceral fat, and bioactive lipid intermediates act together to impair the PI3K-Akt pathway and increase oxidative stress. Insulin resistance and visceral obesity are associated with atherogenic dyslipidemia Semenkovich, Insulin resistance leads to atherogenic dyslipidemia in several ways.
First, insulin normally suppresses lipolysis in adipocytes, so impaired insulin signaling increases lipolysis, resulting in increased FFA levels. Third, insulin regulates the activity of lipoprotein lipase, the rate-limiting and major mediator of VLDL clearance. The TG-enriched HDL is a better substrate for hepatic lipase, so it is cleared rapidly from the circulation, leaving fewer HDL particles to participate in reverse cholesterol transport from the vasculature.
Endothelial dysfunction is the final common pathway between many cardiovascular risk factors and the development of atherosclerosis Gimbrone et al.
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Endothelial cells line the inner surface of blood vessels and serve important mechanical, as well as biological, functions. The endothelium senses and responds to physiological and pathological stimuli, and produces vasoactive substances, including NO, prostacyclin and endothelins. Endothelial expression of cell adhesion molecules governs interactions with circulating leukocytes and monocytes, affecting inflammation, and with circulating platelets, affecting hemostasis and thrombosis.
The endothelium also modulates the response of the vascular smooth muscle layer, which may contribute to intimal formation during the development of atherosclerotic plaques. Normal endothelial function protects against these processes, and endothelial dysfunction is central to the pathogenesis of atherosclerotic lesion development.
Endothelial dysfunction, broadly defined, occurs when the endothelium fails to serve its normal physiological and protective mechanisms. This might be because the endothelium is damaged or missing, as in the case of denuded endothelium in coronary arteries that have been subjected to angioplasty.
It may occur when the normal responses of the endothelium are affected, for example by oxidative stress, hyperglycemia, advanced glycation products, FFAs, inflammatory cytokines or adipokines. A common feature of endothelial dysfunction is the reduced bioavailability of NO in the vasculature. There are several mechanisms for endothelial dysfunction Huang, Superoxide, whether formed by NADPH oxidase or by uncoupled eNOS, reacts with NO in an extremely rapid, diffusion-limited reaction to form peroxynitrite anion, which has its own toxic effects.
S phosphorylation results in an increased electron flux through the reductase domain and reduced calmodulin dissociation. As a result, eNOS becomes more active and produces more NO, even at resting levels of intracellular calcium. The fact that diverse signaling pathways affect multiple kinases that converge to modulate eNOS activity by phosphorylation suggests that this is a common integration point that underlies endothelial dysfunction from various causes. Thus, the phosphorylation of eNOS at S appears to be a crucial step in the regulation of eNOS activity and an important target for intervention to treat endothelial dysfunction Huang, ; Atochin et al.
Insulin resistance causes endothelial dysfunction by decreasing Akt kinase activity, resulting in diminished eNOS phosphorylation and activity. Because the phosphorylation of eNOS at S is required for the hemodynamic actions of insulin, this results in diminished blood flow to skeletal muscle, creating a vicious cycle where endothelial dysfunction then worsens insulin resistance. In addition, insulin-mediated ET-1 expression and vascular smooth muscle mitogenic effects are not affected by insulin resistance, further contributing to endothelial dysfunction.
Atlas of Atherosclerosis and Metabolic Syndrome
By contrast, adiponectin, which stimulates eNOS phosphorylation, is diminished in metabolic syndrome. In visceral fat, leptin resistance also increases the generation of reactive oxygen species. FFAs contribute to endothelial dysfunction by a combination of diminished PI3K-Akt signaling, increased reactive oxygen species and increased ET-1 production. In summary, the central features of the metabolic syndrome are insulin resistance, visceral adiposity, atherogenic dyslipidemia and endothelial dysfunction. These conditions are interrelated and share common mediators, pathways and pathophysiological mechanisms.
A comprehensive definition of the metabolic syndrome, expressed as simply as possible, would contain only these features. The requirement of multiple criteria would ensure the exclusion of people with individual components e. Inclusion of both TG and HDL criteria increases the specificity for atherogenic dyslipidemia, and inclusion of the blood pressure criterion ensures that the physiologic derangements are severe enough to have resulted in endothelial dysfunction.
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Of the various definitions for the metabolic syndrome, the NCEP ATP III definition is the easiest to apply clinically and epidemiologically, because it uses straightforward criteria that are measured readily. Despite the ongoing controversy about whether the concept of metabolic syndrome is useful, it clearly defines specific pathophysiological mechanisms that link the central features.
Consideration of metabolic syndrome as a specific entity allows for research on the genetic basis for susceptibility to this syndrome, a better understanding of its underlying pathophysiology and the development of treatment approaches. This Issue.
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