The Metabolic Syndrome What Have We Learned by trendy3


J Chin Med Assoc

The Metabolic Syndrome: What Have We Learned?
Wayne Huey-Herng Sheu
Divisions of Endocrinology and Metabolism and Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung; National Yang-Ming University School of Medicine, Taipei; Chung-Shan Medical University, Taichung, Taiwan, R.O.C.

n his Banting Award lecture for the American Diabetes Association in 1988, Professor Gerald M. Reaven discussed the clustering effect of the insulin resistance syndrome, or syndrome X, as an important risk factor for atherosclerosis.1 Although Professor Reaven was not the first to describe the insulin resistance syndrome, his research had expanded the concept of insulin resistance from its origins in the pathophysiology of type 2 diabetes mellitus to several chronic human diseases that relate to cardiovascular diseases.2-4 The intimate association of type 2 diabetes with cardiovascular disease led to the hypothesis that these two arise from a common antecedent and play a pivotal role in the subsequent development of cardiovascular diseases. The importance of insulin resistance has been acknowledged since early 1990. In 1998, the World Health Organization (WHO) provided the first definition of the metabolic syndrome.5 In 2001, a clinically oriented definition of the metabolic syndrome was proposed by the adult treatment panel III of the National Cholesterol Education Program.6 A third criterion was proposed by the American Association of Clinical Endocrinologists (AACE) in 2003.7 The WHO and AACE definitions center mainly on insulin resistance and, thus, recommend an oral glucose tolerance test for patients without elevated fasting glucose. However, the definition from the ATP III of the NCEP stresses the equal importance of 5 components and that the presence of 3 of these factors is considered sufficient for diagnosis. There is accumulating evidence that subjects with the metabolic syndrome are at increased risk of incident diabetes8,9 or cardiovascular diseases and total mortality relative to subjects without the syndrome.10,11 These findings are not particularly surprising since individual components of the metabolic syndrome contribute to diabetes and cardiovascular disease. The question is whether the clustering of these components, that is, the metabolic


syndrome, implies a greater risk than that predicted by the presence of its individual components. Recent publications seem to indicate that this is the case.10,12 The study by Lakka et al.10 prospectively examined the relationships between the metabolic syndrome and cardiovascular disease and overall mortality rate in middle-aged men participating in the population-based Kuopio Ischemic Heart Disease Risk Factor Study, who were followed up for 11.4 years. They demonstrated that even in the absence of diabetes or prior cardiovascular disease, the presence of the metabolic syndrome was associated with significantly increased risk of cardiovascular disease and all-cause mortality. Golden et al.12 found that the metabolic syndrome interacted to increase carotid intimal-medial thickness to a greater degree than expected solely by its additive effects. On the other hand, Resnick et al.13 indicated that, although the metabolic syndrome and insulin resistance both predict diabetes, neither predicts cardiovascular disease independently of other established traditional risk factors. Therefore, further studies on the outcomes are needed to clarify whether the metabolic syndrome per se contributes to cardiovascular diseases. The recent development of the insulin sensitizer, thiazolidinedione, has shed some light on these issues and studies of the effects of intervention by thiazolidinedione on cardiovascular events are currently ongoing. From the viewpoint of clinical practice, there are 2 reasons to recognize and diagnose metabolic syndrome. One reason is to always consider that individual components would likely cluster in the same subjects. The other reason is to identify subjects who are most likely to benefit from aggressive efforts to achieve optimum weight by increasing physical activity. We should remember that even modest weight loss and a moderate increase in exercise prove very useful in treating the metabolic syndrome.14 In fact, studies from the US and Finland have

Wayne Huey-Herng Sheu

Journal of the Chinese Medical Association Vol. 67, No. 12

indicated that relatively modest lifestyle changes substantially reduce the risk for type 2 diabetes in subjects with impaired glucose tolerance.15,16 In addition, it is well documented that controlling blood pressure and blood lipids substantially reduces the risk of cardiovascular disease events in patients with hypertension or hyperlipidemia. A pro-inflammatory state that may relate to excessive adipose tissue and insulin resistance has recently been well established. Recent observation from the Framingham Offspring Study indicated that both C-reactive protein (hs-CRP) and the metabolic syndrome were independent predictors of new cardiovascular events.17 Whether biomarkers of inflammation should be listed as one of the components of the metabolic syndrome is now the subject of intensive investigation. The study by Chuang et al.18 in this issue of the Journal attempted to determine the prevalence of the metabolic syndrome in a large group of subjects (n = 24,329) obtained from a private physical check-up enterprise in Taiwan from 2000 to 2001. They found that prevalence of the metabolic syndrome is 12.9% (15.5% in men and 10.5% in women) based on the modified criteria of the ATP III of the NCEP (waist circumference 90 cm for men and 80 cm for women). These figures are lower than those reported from the study population of Kinmen, an island off the coast of southern China.19 Their findings are also lower than those reported from US study populations.20 In age-adjusted estimates from the National Health and Nutrition Examination Survey III (1988 to 1994), approximately 24% of adult Americans had ³ 3 of the 5 metabolic syndrome criteria.20 Prevalence rates were highest in Hispanics and were successively lower in whites, African Americans and other racial groups.20 These large variations in the prevalence of the metabolic syndrome could be partly accounted for by differences in study populations, lifestyles, socio-economic status, etc. In addition, a significant association between the metabolic syndrome and a history of stroke and heart disease was also found in the authors’ reports.18 These observations are compatible with previous prospective studies in Caucasians.10,11 In a group of non-diabetic individuals, we 21 recently found that the metabolic syndrome was more prevalent in subjects with angiographically documented CAD than in subjects without CAD (51.8% vs.

18.7%; p < 0.001). Multiple logistic regression analysis showed that hypertension was the strongest predictor of CAD, followed by higher fasting glucose and lowered HDL cholesterol. These 5 factors accounted for 41.3% of the total risk for CAD without diabetes.21 Certainly, prospective studies that aim to investigate the predictive power of metabolic syndrome in subsequent cardiovascular disease and mortality are needed in Asian populations. Several unsolved issues related to the metabolic syndrome need to be explored in the future.22 Studies on whether improved strategies for successful weight reduction and maintenance and increased physical activity lower the risk of metabolic syndrome are needed. A better understanding of the genetic and metabolic contributions leading to the development of the syndrome is currently under study. However, the efficacy of treating insulin resistance and atherogenic dyslipidemia beyond LDL-lowering therapy needs to be investigated further. The relationship between a pro-inflammatory state and the metabolic syndrome and the efficacy of interventions on this state are still unclear at present. Therefore, establishment of the benefit and cost-effectiveness of a specific goal for drug therapies directed toward the metabolic syndrome as a whole or particular risk components is clearly needed.

1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 2. Reaven GM. Insulin resistance: a chicken that has come to roost. Ann N Y Acad Sci 1999;892:45-57. 3. Sheu WH, Jeng CY, Young MS, Le WJ, Chen YT. Coronary artery disease risk predicted by insulin resistance, plasma lipids, and hypertension in people without diabetes. Am J Med Sci 2000;319:84-8. 4. Sheu WH, Shieh SM, Fuh MM, Shen DD, Jeng CY, Chen YDI, Reaven GM. Insulin resistance, glucose intolerance, and hyperinsulinemia: hypertriglyceridemia versus hypercholesterolemia. Arterioscler Thromb 1993;13:367-70. 5. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med 1998;15:539-53.

December 2004
6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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. 7. Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003;9:237-52. 8. Hanson RL, Imperatore G, Bennett PH, Knowler WC. Components of the “metabolic syndrome” and incidence of type 2 diabetes. Diabetes 2002;51:3120-7. 9. Lorenzo C, Okoloise M, Williams K, Stern MP, Haffner SM. The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. Diabetes Care 2003;26:3153-9. 10. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-16. 11. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, Williams GR. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110: 1245-50. 12. Golden SH, Folsom AR, Coresh J, Sharrett AR, Szklo M, Brancati F. Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the Atherosclerosis Risk in Communities Study. Diabetes 2002; 51:3069-76. 13. Resnick HE, Jones K, Ruotolo G, Jain AK, Henderson J, Lu W, Howard BV. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic american indians: the Strong Heart Study. Diabetes Care 2003; 26:861-7.

The Metabolic Syndrome: What Have We Learned?
14. Sheu WH, Chin HM, Su HY, Jeng CY. Effect of weight loss on resting energy expenditure in hypertensive and normotensive obese women. Clin Exp Hypertens 1998;20:403-16. 15. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New Engl J Med 2001;344:1343-50. 16. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New Engl J Med 2002;346:393-403. 17. Rutter MK, Meigs JB, Sullivan LM, D’Agostino RB, Sr., Wilson PW. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 2004;110:380-5. 18. Chuang SY, Chen CH, Chou P. Prevalence of metabolic syndrome in a large health check-up population in Taiwan. J Chin Med Assoc 2004;67:611-20. 19. Chuang SY, Chen CH, Tsai SZ, Chou P. Clinical identification of the metabolic syndrome in Kinmen. Acta Cardiol Sin 2002; 18:16-23. 20. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287: 356-9. 21. Lin RT, Lee WJ, Jeng CY, Sheu WH, Chen YT. Metabolic syndrome and its contribution to coronary artery disease in non-diabetic subjects. J Formos Med Assoc 2004;103:317-20. 22. Grundy SM, Hansen B, Smith SC, Jr., Cleeman JI, Kahn RA. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on Scientific Issues Related to Management. Circulation 2004;109: 551-6.


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