Eugenio Cersosimo, M.D., Ph.D., Associate Professor of Medicine, Clinical Research Director, Texas Diabetes Institute–UHS, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Cardiovascular disease affects approximately 60% of the adult population over the age of 65 years and represents the number one cause of death in the United States. Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events and a number of cardiovascular risk factors have been identified [1,2]. In recent years it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as one of the fundamental pathophysiologic disturbances responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the “Metabolic Syndrome” and that make up the “Cardio-Metabolic Risk” [3]. Vascular endothelial dysfunction is also an important component of the cardio-metabolic risk, which tends to coexist with the metabolic abnormalities that characterize insulin resistance [4]. Vascular dysfunction can be demonstrated early on in individuals at risk, before clinical evidence of disease, by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to various stimuli [4-6]. Deficiency of endothelial-derived nitric oxide was believed to be the primary defect which links insulin resistance and vascular endothelial dysfunction [7], although some additional impaired metabolic and intrinsic vascular smooth muscle cell processes have been proposed, as well [8,9].

Nitric oxide deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen and nitrogen species, which are produced by cellular disturbances in glucose and lipid metabolism in conditions of insulin resistance. This results in abnormal endothelial-dependent nitric oxide-mediated vasodilation, and contributes to reduce insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, has been estimated to represent ~25% of insulin-stimulated tissue glucose and lipid metabolism [10]. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance.

The elevations in circulating lipids, including free fatty acids and triglycerides, and the subsequent accumulation of intra-myocellular and intra-hepatocyte lipid derivatives has been recognized as a critical step in the development of insulin resistance [11,12]. Whether these alterations in tissue composition play a role in vascular dysfunction has not yet been fully elucidated. Evidence from several in vitro experiments indicates that a possible defect in mitochondrial fat oxidation may further contribute to intracellular lipid deposit and divert fat into alternative toxic pathways, such as ceramides and diacyl-glycerol intermediary products [13]. A number of insulin signaling pathways are disrupted by these lipid derivatives and insulin-driven metabolism is hampered. As a consequence, hyperinsulinemia ensues and drives the cellular pathways preferentially towards mitogenic and proliferative downstream endpoints. These are manifest by vascular smooth muscle cell proliferation and neo-intimal thickening [14]. The process of atherosclerosis and the plaque formation thus is facilitated by the accumulation of lipids, which via insulin resistance, stimulates cell mitosis and proliferation.

Inflammation is one interesting and novel aspect underlying the vascular damage [15]. This derives from lipid deposition and the oxidative stress to the vessel wall, which trigger an inflammatory reaction. The production and release of chemo-attractants and cytokines from the monocytes and macrophages pool of white blood cells as well as from the surrounding adipocytes, and the local formation of cellular adhesion molecules by the endothelium worsens the insulin resistance and vascular dysfunction. The common intra-cellular pathway NFkB is activated in skeletal and smooth muscle, and in monocytes, and a nuclear cascade resulting in cytokine generation is launched. These cytokines also inhibit insulin signaling pathways, impeding metabolic insulin action, and help sustain the inflammatory component and fragility of the atheromatous plaque. The evidence for most of these processes has been provided in separate experiments, although the sequence of event and the relative contribution of each one of these steps to the overall atherosclerotic vascular disease is lacking.

From the clinical standpoint, many trials support the concept that therapies which improve in insulin resistance and endothelial dysfunction reduce cardiovascular morbidity and mortality. Moreover, interventional strategies that reduce insulin resistance ameliorate endothelial dysfunction, while interventions that improve tissue sensitivity to insulin enhance vascular endothelial function. There is general agreement that aggressive therapy aimed simultaneously at improving insulin-mediated glucose/lipid metabolism and endothelial dysfunction represents an important strategy in preventing/delaying the appearance of atherosclerosis [16]. Interventions which 1) correct carbohydrate and lipid metabolism, 2) improve insulin resistance, 3) reduce blood pressure and restore vascular reactivity, and 4) attenuate pro-coagulant and inflammatory responses in adults at high risk of developing cardiovascular disease reduce cardiovascular morbidity and mortality. Whether these benefits hold when the same prevention strategies are applied to younger, high-risk individuals remains to be determined.

References

1. Centers for Disease Control and Prevention. Fast Statistics, September 11, 2003, National Center for Health Statistics.
2. American Heart Association. Heart Disease and Stroke Statistics-2003 Update. Dallas, Texas: American Heart Association; 2002.
3. Lakka HM, Laaksonen DE Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. WHO Guidelines. JAMA.2002: 228:2709-16.
4. Quinones MJ, Hernandez-Pamplona M, Schelbert H, et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Int Med 2004;140:700-708.
5. Lteif AA, Han K, Mather KJ. Obesity, insulin resistance and the metabolic syndrome: determinants of endothelial dysfunction in whites and blacks. Circulation Jul 2005;112:32-38.
6. Zeng G, Nystrom FH, Ravichandran LV, et al. Roles of insulin receptor, PI3-kinase, and Akt I insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000;101:1539-45.
7. Makimattila S, Yki-Jarvinen H. Endothelial dysfunction in human diabetes. Curr Diabetes Rep 2002;2:26-36.
8. Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567-74.
9. Cersosimo E. Relationship between hemodynamic and metabolic insulin action. Nutrition Week Symposium, A.S.P.E.N. Meeting, San Antonio, TX, January 22, 2002.
10. Vincent MA, Dawson D, Clark ADH, et al. Skeletal muscle microvascular recruitment by physiological hyperinsulinemia precedes increases in total blood flow. Diabetes 2002;51:42-48.
11. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004;88:787-35.
12. Bajaj M, Suraamornkul S, Cersosimo E, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 2004;89(1):200-206.
13. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria inhuman skeletal muscle in type 2 diabetes. Diabetes 2002;51:2944-50.
14. Law RE, Meehan WP, Xi XP, et al. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest 1996;98:1897-1905.
15. Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999;340:115-26.
16. Gaeda P, Vedel P, Larsen N, et al. Multi-factorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.