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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Clin Hypertens (Greenwich). Author manuscript; available in PMC 2010 April 24.
Published in final edited form as:
PMCID: PMC2859214
NIHMSID: NIHMS194443

Pathogenesis and Pathophysiology of the Cardiometabolic Syndrome

Abstract

The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Non-infectious systemic inflammation, associated with adipocyte and adipose tissue macrophage cytokine production, can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very-low-density lipoprotein triglyceride production leading to dyslipidemia.

Keywords: obesity, insulin resistance, dyslipidemia, fatty acids

The cardiometabolic syndrome represents a constellation of metabolic abnormalities that are risk factors for cardiovascular disease. The risk of coronary heart disease, myocardial infarction and stroke is much higher in persons who have the cardiometabolic syndrome than in those without the syndrome1. No universally accepted definition of the cardiometabolic syndrome has been established, and at least five independent groups have proposed clinical criteria for establishing its diagnosis 2. The most widely used clinical criteria for diagnosing the cardiometabolic syndrome are those proposed by the World Health Organization (WHO) 3 and the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)4 (Table 1). The common characteristics of the cardiometabolic syndrome among all groups include abdominal obesity (high body mass index and/or large waist circumference), insulin-resistant glucose metabolism (hyperinsulinemia, impaired fasting glucose, impaired glucose tolerance, type 2 diabetes), dyslipidemia (high serum triglyceride and low serum high density lipoprotein-cholesterol concentrations), and increased blood pressure.

Table 1
Clinical identification of the cardiometabolic syndrome based on National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III or World Health Organization criteria ...

Prevalence

The cardiometabolic syndrome has become a major public health problem in the United States and many other countries worldwide because of its increasing prevalence. Data from the third National Health and Nutrition Examination Survey (NHANES) (1988–1994) found the age-adjusted prevalence of the cardiometabolic syndrome, defined by using the Adult Treatment Panel III criteria, was 24 % in the adult United States population 4. The prevalence of the cardiometabolic syndrome increases linearly with age from ~7% in those who are 20–29 years old to ~45% in those who are age 60 years and older. Moreover, the latest NHANES data found the prevalence of the cardiometabolic syndrome is increasing in both men and women of all age groups 4.

Pathophysiology

Fatty acid metabolism

The cardiometabolic syndrome is also known as the insulin resistance syndrome, because it has been hypothesized that insulin resistance is the major mechanism responsible for the metabolic abnormalities of the syndrome 5. Alterations in free fatty acid metabolism are likely a major factor involved in the pathogenesis of hyperglycemia and dyslipidemia associated with the cardiometabolic syndrome (Figure 1). Excessive release of free fatty acids from adipose tissue into plasma and increased plasma free fatty acids concentration can impair the ability of insulin to stimulate muscle glucose uptake 6 and suppress hepatic glucose production 7. In addition, increased free fatty acids delivery to the liver can increase hepatic very-low density lipoprotein triglyceride production 8, 9 and plasma triglyceride concentration10. An increase in plasma triglycerides increases the transfer of triglyceride from very-low density lipoprotein to high density lipoprotein, which leads to increased high density lipoprotein clearance and decreased plasma high density lipoprotein concentration 11.

Figure 1
Physiological interrelationships between fatty acid metabolism, insulin resistance and features of the cardiometabolic syndrome. CETP=cholesterol ester transfer protein; VLDL= very-low density lipoprotein triglyceride, HDL= high density lipoprotein.

Insulin, which inhibits lipolysis, is the major physiological regulator of basal adipose tissue lipolytic activity 12, 13. Lipolysis of adipose tissue triglycerides is the major source of plasma FFA 14. Therefore, insulin resistance in adipose tissue stimulates an increase in lipolytic rate and FFA release into the bloodstream. The typical increase in plasma insulin concentrations associated with obesity does not completely compensate for adipose tissue insulin resistance, so insulin-resistant obese subjects have high basal lipolytic rates and plasma FFA concentrations 13.

In skeletal muscle, the cellular mechanism responsible for free fatty acids-induced insulin resistance involves alterations in intracellular insulin signaling and impaired insulin-mediated glucose uptake 15, 16 (Figure 2). An acute increase in plasma free fatty acids concentrations from approximately 400 μM (normal basal concentration) to approximately 800 μM (concentration during short-term fasting) causes a marked increase in intramyocellular fatty acid metabolites, including long-chain fatty acyl-CoA and diacylglycerol 15, 17, 18. These metabolites are potent allosteric activators of protein kinase C, a serine/threonine kinase, which phosphorylates serine/threonine sites of insulin receptor substrate-1, thereby inhibiting insulin’s ability to activate phosphoinositide 3-kinase activity 1921 and decreasing downstream events, including translocation of glucose transporter 4 from the cytoplasm to the cell membrane needed for glucose transport.

Figure 2
Potential cellular mechanisms for fatty acid-induced insulin resistance. IRS=insulin receptor substrate; PI3 kinase = phosphoinositide 3-kinase; PKC=protein kinase C; TG=triglyceride; ROS=reactive oxygen species; IKKβ=I-kappa B kinase Beta; NFκB, ...

Other factors related to intracellular fatty acid metabolism can also contribute to insulin resistance (Figure 2). Defective skeletal muscle mitochondrial function has been identified in persons who have insulin resistance and are at increased risk for developing type 2 diabetes 22. Impaired mitochondrial fatty acid oxidation can contribute to impaired insulin action by increasing the intracellular accumulation of fatty acids. In addition, excessive intracellular fatty acids can increase the production of reactive oxygen species, which leads to leads to activation of the proinflammatory nuclear factor kappa B pathway 17, 23, thereby increasing insulin resistance.

The cellular events responsible for fatty acid-induced insulin resistance in the liver have not been as carefully evaluated as in skeletal muscle. Increased delivery of free fatty acids to the liver and possibly increased release of fatty acids from lipolysis of intrahepatic triglycerides stimulate hepatic glucose production 1921. Free fatty acid-induced insulin resistance in liver is associated with activation of protein kinase C 24.

Abdominal adipose tissue

Excess abdominal fat mass, particularly visceral (intraperitoneal) fat, is associated with insulin resistance 6, 7, 25, 26. However, it is not known whether visceral fat causes insulin resistance or is simply associated with insulin resistance. Visceral fat represents a small component of total body fat mass. Visceral fat accounts for about 10% of total body fat mass in lean men and for about 15% of total body fat mass in obese men26. Nonetheless, it has been hypothesized that fatty acids released during lipolysis of visceral adipose tissue are an important cause of insulin resistance because these fatty acids enter the portal vein and are delivered directly to the liver 27. Data from studies that used isotope tracers to assess visceral fat metabolism in vivo in obese subjects found that ~20% of free fatty acids delivered to the liver and ~15% of free fatty acids delivered to skeletal muscle are derived from lipolysis of visceral fat 28. Therefore, visceral fat might contribute to hepatic insulin resistance, but it is unlikely that visceral fat is responsible for insulin resistance in skeletal muscle.

Ectopic fat

Ectopic accumulation of fat in liver and muscle cells is associated with insulin resistance in those tissues 29, 30. Increased intrahepatic fat content is associatedwith hepatic insulin resistance in the liver and impaired insulin-mediated suppression of hepatic glucose production 30, and increased intramyocellular fat content is associated with skeletal muscle insulin resistance and impaired insulin-mediated glucose disposal 29.

Adipose tissue secretory proteins

Adipose tissue produces several inflammatory cytokines (adipokines), which can induce insulin resistance, and adiponectin which increases insulin sensitivity 23, 31. For example, tumor necrosis factor-alpha suppresses insulin signaling 32, interleukin-6 increase inflammation directly or by stimulating hepatic c-reactive protein production 33, macrophage chemoattractant protein 1is a potent chemoattractant for macrophages 34, and interleukin-8, which activates neutrophil granulocytes and is chemotactic for all known migratory immune cells 35. Adiponectin increases insulin sensitivity in the liver, decreases hepatic glucose production 36, and increases skeletal muscle glucose and fatty acid oxidation 37.

Increased blood pressure

The relationship between insulin resistance and hypertension is well established 38. Fatty acids themselves can cause vasoconstriction 39. Additionally, insulin resistance can increase blood pressure because insulin is a vasodilator 40, and hyperinsulinemia increases renal sodium reabsorption 41. Persons who are insulin resistant tend to lose the vasodilatory effect of insulin 42 but preserve the renal effect on sodium reabsorption 41, and sodium reabsorption is increased in subjects with the cardiometabolic syndrome 43.

Summary

The cardiometabolic syndrome includes a cluster of conditions which include abdominal obesity, insulin resistant glucose metabolism, dyslipidemia, and increased blood pressure. Alterations in fatty acid metabolism (i.e. excessive fatty acid release into plasma) likely contribute to these metabolic abnormalities. Increased free fatty acids can: 1) impair insulin action in skeletal muscle and liver, leading to increased blood glucose concentration, 2) stimulate hepatic very-low density lipoprotein triglyceride production, leading to increased serum triglyceride and decreased high density lipoprotein concentrations, and 3) stimulate vasoconstriction and increase sodium reabsorption, possibly leading to increased blood pressure.

Footnotes

Financial Disclosers: None to report.

References

1. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683–9. [PubMed]
2. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary Cardiol Rev. 2005;13:322–7. [PubMed]
3. Obesity: Preventing and Managing the Global Epidemic: Report of a WHO Consultation. Geneva, Switzerland: World Health Organization; 2000. [PubMed]
4. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) Jama. 2001;285:2486–97. [PubMed]
5. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–607. [PubMed]
6. Abate N, Garg A, Peshock RM, Stray-Gundersen J, Adams-Huet B, Grundy SM. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes. 1996;45:1684–93. [PubMed]
7. Pouliot MC, Despres JP, Nadeau A, et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992;41:826–34. [PubMed]
8. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995;95:158–66. [PMC free article] [PubMed]
9. Zhang YL, Hernandez-Ono A, Ko C, Yasunaga K, Huang LS, Ginsberg HN. Regulation of hepatic apolipoprotein B-lipoprotein assembly and secretion by the availability of fatty acids. I. Differential response to the delivery of fatty acids via albumin or remnant-like emulsion particles. J Biol Chem. 2004;279:19362–74. [PubMed]
10. Mittendorfer B, Patterson BW, Klein S. Effect of sex and obesity on basal VLDL-triacylglycerol kinetics. Am J Clin Nutr. 2003;77:573–9. [PubMed]
11. Hopkins GJ, Barter PJ. Role of triglyceride-rich lipoproteins and hepatic lipase in determining the particle size and composition of high density lipoproteins. J Lipid Res. 1986;27:1265–77. [PubMed]
12. Klein S, Peters EJ, Holland OB, Wolfe RR. Effect of short- and long-term beta-adrenergic blockade on lipolysis during fasting in humans. Am J Physiol Endocrinol Metab. 1989;257:E65–73. [PubMed]
13. Horowitz JF, Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women. Am J Physiol EndocrinolMetab. 2000;278:E1144–E52. [PubMed]
14. Mittendorfer B, Liem O, Patterson BW, Miles JM, Klein S. What does the measurement of whole-body fatty acid rate of appearance in plasma by using a fatty acid tracer really mean? Diabetes. 2003;52:1641–8. [PubMed]
15. Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001;50:1612–7. [PubMed]
16. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106:171–6. [PMC free article] [PubMed]
17. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002;51:2005–11. [PubMed]
18. Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002;277:50230–6. [PubMed]
19. Kelley DE, Mokan M, Simoneau JA, Mandarino LJ. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest. 1993;92:91–8. [PMC free article] [PubMed]
20. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87:3023–8. [PubMed]
21. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983;72:1737–47. [PMC free article] [PubMed]
22. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664–71. [PMC free article] [PubMed]
23. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230–9. [PMC free article] [PubMed]
24. Lam TK, Yoshii H, Haber CA, et al. Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-delta. Am J Physiol Endocrinol Metab. 2002;283:E682–91. [PubMed]
25. Ross R, Aru J, Freeman J, Hudson R, Janssen I. Abdominal adiposity and insulin resistance in obese men. Am J Physiol Endocrinol Metab. 2002;282:E657–63. [PubMed]
26. Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995;96:88–98. [PMC free article] [PubMed]
27. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest. 2004;113:1582–8. [PMC free article] [PubMed]
28. Havel RJ, Kane JP, Balasse EO, Segel N, Basso LV. Splanchnic metabolism of free fatty acids and production of triglycerides of very low density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans. J Clin Invest. 1970;49:2017–35. [PMC free article] [PubMed]
29. Krssak M, Falk Petersen K, Dresner A, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia. 1999;42:113–6. [PubMed]
30. Seppala-Lindroos A, Vehkavaara S, Hakkinen A-M, et al. Fat Accumulation in the Liver Is Associated with Defects in Insulin Suppression of Glucose Production and Serum Free Fatty Acids Independent of Obesity in Normal Men 10.1210/jc.87.7.3023. J Clin Endocrinol Metab. 2002;87:3023–8. [PubMed]
31. Perseghin G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord. 2003;27 (Suppl 3):S6–11. [PubMed]
32. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158–63. [PubMed]
33. Park SH, Kim BI, Yun JW, et al. Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men. J Gastroenterol Hepatol. 2004;19:694–8. [PubMed]
34. Christiansen T, Richelsen B, Bruun JM. Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes (Lond) 2005;29:146–50. [PubMed]
35. Baggiolini M, Loetscher P, Moser B. Interleukin-8 and the chemokine family. Int J Immunopharmacol. 1995;17:103–8. [PubMed]
36. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–53. [PubMed]
37. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–95. [PubMed]
38. Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. The New England Journal Of Medicine. 1987;317:350–7. [PubMed]
39. Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003;52:2882–7. [PubMed]
40. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. The Journal Of Clinical Investigation. 1994;94:1172–9. [PMC free article] [PubMed]
41. DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. The Journal Of Clinical Investigation. 1975;55:845–55. [PMC free article] [PubMed]
42. Tooke JE, Hannemann MM. Adverse endothelial function and the insulin resistance syndrome. Journal Of Internal Medicine. 2000;247:425–31. [PubMed]
43. Barbato A, Cappuccio FP, Folkerd EJ, et al. Metabolic syndrome and renal sodium handling in three ethnic groups living in England. Diabetologia. 2004;47:40–6. [PubMed]