The presence of IGT indicates an increased risk for type 2 diabetes 8. Additional testing can provide confirmation of the metabolic syndrome. Confirmatory biomarkers for this syndrome include high levels of fasting insulin, 2-h postprandial insulin, apo B, increased small LDL particles, C-reactive protein CRP , fibrinogen, and plasminogen activator inhibitor PAI The clinical utility of detecting these additional abnormalities beyond confirmation of the syndrome is uncertain, although investigations are underway to evaluate potential utility.

For example, the presence of elevated CRP may indicate a greater risk for acute coronary syndromes 9. A disputed area in the relation of obesity and metabolic syndrome concerns the role of insulin resistance.

Most persons with multiple metabolic risk factors are insulin resistant. This observation led to the concept that insulin resistance is the cause of the metabolic syndrome This concept in turn generated an alternative term for the metabolic syndrome, namely the insulin resistance syndrome Various pathogenic schemes have been proposed to explain the connection between insulin resistance and metabolic risk factors.

There is no doubt that insulin resistance is a risk factor for IGT and type 2 diabetes. A causal relationship between insulin resistance and other metabolic risk factors is less certain.

Moreover, the interaction between obesity and defects in insulin signaling is so complex that it is so far not possible to disentangle the two. For example, obesity causes insulin resistance, whereas insulin resistance seemingly exacerbates the adverse effects of obesity.

A strong case can be made for a role of genetic forms of insulin resistance being a contributor to the metabolic syndrome in the general population. Our understanding of the relation between obesity and metabolic risk factors is growing rapidly. This understanding is based on the discovery of multiple products released from adipocytes.

In the presence of obesity, these products are released in abnormal amounts. Each of these products has been implicated in the causation of one or another of the metabolic risk factors. The following is a list of the factors most implicated in the development of metabolic syndrome 12 : Nonesterified fatty acids NEFAs.

Current concepts of the relation of each of these products to metabolic risk factors can be reviewed. Obese persons release increased amounts of NEFAs into the circulation NEFAs are derived by lipolysis of adipose tissue triglycerides.

The greater the amount of fat in adipose tissue, the more the amounts of NEFAs released will be. This greater release of NEFAs proceeds despite the higher insulin levels that are present in obese persons.

Even though high insulin levels suppress adipose tissue lipolysis, they cannot reduce NEFA release to normal in obesity. NEFAs are the primary source of nutrient energy in the fasting state. With obesity, however, NEFA flux exceeds tissue needs, and defense mechanisms must come into play.

The consequences of these defense mechanisms undoubtedly contribute to metabolic risk factors. Excessive influx of NEFAs into muscle leads to insulin resistance. The mechanisms whereby increased fatty acids in muscle cause insulin resistance have not been fully elucidated.

Randle et al. Recent research 15 suggests that muscle levels of diacylglycerol are raised, which stimulates the serine phosphorylation of the insulin receptors and thereby inhibits normal insulin signaling. Other mechanisms have been proposed and may play a role The resulting insulin resistance in muscle predisposes to hyperglycemia; the latter becomes clinically manifest in those persons to acquire a defect in insulin secretory capacity.

Influx of excess NEFAs into the liver increases the triglyceride content of the liver fatty liver Fat accumulation in the liver seemingly produces insulin resistance as it does in muscle. Reduction in insulin action in liver allows for enhanced glyconeogenesis and increased hepatic glucose output; this will accentuate hyperglycemia in those patients who have reduced insulin secretory capacity.

Increased fat in the liver also promotes development of atherogenic dyslipidemia. It provides a stimulus for increased formation and secretion of very LDL VLDL particles.

The result is higher serum levels of triglyceride, apo B, and small LDL particles. High serum triglycerides reduce HDL-cholesterol concentrations through exchange of VLDL triglycerides with HDL cholesterol esters.

HDL-cholesterol lowering is accentuated by an increase in synthesis of hepatic lipase that occurs in people with obesity-induced fatty liver; lipase degrades HDL particles, converting large HDL into small HDL.

An important but unresolved question is whether high NEFA levels contribute to higher blood pressure or a proinflammatory state. Hypotheses have been developed to link higher NEFA levels to higher blood pressures Whether the link is causal remains to be determined.

Moreover, accumulation of fat in the liver has been reported to be associated with increased hepatic synthesis of PAI-1, fibrinogen, and inflammatory cytokines, the key mediators of the prothrombotic and proinflammatory states Adipose tissue synthesizes and secretes TNFα, IL-6, and other cytokines.

The production of these cytokines is increased in obese persons. This increased synthesis may interfere with the action of insulin to suppress lipolysis; if so, this would represent insulin resistance of adipose tissue.

Obese persons in addition have elevated circulating cytokines; so far, it is uncertain whether these circulating cytokines have systemic effects, i. promoting insulin resistance in muscle 15 , increased synthesis of acute-phase reactants in the liver CRP and fibrinogen , or activation of macrophages in atheromatous plaques It is possible increased release of acute-phase reactants from liver may be the result entirely of lipid accumulation in this organ.

Adipose tissue synthesizes PAI-1, too. Reports suggest that abdominal adipose tissue is more active in PAI-1 synthesis than lower-body adipose tissue A fatty liver may be another source of PAI The resulting high PAI-1 levels in obese persons together with the high plasma fibrinogen observed in such persons contributes to a prothrombotic state.

Several other products of adipose tissue may influence development of the metabolic syndrome. Their precise role, however, remains to be fully determined. Adiponectin is one potentially important product This substance has been reported to have antiinflammatory and antiatherogenic properties.

Obese persons generally have low levels of adiponectin and hence may be deprived of its protective effects against the metabolic syndrome. Leptin also may play a systemic role beyond being an adipose tissue-derived appetite suppressant. Whether the systemic effects of leptin are direct or secondary to its action on the central nervous system is currently being debated.

Regardless, this hormone has been reported to have a beneficial effect on the liver to protect against fatty liver Its mechanism may be to enhance fatty acid oxidation in the liver. Finally, resistin is an adipose tissue-derived hormone that seemingly opposes the action of insulin Whether it has a physiological role in humans has not yet been determined.

Several recent reports 25 — 28 indicate that the presence of the metabolic syndrome is associated with increased risk for both ASCVD and type 2 diabetes. Persons with the metabolic syndrome have at least a 2-fold increase in risk for ASCVD, compared with those without 1.

Risk for type 2 diabetes in both men and women is increased about 5-fold 1. The risk for diabetes is highest in those with impaired fasting glucose or IGT. Once a patient develops type 2 diabetes, risk for ASCVD is enhanced. Not only is relative risk for coronary heart disease CHD raised by 2- to 3-fold, but once CHD becomes manifest in a patient with diabetes, the prognosis for survival is greatly reduced 2.

In addition, diabetes is accompanied by microvascular disease, which is a common cause of chronic renal failure. The relationship between the metabolic risk factors and development of ASCVD is complex and certainly not well understood.

Nonetheless, a brief review of hypothesized mechanisms may be of interest. This condition is characterized by an increase in elevated triglycerides and increased VLDL particle number , increased small LDL particles, and low HDL cholesterol 2.

It is commonly present in obese persons. The increased number of VLDL and LDL particles accounts for the increased level of total apo B usually observed with atherogenic dyslipidemia. The atherogenic potential of each lipoprotein abnormality has long been a topic of great interest but one that is not fully resolved.

For many years triglyceride-rich lipoproteins TGRLPs were thought not to be atherogenic. Nonetheless, there is growing evidence that smaller TGRLP remnant lipoproteins are in fact atherogenic This evidence comes from studies in laboratory animals, patients with genetic disorders causing remnant accumulation, metaanalysis of epidemiological studies, and clinical trials 1.

TGRLPs as a class are a mixture of lipoproteins, and it has been difficult to differentiate between atherogenic and nonatherogenic forms of TGRLPs. Nonetheless, there is a growing consensus among investigators that TGRLP fraction definitely contains atherogenic lipoproteins.

The LDL particles associated with the metabolic syndrome and atherogenic dyslipidemia tend to be small and dense. A theory widely held is that smaller LDL particles are more atherogenic than larger LDLs Smaller LDLs may filter more readily into the arterial wall.

They further may be more prone to atherogenic modification. Even so, not all investigations are convinced that small LDL particles are unusually atherogenic, compared with other apo B-containing lipoproteins. Nonetheless, when small LDLs are present, the total number of lipoprotein particles in the LDL fraction usually is increased Most researchers will agree that the higher the number of LDL particles present, the higher will be the atherogenic potential.

In other words, small LDL particles are often a surrogate for an increased LDL particle number These measurements should be used increasingly both in risk assessment and as targets of therapy in persons with the metabolic syndrome A low HDL level is another characteristic of atherogenic dyslipidemia 2.

This fact has led to the concept that HDL is intimately involved in the atherogenic process. The theories abound as to the mechanisms whereby HDL is antiatherogenic, e. enhanced reverse cholesterol transport, antiinflammatory properties, ability to protect against LDL modification, among others.

Although HDL in fact may be directly antiatherogenic, it also is a marker for the presence of other lipid and nonlipid risk factors. Obesity itself reduces HDL levels 4 , and obese patients with metabolic syndrome and atherogenic dyslipidemia almost always have low HDL levels.

Thus, the association between low HDL and ASCVD risk is complex 2 , and the various components of this association are difficult to differentiate. Regardless of mechanism, however, the presence of a low HDL level carries strong predictive power for development of ASCVD.

Obese persons have a higher prevalence of elevated blood pressure than lean persons. Moreover, a higher blood pressure is a strong risk factor for cardiovascular disease CVD Well-known complication of hypertension are CHD, stroke, left ventricular hypertrophy, heart failure, and chronic renal failure.

Yet some reports 34 , 35 suggest that the elevated blood pressure accompanying obesity is less likely to produce CVD than when it occurs in lean persons. The implication is that obesity-induced hypertension is not particularly dangerous to the cardiovascular system.

This concept generally is not accepted by the hypertension community, nor was it supported by the Framingham Heart Study There is no question that persons with diabetes are at increased risk for ASCVD.

In epidemiological studies, the onset of diabetes is accompanied by increased risk for ASCVD, suggesting that hyperglycemia per se is atherogenic. Limited data that directly address the question of whether hyperglycemia accelerates the development of atherosclerosis are available. Nonetheless, one recent study 37 indicated that intensive diabetes therapy in type 1 diabetes is accompanied by a reduction in intima-media thickness of carotid arteries.

Although this finding is consistent with epidemiology, it generally has not been possible to demonstrate an atherogenic potential of hyperglycemia in animal models. Moreover, whether the hyperglycemia of type 1 diabetes promotes atherogenesis has been uncertain.

The major cause of death in persons with type 1 diabetes is CVD; even so, it is possible that most atherosclerotic disease develops later in the course of the disease after development of chronic renal failure and hypertension.

A variety of mechanisms have been proposed whereby hyperglycemia might promote atherosclerosis Examples include nonenzymatic glycosylation of lipids and proteins, pathogenic effects of advanced glycation products, increased oxidative stress, activation of protein kinase C, and microvascular disease of the vasa vasorum of the coronary arteries.

All of these potential mechanisms are of interest, but so far, none has been shown to play a direct role in atherogenesis; most likely all are involved in one way or another.

But a fundamental question remains to be answered, namely whether hyperglycemia is directly atherogenic. Another possibility is that insulin resistance per se is independently atherogenic. In prospective studies, the presence of insulin resistance is associated with increased ASCVD risk But in persons with insulin resistance, confounding by other known risk factors makes it difficult to be certain that insulin resistance or resulting hyperinsulinemia is directly atherogenic If so, the mechanisms for such an effect are entirely speculative at this time.

Obesity is accompanied by a large number of coagulation and fibrinolytic abnormalities This suggests that obesity induces a prothrombotic state. What is not known at present is how a prothrombotic state will either promote the development of atherosclerosis or participate in the development of acute ASCVD events.

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Lipodystrophies: rare disorders causing metabolic syndrome. North Am. Danforth, E. When to see a doctor. Risk factors. Apple and pear body shapes. A Book: The Essential Diabetes Book. A Book: The Mayo Clinic Diet Bundle. Request an appointment. From Mayo Clinic to your inbox.

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You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail. Metabolic syndrome is closely linked to overweight or obesity and inactivity.

The following factors increase your chances of having metabolic syndrome: Age. Your risk of metabolic syndrome increases with age. In the United States, Hispanics — especially Hispanic women — appear to be at the greatest risk of developing metabolic syndrome.

The reasons for this are not entirely clear. Carrying too much weight, especially in your abdomen, increases your risk of metabolic syndrome. You're more likely to have metabolic syndrome if you had diabetes during pregnancy gestational diabetes or if you have a family history of type 2 diabetes.

Other diseases. Your risk of metabolic syndrome is higher if you've ever had nonalcoholic fatty liver disease, polycystic ovary syndrome or sleep apnea. Having metabolic syndrome can increase your risk of developing: Type 2 diabetes.

If you don't make lifestyle changes to control your excess weight, you may develop insulin resistance, which can cause your blood sugar levels to rise. Eventually, insulin resistance can lead to type 2 diabetes. Heart and blood vessel disease.

High cholesterol and high blood pressure can contribute to the buildup of plaques in your arteries. These plaques can narrow and harden your arteries, which can lead to a heart attack or stroke.

A healthy lifestyle includes: Getting at least 30 minutes of physical activity most days Eating plenty of vegetables, fruits, lean protein and whole grains Limiting saturated fat and salt in your diet Maintaining a healthy weight Not smoking.

By Mayo Clinic Staff. May 06, Show References. Ferri FF. Metabolic syndrome.