Metabolic Madness

Nowadays, with heightened concern about obesity, people who are lean might feel complacent: If excess weight means disease, then normal weight must mean health.

Not so fast - a silent killer called the metabolic syndrome can strike anyone, overweight or not. Metabolic syndrome is a set of disorders that significantly increases the risk of heart disease. Its biochemical underpinnings are tremendously complicated and are still being worked out.

Among the major features of Metabolic Syndrome we find, in parallel with each other, various warning signs - only a few need to be present for a diagnosis of Metabolic Syndrome:

• excess weight or accumulation of abdominal fat
• waist-hip ratio and/or large waistline
• high blood pressure
• dyslipidemia (high triglycerides and/or LDL and/or low HDL)
• insulin resistance
• high blood sugars
• inflammation

Individually, each is a risk factor for heart disease, but a person with several of these - that is, a person with metabolic syndrome - is at a higher risk. Increasingly, the medical community is identifying and treating people with the metabolic syndrome.

In practice, diagnosis is based on easily measurable parameters: fat accumulation around the waist, blood pressure, levels of key lipids, and levels of glucose. We've come to understand that lifestyle contributes enormously to abnormalities in these parameters, and doctors typically admonish patients to "eat right and exercise" as the first line of defense.

But even for people who dutifully eat a low-fat, carbohydrate rich diet (the current recommendation) and exercise, those measures often do not halt the progression of metabolic syndrome.

In the US, it is estimated that 25% of adults - some 47 million people - are likely to have metabolic syndrome. With the rapidly rising incidence of obesity among children and youth, the number of people with metabolic syndrome is likely to swell.

According to the CDC, about 16% of 6-to-19-year-olds in 1999–2002 (more than 9 million youngsters) were overweight. Studies find that in this group, metabolic syndrome is already highly prevalent.

The causes of the syndrome are not yet fully understood but we have an understanding of some influencial factors.

Genetics is a factor. A recent study has shown that a cluster of abnormalities similar to those in metabolic syndrome can be caused by a single mutation in a mitochondrial gene.

Lifestyle is a factor. Physical inactivity and diets that generate high levels of fat in the blood and accumulation of central fat on the torso correlate strongly with metabolic syndrome.

Age is a factor. If you are at least 35 years old, there is a 25% probability that you have the syndrome; by age 60, the probability increases to 40%.

Several mechanisms may operate concurrently to give rise to the features of metabolic syndrome. Obesity is high on the list of some researchers, mainly because anyone who has a large waist circumference that meets the criteria is almost always obese. But, let's be clear, obesity is not just a matter of excess weight, we now recognize the deadly relationship between a larger waist and accumulation of fat in the middle. Metabolic syndrome occurs in people who are lean and people who are obese - the data shows that 18% of men and 22% of women who are of normal weight or slightly overweight have the metabolic syndrome.

So, you can be of normal weight but have a high percentage of body fat - what matters is how much of that fat is visceral and how much is subcutaneous. This central fatness is harmful because fat cells do not merely store fat - they send out bioactive molecules with powerful effects throughout the body. Some of these are low-molecular-weight proteins that induce inflammation, now understood to be a major cause of cardiovascular disease.

Fat in the deep visceral area is the most dangerous. Unlike the fat under the skin, visceral fat is more easily mobilized and is a richer source of proinflammatory proteins. When hydrolyzed, visceral fat releases free fatty acids. When these reach the liver, they are converted to triglycerides and stored.

Researchers agree that insulin resistance is central to metabolic syndrome. When cells are unresponsive to insulin, the pancreas responds by pouring even more insulin into the bloodstream, leading to high levels of the hormone in the blood, a condition called compensatory hyperinsulinemia. The high level of insulin in the blood forces glucose into cells but also begins the process of events leading to arterial damage and eventually a heart attack. Under these conditions, a person may not manifest either diabetes or heart disease but could well be on the way to either or both.

In general, excess insulin causes problems because insulin affects many other processes. For example, it stimulates the uptake of amino acids and increases the permeability of cells to key ions, such as potassium. In muscle cells, it promotes storage of glucose as glycogen. It also induces the secretion of angiotensin II, a peptide hormone that constricts arteries and raises blood pressure, so when insulin levels go up, hypertension follows.

In the liver, insulin promotes the synthesis of free fatty acids. However, excess fat makes liver cells insulin resistant. When free fatty acids are exported from the liver, they are taken up by other tissues, including fat (adipose) tissue, which stores free fatty acids as triglycerides. Couple that with the inhibition of the breakdown of fat in adipose tissue because insulin spares fat - more insulin means more fat sparing and fat storage - more fat produce fewer insulin receptors and increase insulin resistance. In a vicious cycle, the pancreas responds by pumping more insulin until the insulin-producing cells die from exhaustion. Type 2 diabetes ensues.

Under conditions of insulin resistance and compensatory hyperinsulinemia, the liver makes more very low density lipoprotein (VLDL). Among the lipoproteins that the body uses to transport fat, VLDL contains the greatest amount of triglycerides. Release of VLDL from the liver raises the levels of trigylcerides in the blood - and when VLDL is converted to low-density lipoprotein, levels of LDL rise. VLDL also tends to exchange some of its triglycerides with the cholesterol contained in high-density lipoprotein (HDL), the so-called "good cholesterol." This reduces the levels of HDL cholesterol. High triglycerides, high LDL, and low HDL all increase the risk of a heart attack.

The impact of fat on insulin resistance is even more pronounced during periods of stress, which releases the stress hormones adrenaline and cortisol. Adrenaline in turn stimulates the hydrolysis of fat in fat tissue, raising the amount of free fatty acids in circulation, which eventually end up in the liver. On the other hand, cortisol builds back the fat in fat tissue.

Left unchecked, insulin resistance will progress to diabetes because glucose will increasingly flood the bloodstream as insulin resistance increases. People with diabetes are likely to suffer damage to the eyes, nerves, and kidney; be more susceptible to infection, ulceration, and gangrene; are at a high risk for limb amputation and eventually will develop heart disease.

These complications are probably due to the reactivity of the excess glucose in the bloodstream because of a reaction called glycation, where glucose attaches to various proteins and causes them to cross-link and form so-called advanced glycation end products. These are known to trap LDL particles in artery walls and have been linked to cataract formation and reduced kidney function. Glycation also releases reactive oxygen radicals, which damage many entities, such as LDL. Oxidized LDL particles are very atherosclerotic - that is, they contribute significantly to the formation of plaque in arterial walls.

This oversimplified picture of the metabolic syndrome belies the complexity of the interconnections among insulin action, fat storage, energy metabolism, and cardiovascular disease. Diagnosis of metabolic syndrome is based on comparing a patient's values for risk factors against levels defined by several bodies. The most widely cited set of criteria is that of the U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III). According to ATP III, a patient has metabolic syndrome if he or she meets the criteria for at least three of five parameters:

• Waist circumference 40+ inches (men) or 35+ inches (women)
• Triglycerides 150+ mg/dL
• HDL cholesterol -40 mg/dL (men) or -50 mg/dL (women)
• Blood pressure 130/85 mm Hg
• Fasting glucose 110+ mg/dL

That definition is straightforward, but not everyone is happy with it. For example, among many of its shortcomings - the definition does not work well with certain ethnic groups, it gives equal weight to each parameter, it does not factor in the effect of age or gender and it does not address the core issues of insulin resistance or inflammation.

As for treatment, doctors overwhelmingly recommend losing weight through a "balanced diet" and regular exercise. "Eating right" means eating modest amounts of food and avoiding foods that contain high levels of fat. Physical activity is thought to ensure that calories consumed are expended.

But, as numerous dietary and lifestyle intervention studies show, a carbohydrate rich diet that is low in fat may exacerbate metabolic syndrome, even when weight is lost following the diet used as intervention. You may recall last week one study I reviewed from the American Journal of Clinical Nutrition (November 2005) and the editorials that followed - these clearly pointed out that low-fat diets are counter productive for those with insulin resistance and metabolic syndrome.

Numerous other studies point to an alternative dietary approach - a controlled-carb diet - that reverses the features of metabolic syndrome! Findings from dozens of studies show marked improvement in insulin sensitivity, decreased fasting glucose, increased HDL, significantly reduced triglycerides, stablized blood pressure, reduced inflammatory markers and weight loss too.

An extensive review was published last November in the Nutrition & Metabolism Journal - Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction.

Yet the powers that be - the established medical and scientific organizations tasked with providing the public with accurate, objective information in an evidence-based manner - simply dismiss this data and continue with the entrenched dogma that a diet with 30% or less calories from total fat and 10% of less calories from saturated fat is optimal for everyone. It's not - I know and they know it - now you know it too.

If you have metabolic syndrome or think you may be at risk - see your physician and find out for sure. Metabolic syndrome really is a silent killer - it's progressive and leads to poor long-term health and quality of life. Even if you're thin, you may already have the features of metabolic syndrome - and you can do something about it now to start to reverse the deadly effects on your long-term health...a well designed low/controlled-carb diet can and will offer you improvements.