Contemporary Reviews in Cardiovascular Medicine Metabolic Syndrome A Comprehensive Perspective Based on Interactions Between Obesity, Diabetes, and Inflammation

Received June 28, 2004; revision received August 26, 2004; accepted October 15, 2004. The original description of the metabolic syndrome by Reaven1 consisted of obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, hyperinsulinemia and dyslipidemia characterized by elevated triglyceride, and low HDL concentrations. All of the features described above are risk factors for atherosclerosis, and thus, metabolic syndrome constituted a significant risk for coronary heart disease2–5 (Table). The features of obesity/overweight and insulin resistance also provided a significant risk for developing type 2 diabetes.5,6 The risks for coronary heart disease and diabetes with metabolic syndrome are greater than those for simple obesity alone, and therefore, an understanding of the pathogenesis and through it, a rational approach to its therapy are of prime importance. View this table: Classic Biological Effects of Insulin and Classic Metabolic Syndrome Based on Resistance to the Metabolic Effects of Insulin As our understanding of the action of insulin evolves to comprehensively include the recent discoveries,7 we can better see that insulin resistance is the basis of most if not all of the features of this syndrome. The original conceptualization of this syndrome was on the basis of resistance to the metabolic actions of insulin. Thus, hyperinsulinemia, glucose intolerance, type 2 diabetes, hypertriglyceridemia, and low HDL concentrations could be accounted for by resistance to the actions of insulin on carbohydrate and lipid metabolism. Although the features described above would to some extent explain the atherogenesis, Reaven has maintained that hyperinsulinemia itself contributes to atherogenicity, and thus, insulin is atherogenic, leading to the coronary heart disease and cerebrovascular disease associated with this syndrome. Obesity probably leads to hypertension through (1) increased vascular tone created by a reduced bioavailability of NO because of increased oxidative stress,8 (2) increased asymmetric dimethylarginine (ADMA) concentrations,9 (3) increased sympathetic …

[1]  A. Aljada,et al.  Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. , 2004, The Journal of clinical endocrinology and metabolism.

[2]  HusamGhanim,et al.  Circulating Mononuclear Cells in the Obese Are in a Proinflammatory State , 2004 .

[3]  R. Einspanier,et al.  Insulin attenuates the systemic inflammatory response in endotoxemic rats. , 2004, Endocrinology.

[4]  A. Kitabchi,et al.  Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. , 2004, Diabetes.

[5]  A. Aljada,et al.  Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. , 2004, The American journal of clinical nutrition.

[6]  Nader Rifai,et al.  Plasma adiponectin levels and risk of myocardial infarction in men. , 2004, JAMA.

[7]  A. Aljada,et al.  Evidence for a potent antiinflammatory effect of rosiglitazone. , 2004, The Journal of clinical endocrinology and metabolism.

[8]  Y. Aso,et al.  Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes. , 2004, Metabolism: clinical and experimental.

[9]  A. Aljada,et al.  Increase in intranuclear nuclear factor κB and decrease in inhibitor κB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect , 2004 .

[10]  Devjit Tripathy,et al.  Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells. , 2004, Metabolism: clinical and experimental.

[11]  N. Wong,et al.  Transcriptional control of apolipoprotein A-I gene expression in diabetes. , 2004, Diabetes.

[12]  Michael F. Wilson,et al.  Anti-Inflammatory and Profibrinolytic Effect of Insulin in Acute ST-Segment–Elevation Myocardial Infarction , 2004, Circulation.

[13]  G. Pellegrini,et al.  G972R IRS-1 Variant Impairs Insulin Regulation of Endothelial Nitric Oxide Synthase in Cultured Human Endothelial Cells , 2004, Circulation.

[14]  Anthony Gamst,et al.  Association of the Metabolic Syndrome With History of Myocardial Infarction and Stroke in the Third National Health and Nutrition Examination Survey , 2004, Circulation.

[15]  A. Aljada,et al.  Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect. , 2004, The American journal of clinical nutrition.

[16]  A. Aljada,et al.  Inflammation: the link between insulin resistance, obesity and diabetes. , 2004, Trends in immunology.

[17]  A. La Cava,et al.  Unraveling the multiple roles of leptin in inflammation and autoimmunity , 2004, Journal of Molecular Medicine.

[18]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[19]  A. Aljada,et al.  Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. , 2003, Diabetes care.

[20]  A. Aljada,et al.  Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. , 2003, Diabetes.

[21]  S. Aizawa,et al.  Kadowaki and Tetsu Yamaguchi Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Response to Vessel Injury , 2022 .

[22]  Marc Montminy,et al.  TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in Liver , 2003, Science.

[23]  K. Irani,et al.  Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1 , 2003, Cell Death and Differentiation.

[24]  T. Zimmers,et al.  Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes* , 2003, The Journal of Biological Chemistry.

[25]  R. Coleman,et al.  Oral Insulin Supplementation Attenuates Atherosclerosis Progression in Apolipoprotein E-Deficient Mice , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[26]  Jukka T Salonen,et al.  The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. , 2002, JAMA.

[27]  N. Chan,et al.  Asymmetric dimethylarginine (ADMA): a potential link between endothelial dysfunction and cardiovascular diseases in insulin resistance syndrome? , 2002, Diabetologia.

[28]  M. White,et al.  SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2* , 2002, The Journal of Biological Chemistry.

[29]  J. Kampert,et al.  Associations Between Cardiorespiratory Fitness and C-Reactive Protein in Men , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[30]  Ronald Klein,et al.  Components of the metabolic syndrome and risk of cardiovascular disease and diabetes in Beaver Dam. , 2002, Diabetes care.

[31]  O. Ukkola,et al.  Adiponectin: a link between excess adiposity and associated comorbidities? , 2002, Journal of Molecular Medicine.

[32]  T. Buchanan,et al.  Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. , 2002, Diabetes.

[33]  P. Tsao,et al.  Impaired Nitric Oxide Synthase Pathway in Diabetes Mellitus: Role of Asymmetric Dimethylarginine and Dimethylarginine Dimethylaminohydrolase , 2002, Circulation.

[34]  R. Einspanier,et al.  Insulin Attenuates the Systemic Inflammatory Response to Thermal Trauma , 2002, Molecular medicine.

[35]  Philippe Froguel,et al.  Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation* , 2002, The Journal of Biological Chemistry.

[36]  A. Aljada,et al.  Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells. , 2002, The American journal of clinical nutrition.

[37]  P. Tsao,et al.  Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. , 2002, JAMA.

[38]  A. Aljada,et al.  Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. , 2002, The Journal of clinical endocrinology and metabolism.

[39]  S. Fowler,et al.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. , 2002 .

[40]  A. Aljada,et al.  The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm , 2002, Diabetologia.

[41]  D. Yellon,et al.  Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling , 2001, Circulation research.

[42]  E. Van Obberghen,et al.  SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-α in the Adipose Tissue of Obese Mice* , 2001, The Journal of Biological Chemistry.

[43]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[44]  A. Aljada,et al.  Nuclear Factor-κB Suppressive and Inhibitor-κB Stimulatory Effects of Troglitazone in Obese Patients with Type 2 Diabetes: Evidence of an Antiinflammatory Action?1 , 2001 .

[45]  A. Aljada,et al.  Insulin Inhibits Intranuclear Nuclear Factor κB and Stimulates IκB in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect? , 2001 .

[46]  C Bogardus,et al.  Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. , 2001, Obesity research.

[47]  K. Kaestner,et al.  Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) , 2001 .

[48]  M. Esler,et al.  The sympathetic neurobiology of essential hypertension: disparate influences of obesity, stress, and noradrenaline transporter dysfunction? , 2001, American journal of hypertension.

[49]  A. Aljada,et al.  Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations. , 2001, The Journal of clinical endocrinology and metabolism.

[50]  T. Valle,et al.  Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. , 2001, The New England journal of medicine.

[51]  L Wood,et al.  Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. , 2001, American journal of physiology. Endocrinology and metabolism.

[52]  A. Aljada,et al.  Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. , 2001, The Journal of clinical endocrinology and metabolism.

[53]  A. Aljada,et al.  Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? , 2001, The Journal of clinical endocrinology and metabolism.

[54]  A. Aljada,et al.  Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? , 2001, The Journal of clinical endocrinology and metabolism.

[55]  K. Kaestner,et al.  Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). , 2001, Science.

[56]  A. Aljada,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society The Suppressive Effect of Dietary Restriction and Weight Loss in the Obese on the Generation of Reactive Oxygen Species by Leukocytes, Lipid Per , 2022 .

[57]  S. Homma,et al.  Acute Elevations of Plasma Asymmetric Dimethylarginine and Impaired Endothelial Function in Response to a High-Fat Meal in Patients With Type 2 Diabetes , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[58]  A. Aljada,et al.  Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. , 2000, The Journal of clinical endocrinology and metabolism.

[59]  G. Giacchetti,et al.  Gene expression of angiotensinogen in adipose tissue of obese patients , 2000, International Journal of Obesity.

[60]  Sridevi Devaraj,et al.  Low-Density Lipoprotein Postsecretory Modification, Monocyte Function, and Circulating Adhesion Molecules in Type 2 Diabetic Patients With and Without Macrovascular Complications The Effect of α-Tocopherol Supplementation , 2000 .

[61]  S. Haffner,et al.  Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). , 2000, Circulation.

[62]  Cai Li,et al.  Leptin: a multifunctional hormone , 2000, Cell Research.

[63]  S. Devaraj,et al.  Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation. , 2000, Circulation.

[64]  Xianglin Shi,et al.  The role of superoxide radical in TNF-alpha induced NF-kappaB activation. , 1999, Annals of clinical and laboratory science.

[65]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[66]  R. Cantor,et al.  Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia. , 1999, Journal of lipid research.

[67]  M. Nakata,et al.  Leptin promotes aggregation of human platelets via the long form of its receptor. , 1999, Diabetes.

[68]  H. Lebovitz,et al.  Body composition, visceral fat, leptin, and insulin resistance in Asian Indian men. , 1999, The Journal of clinical endocrinology and metabolism.

[69]  T. Wadden,et al.  Tumor Necrosis Factor-α in Sera of Obese Patients: Fall with Weight Loss , 1998 .

[70]  I. Wakabayashi.  Age-related change in relationship between body-mass index, serum sialic acid, and atherogenic risk factors. , 1998, Journal of atherosclerosis and thrombosis.

[71]  T. Wadden,et al.  Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. , 1998, The Journal of clinical endocrinology and metabolism.

[72]  Mike Rothe,et al.  IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK , 1997 .

[73]  D. Goeddel,et al.  IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. , 1997, Science.

[74]  M. Díaz-Guerra,et al.  Rapid Up-regulation of IκBβ and Abrogation of NF-κB Activity in Peritoneal Macrophages Stimulated with Lipopolysaccharide* , 1997, The Journal of Biological Chemistry.

[75]  G. Reaven.  Banting lecture 1988 , 1997 .

[76]  M. Díaz-Guerra,et al.  Rapid Up-regulation of IkappaBbeta and abrogation of NF-kappaB activity in peritoneal macrophages stimulated with lipopolysaccharide. , 1997, The Journal of biological chemistry.

[77]  Roy Taylor,et al.  Effects of an Engineered Human Anti–TNF-α Antibody (CDP571) on Insulin Sensitivity and Glycemic Control in Patients With NIDDM , 1996, Diabetes.

[78]  B. Spiegelman,et al.  IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance , 1996, Science.

[79]  E M Schwarz,et al.  Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. , 1995, Genes & development.

[80]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[81]  W. Pryor,et al.  Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. , 1992, Chemical research in toxicology.

[82]  G. Reaven.  Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[83]  G. Reaven.  Banting lecture 1988. Role of insulin resistance in human disease. , 1988, Diabetes.

[84]  K. Pyörälà,et al.  Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. , 1979, Diabetes care.