Metabolic Syndrome and Insulin Resistance

The metabolic syndrome is a constellation of risk factors, most usually associated with increased body weight, fat accumulation around the abdominal organs often termed central, or visceral obesity (1), and increased resistance to the effects of insulin.

Metabolic Syndrome (Insulin Resistance Syndrome)Other names that have been used to describe the metabolic syndrome are syndrome X, the insulin resistance syndrome, the deadly quartet (2) and obesity dyslipidemia syndrome (3).

The first description of metabolic syndrome can be traced to Eskil Kylin (1889-1975) (4), a Swedish physician who described a cluster of conditions, including high blood sugar, high blood pressure, obesity, and high blood levels of uric acid (5) which can lead to gout (6).

The prevalence of metabolic syndrome has grown rapidly. It is estimated that around 70 million people in the US have metabolic syndrome or about one-third of all adults in the country (7).

Data from NHANES III (8) have shown that factors associated with the risk of developing metabolic syndrome, apart from age, race and body weight, are postmenopausal status among women, smoking, low household income, high carbohydrate diet, no alcohol consumption, and physical inactivity.

The fact that the metabolic syndrome is highly related to the risk of developing type 2 diabetes and cardiovascular disease underscores the importance of understanding, preventing and treating the disorder.

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Definition of The Metabolic Syndrome

It is debated whether the factors associated with the metabolic syndrome have enough in common to warrant classifying it as a true syndrome (9).

Although the metabolic syndrome is often referred to as a uniform entity, it is important to recognize that no single underlying mechanism has been defined, nor may one exist. Thus, the syndrome could range from a cluster of unrelated risk factors to a constellation of factors linked through a common underlying mechanism (10).

For scientific and public health purposes, for example, when large numbers of people are targeted, using the term metabolic syndrome may be useful.

For the individual, it may be more practical to look at the different components of the metabolic syndrome because the clinical picture varies between patients.

The five conditions described below are used to define the metabolic syndrome. Three of these must be present in order to be diagnosed with the condition.

  • Abdominal obesity, defined as waist circumference > 40 inches (102 cm) in men and > 35 inches (88 cm) in women
  • A high triglyceride level in blood, defined as > 150 mg/dL (1.7 mmol/L)
  • A low HDL cholesterol level in blood, defined as < 40 mg/dL (1 mmol/L)
  • High blood pressure, defined as > 130/85 mmHg or drug treatment for elevated blood pressure
  • Elevated blood sugar, defined as fasting blood glucose >100 mg/dL (5.6 mol/L) or drug treatment for diabetes

The Role of Body Weight

Gaining weight is a major risk factor for the metabolic syndrome. Data from NHANES III have shown that the metabolic syndrome was present in 5 percent of normal weight individuals, 22 percent of those who were overweight and 60 percent of those who were obese (8).

Abdominal obesity appears to play a key role. A large waistline alone identifies up to 46 percent of individuals who will develop metabolic syndrome within five years (11).

The rapidly increasing prevalence of obesity in most countries around the world (12) is likely to raise the prevalence of the metabolic syndrome further in the near future.

The Role of Insulin Resistance

Insulin resistance plays a key role in the pathophysiology of the metabolic syndrome and the term “insulin resistance syndrome” has been used by some experts (13).

Insulin is a peptide hormone produced by beta cells in the pancreas (14). It plays an important role in the metabolism of carbohydrates and fats.

When sugar and carbohydrates are ingested, insulin promotes the uptake of glucose (sugar) from the blood into the cells of skeletal muscle and fat tissue. Hence, it is often said that insulin unlocks the cell to allow sugar to enter and be used for energy. Insulin also promotes the storage of energy in the form of glycogen and fat.

When blood glucose levels fall, stored glucose is released for energy utilization from the breakdown of glycogen stores in the liver and skeletal muscle.

If the pancreas is unable to produce enough insulin in response to meals or if the action of insulin is impaired, glucose will accumulate in the blood and blood sugar will become high as is the case in diabetes.

The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals (15). Between 25-35% of the variability in insulin action is related to being overweight. In other words, when body weight increases, insulin resistance becomes more likely.

Insulin resistance is defined as a diminished response to a given concentration of insulin. Initially, the pancreas responds by producing more insulin. For this reason, individuals with insulin resistance often have high levels of insulin in their blood. However, as diabetes develops, the beta cells of the pancreas often become unable to produce more insulin and its blood levels drop.

Individuals with insulin resistance are at greatly increased risk to develop heart disease, type 2 diabetes, high blood pressure, stroke, nonalcoholic fatty liver disease (16), polycystic ovary syndrome (17), and certain forms of cancer.

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How to Identify Insulin Resistance

Insulin resistance appears to be associated with increased risk of type 2 diabetes, heart disease, and certain cancers associated with obesity. For this reason, it would be useful to identify obese individuals who are insulin resistant. However, there is currently no validated test for measuring insulin resistance in a clinical setting.

Blood levels of triglycerides, the ratio of triglyceride to HDL cholesterol concentrations (18), and fasting insulin concentration may be useful markers for identifying those who may be insulin resistant. A study in which most of the participants were Caucasian and overweight identified triglyceride/HDL cholesterol ratio of 3 or greater as a reliable predictor of insulin resistance (19).

The most widely used test is the homeostasis model assessment of insulin resistance (HOMA-IR), which employs fasting glucose and insulin levels (20). Due to biological variability requiring repeat testing and lack of insulin assay standardization, HOMA-IR continues to be used more for research than for clinical applications.

Recently, a so-called Lipoprotein Insulin Resistance Index (LP-IR), based on blood measurements of lipoprotein subclasses and particle concentration, has been used to measure insulin resistance (21). This test is being performed in some laboratories in the US.

Metabolic Syndrome and Insulin Resistance

Metabolic Syndrome – Why We Should Care

The metabolic syndrome is an important risk factor for the development of type 2 diabetes and cardiovascular disease.

A meta-analysis of 16 prospective observational studies showed that the metabolic syndrome is a significant predictor of incident diabetes in many different populations, including Native Americans, U.S. Hispanics, Mexicans, Turks, Iranians, Mauritians, Chinese, Europeans, and those of European descent(22).

A 2005 meta-analysis (23) found that the presence of the metabolic syndrome was associated with a 12-17 percent increased risk of cardiovascular mortality, and 6-7 percent increased risk of overall mortality.

The increased risk of diabetes and cardiovascular disease appears to be related to the presence of risk factor clustering and insulin resistance associated with the metabolic syndrome, rather than obesity by itself (24).

The metabolic syndrome is associated with elevated levels of inflammatory markers (25). Chronic low-grade inflammation is associated with increased risk of type 2 diabetes and heart disease (26).

In the presence of obesity, adipose tissue produces inflammatory cytokines, whereas adiponectin (27) production is diminished (24). Inflammatory cytokines induce insulin resistance in both adipose tissue and muscle (28).

Hence, inflammation might be an important pathogenic link between cardiovascular diseases, insulin resistance, and metabolic syndrome.

Other disorders associated with the metabolic syndrome are non-alcoholic fatty liver disease, chronic kidney disease, polycystic ovary syndrome, obstructive sleep apnea and gout.

Treatment of Metabolic Syndrome

There are two major treatment targets in patients with the metabolic syndrome. The first aims at treating underlying causes such as obesity and physical inactivity. The second aims at treating cardiovascular risk factors if they persist despite lifestyle modification.

Lifestyle modification should focus primarily on weight reduction and increased physical activity (29).

Diet

Any diet that promotes weight reduction and reduces insulin resistance is likely to be beneficial for people with metabolic syndrome.

A Mediterranean diet is characterized by high consumption of monounsaturated fatty acids, primarily from olives and olive oil. It encourages daily consumption of fruits, vegetables, whole grains, and low-fat dairy products; weekly consumption of fish, poultry, tree nuts, and legumes; a relatively low consumption of red meat, as well as a moderate daily consumption of alcohol, normally with meals.

A meta-analysis of epidemiological studies and clinical trials published 2011 shows that adherence to the Mediterranean dietary pattern was associated with lower prevalence and progression of metabolic syndrome (30). Waist circumference, HDL cholesterol levels, triglyceride levels, blood pressure levels, and glucose metabolism were all positively affected.

In a study comparing a Mediterranean diet with a prudent low-fat, high carbohydrate diet, individuals on the Mediterranean diet had greater weight loss, lower blood pressure, less insulin resistance and better lipid profile (31). Markers of inflammation were also lower compared with the prudent diet.

Metabolic Syndrome (Insulin resistance Syndrome)Several studies suggest that carbohydrate restriction has more favorable effects on the metabolic syndrome than a low-fat diet (32, 33, 34, 35, 36). Low-carbohydrate diets tend to lead to more weight loss, less insulin resistance, lower triglyceride levels, and higher levels of HDL-cholesterol.

A 2012 meta-analysis of randomized trials of low-carbohydrate diets for weight loss showed positive effects on body weight, body mass index (BMI), abdominal circumference, blood pressure, blood sugar, plasma triglycerides and HDL cholesterol (37).

Exercise

Regular exercise is highly recommended for individuals with metabolic syndrome.

Exercise may be beneficial, beyond its effects on weight loss. One study suggests exercise may reduce abdominal fat among women (38).

A standard exercise recommendation is a daily minimum of 30 minutes moderate exercise such as brisk walking.

Increasing the level of physical activity may provide further benefits.

Treating Cardiovascular Risk Factors

Cessation of smoking and treatment of high blood pressure, lipid abnormalities, and diabetes is important for patients with metabolic syndrome.

Statins (cholesterol-lowering drugs) are usually recommended if diabetes is present or if levels of LDL cholesterol are high (39).

Metformin (40) is usually the first drug of choice if type 2 diabetes becomes manifest.

The Take Home Message

The prevalence of metabolic syndrome has increased rapidly in recent years.

Metabolic syndrome is usually associated with overweight, abdominal obesity and insulin resistance.

The metabolic syndrome is highly related to the risk of developing type 2 diabetes and cardiovascular disease

Treatment aims at weight reduction and increased physical exercise.

Scientific evidence suggests the Mediterranean diet and low-carbohydrate diets are more effective than other diets for treating metabolic syndrome.

Cessation of smoking and treatment of hypertension, lipid abnormalities, and diabetes is important.

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