Abstract
The insulin resistance syndrome, otherwise known as the metabolic syndrome, describes a cluster of cardiovascular and metabolic abnormalities, which are strongly associated with overweight and obesity. The importance of the syndrome is due to its increased rates of cardiovascular morbidity and mortality. Insulin resistance is also characterized by elevated free fatty acid (FFA) levels. In otherwise healthy human subjects, elevation of FFA impairs endothelial function. This appears to be largely the result of blunting of nitric oxide-dependent tone, most likely at the level of the endothelial isoform of nitric oxide synthase (eNOS). Some of the potential mediatory mechanisms include oxidative stress, proinflammatory cytokines, C-reactive protein, or endogenous inhibitors of eNOS. Regardless of the mechanism(s) that mediates the effects of increased FFA on the vasculature, impaired vascular function is likely to account, at least in part, for the increase in cardiovascular mortality in subjects with the insulin resistance syndrome.
Similar content being viewed by others
References and Recommended Reading
Reaven GM: Role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607.
Fontbonne A, Charles MA, Thibult N, et al.: Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia 1991, 34:356–361.
Fontbonne A, Eschwege E: Insulin-resistance, hypertriglyceridaemia and cardiovascular risk: the Paris Prospective Study. Diabetes Metab 1991, 17(1 Pt 2):93–95.
Nilsson P, Nilsson JA, Hedblad B, et al.: Hyperinsulinaemia as long-term predictor of death and ischaemic heart disease in nondiabetic men: the Malmo Preventive Project. J Intern Med 2003, 253:136–145.
Lempiainen P, Mykkanen L, Pyorala K, et al.: Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men. Circulation 1999, 100:123–128.
Hedblad B, Nilsson P, Engstrom G, et al.: Insulin resistance in non-diabetic subjects is associated with increased incidence of myocardial infarction and death. Diabet Med 2002, 19:470–475.
Steinberg HO, Chaker H, Leaming R, et al.: Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996, 97:2601–2610.
Reaven GM: Syndrome X: 6 years later. J Intern Med 1994, 236(suppl 736):13–22.
Boden, G, Chen X, Ruiz J, et al.: Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994, 93:2438–2446.
Dresner A, Laurent D, Marcucci M, et al.: Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999, 103:253–259.
Boden G, Lebed B, Schatz M, et al.: Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 2001, 50:1612–1617.
Steinberg HO, Tarshoby M, Monestel R, et al.: Elevated circulating free fatty acid levels impair endotheliumdependent vasodilation. J Clin Invest 1997, 100:1230–1239.
Steinberg HO, Baron AD: Vascular function, insulin resistance and fatty acids. Diabetologia 2002, 45:623–634.
de Kreutzenberg SV, Crepaldi C, Marchetto S, et al.: Plasma free fatty acids and endothelium dependent-vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab 2000, 85:793–798.
Lundman P, Eriksson M, Schenck-Gustafsson K, et al.: Transient triglyceridemia decreases vascular reactivity in young, healthy men without risk factors for coronary heart disease. Circulation 1997, 96:3266–3268.
de Jongh RT, Serne EH, Ijzerman RG, et al.: Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy. Diabetes 2004, 53:2873–2882.
Fugmann A, Millgard J, Sarabi M, et al.: Central and peripheral haemodynamic effects of hyperglycaemia, hyperinsulinaemia, hyperlipidaemia or a mixed meal. Clin Sci (Lond) 2003, 105:715–721.
Sarabi M, Vessby B, Millgard J, Lind L: Endothelium-dependent vasodilation is related to the fatty acid composition of serum lipids in healthy subjects. Atherosclerosis 2001, 156:349–355.
Davda RK, Stepniakowski KT, Lu G, et al.: Oleic acid inhibits endothelial nitric oxide synthase by a protein kinase C-independent mechanism. Hypertension 1995, 26:764–770.
Kuroda R, Hirata K, Kawashima S, Yokoyama M: Unsaturated free fatty acids inhibit Ca2+ mobilization and NO release in endothelial cells. Kobe J Med Sci 2001, 47:211–219.
Verma S, Wang CH, Li SH, et al.: A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002, 106:913–919.
Stuhlinger MC, Abbasi F, Chu JW, et al.: Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 2002, 287:1420–1426. This study was the first to suggest that the insulin resistance syndrome may be associated with impaired regulation of the endogenous inhibitor of nitric oxide synthase, ADMA.
Tripathy D, Mohanty P, Dhindsa S, et al.: Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003, 52:2882–2887. This article demonstrated that acute FFA elevation also changes the behavior of leukocytes.
Ghanim H, Aljada A, Hofmeyer D, et al.: Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 2004, 110:1564–1571.
Bluher M, Unger R, Rassoul F, et al.: Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or type II diabetes. Diabetologia 2002, 45:210–216.
Toborek M, Lee YW, Garrido R, et al.: Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells. Am J Clin Nutr 2002, 75:119–125.
Steinberg HO, Paradisi G, Hook G, et al.: Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 2000, 49:1231–1238.
Baron AD: Hemodynamic actions of insulin. Am J Physiol 1994, 267:E187-E202.
Steinberg HO, Brechtel G, Johnson A, et al.: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. J Clin Invest 1994, 94:1172–1179.
Scherrer U, Randin D, Vollenweider P, et al.: Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 1994, 94:2511–2515.
Laakso M, Edelman SV, Brechtel G, Baron AD: Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 1992, 41:1076–1083.
Coggins M, Lindner J, Rattigan S, et al.: Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes 2001, 50:2682–2690.
Vincent MA, Barrett EJ, Lindner JR, et al.: Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab 2003, 285:E123-E129.
Hedman A, Andersson PE, Reneland R, Lithell HO: Insulinmediated changes in leg blood flow are coupled to capillary density in skeletal muscle in healthy 70-year-old men. Metabolism 2001, 50:1078–1082.
Clerk LH, Rattigan S, Clark MG: Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes 2002, 51:1138–1145. This study was the first to demonstrate that FFA elevation decreases insulin-induced capillary recruitment.
Zeng G, Nystrom FH, Ravichandran LV, et al.: Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000, 101:1539–1545.
Lynn MA, Rupnow HL, Kleinhenz DJ, et al.: Fatty acids differentially modulate insulin-stimulated endothelial nitric oxide production by an Akt-independent pathway. J Investig Med 2004, 52:129–136.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shankar, S.S., Steinberg, H.O. FFAs: Do they play a role in vascular disease in the insulin resistance syndrome?. Curr Diab Rep 5, 30–35 (2005). https://doi.org/10.1007/s11892-005-0064-6
Issue Date:
DOI: https://doi.org/10.1007/s11892-005-0064-6