SYNDROME THE RISKS OF HIGH INSULIN.

Dr. Atkins' New Diet Revolution. Protein Power. The Zone.

All the best-selling anti-carbohydrate diet books cite the work of Gerald Reaven, professor of medicine at Stanford University. And they all misinterpret that work, says Reaven. Reaven's research team first recognized that people with high blood insulin levels have an elevated risk of heart disease. He coined the term "Syndrome X" to describe the cluster of heart-threatening abnormalities in those people. And he showed that a high-carbohydrate diet could raise their insulin--and presumably their risk of heart disease--even further.

Now Reaven has written his own book, Syndrome X: Overcoming the Silent Killer That Can Give You a Heart Attack.

"I wrote the book because I got so upset about the misinformation in the other books," he explains.

Q: What is Syndrome X?

A: It is a cluster of risk factors that represent a major cause of coronary heart disease. Syndrome X, which is also called The Metabolic Syndrome, is seen in people who ate insulin-resistant. Like people with type 2 diabetes, their insulin is less able to dispose of glucose, or blood sugar, by moving it into muscle and fat cells [see "The Diabetes Story," p. 5].

Q: But they don't get diabetes?

A: Right. When insulin doesn't dispose of blood sugar, blood sugar goes up and you have, by definition, type 2 diabetes. But in people with Syndrome X, the pancreas responds by secreting enough insulin to overcome the resistance and people don't get diabetes.

HOW IT STARTED

Q: When did you first use the term Syndrome X?

A: In 1988, when I gave the Banting Lecture to the annual meeting of the American Diabetes Association. `X' was meant to be the unknown. I realized that it wasn't clear to the medical profession that most people who were insulin-resistant did not get type 2 diabetes. They could secrete large amounts of insulin and although their glucose might be a little high, it never got high enough to warrant the diagnosis of diabetes. But these individuals were at great risk of developing other problems that increased the risk of coronary heart disease.

Q: What problems?

A: When I first described the syndrome, they included high triglycerides and low HDL [`good'] cholesterol, high blood pressure, and some degree of glucose intolerance, but not diabetes. In the succeeding years, the cluster of problems that are associated with Syndrome X has increased to include smaller and denser LDL [`bad'] cholesterol particles and an increase in postprandial lipemia, which is the accumulation of triglyceride-rich lipoproteins in the blood after meals and throughout the day as you eat.

People with Syndrome X also have a high plasminogen activator-1, which means their ability to break up blood clots is reduced, so they have an increased risk of heart attack.

Q: How much does Syndrome X raise the risk of heart disease?

A: It's unclear. We've published two prospective studies. In one we followed 147 individuals who were roughly age 50 and healthy when the study started.[1] We measured their insulin resistance at the beginning, and we followed them for five years. Of the third who were the most insulin-resistant, one out of seven had a heart attack during the five years. Of the third who were the least insulin-resistant, not a single person had a heart attack.

In another study we followed about 650 people over roughly a ten-year period.[2] In the quarter of the people with the highest insulin levels, about eight percent had a heart attack during the study. In the rest of the people, only one or two percent had a heart attack. The Quebec Cardiovascular Study found roughly the same thing.[3]

Q: How many Americans have Syndrome X?

A: When we measure insulin resistance in non-obese, non-diabetic individuals without high blood pressure, about 25 to 30 percent of them are insulin-resistant. If you assume that there are 200 million adults in the U.S., that works out to 33 to 40 million people, not counting those with diabetes and high blood pressure. It's a very rough estimate.

Q: Why don't most physicians know about Syndrome X?

A: The country is very much focused on LDL cholesterol. LDL is important, but it's not the only cause of a heart attack. The medical profession still lacks an appreciation of causes other than LDL because the half dozen companies that have drugs that lower LDL cholesterol put on very extensive educational programs about it.

Parke-Davis has a drug called gemfibrozil that lowers triglycerides. At one time, they were very anxious to point out that low HDL and high triglycerides are an important risk factor for heart disease. But the moment the patent for gemfibrozil ran out, their educational programs ended. The programs have now restarted because the company claims that Lipitor, its LDL-lowering statin drug, lowers triglycerides better than the other statins.

THE SIGNS OF SYNDROME X

Q: How do you know if you have Syndrome X?

A: The most common sign is a high insulin level. But I don't recommend getting your insulin measured at a commercial lab, because the labs vary and interpretation varies.

It's better to test for other links. For example, if you take people who have a normal glucose tolerance--who are not diabetic--people with Syndrome X have higher levels within that normal range.

Q: How high?

A: Diabetes is defined as having either fasting glucose of more than 126 of blood glucose of at least 200 two hours after drinking 75 grams of glucose. What we see in people with Syndrome X is fasting glucose between 110 and 126, which is called impaired fasting glucose, or blood glucose between 140 and 200 two hours after drinking 75 grams of glucose, which is called impaired glucose tolerance.

Q: How high ate the triglycerides of people with Syndrome X?

A: We typically see fasting triglycerides above 200 mg/dL, which usually accompany low HDL cholesterol--that is, HDL under 40. HDL above 40 and triglycerides below 200 are usually considered to be healthy, though there's some concern that problems like smaller, denser LDL and postprandial lipemia start at triglyceride levels of 150.

Q: Does insulin resistance cause high triglycerides?

A: Triglycerides are made out of fat. If you're insulin-resistant, your fat cells release more fat into the blood-stream. And that leads the liver to produce more triglycerides.

Q: Insulin affects fat cells?

A: In the morning when you wake up, before you eat, your insulin levels are low. That means you're taking up almost no glucose into your muscle. Because your insulin is low, your fat cells release free fatty acids. That's the major source of energy for your heart and skeletal muscles.

Once you eat, glucose and insulin levels go up, and the insulin inhibits the release of fatty acids for fuel. Instead, insulin starts putting glucose into your muscle. But if you're insulin-resistant, your insulin isn't very effective, so it doesn't keep your fat cells from sending high levels of free fatty acids into the blood.

Q: Ate there any other signs of Syndrome X?

A: For years, it's been shown that people who have had heart attacks have higher uric acid levels than normal. The more insulin-resistant you are, the more likely your uric acid will be high. Whether or not the uric acid is the cause of a heart attack or just an innocent bystander because of the insulin resistance is not clear.

CAUSES OF INSULIN RESISTANCE

Q: What causes insulin resistance?

A: We know that the ability of insulin to do its job varies about ten-fold in healthy populations--not counting diabetics. Probably half of that is genetic. The other half--the other two major players--are how heavy you are and how fit you are.

Obesity has been overplayed because most studies haven't taken into consideration that obese individuals are often sedentary. If you take objective measures of fitness versus obesity, you end up getting roughly equal impact. So maybe 20 to 25 percent of your risk of insulin resistance depends on how heavy you are and maybe another 20 to 25 percent depends on how fit you are.

Q: Nothing else affects insulin resistance?

A: Smoking makes it somewhat worse, moderate drinking--one or two servings of alcohol a day--makes it somewhat better, and magnesium makes it a little better, but these are trivial compared to being fat of unfit.

Q: Why do the Chinese have low rates of heart attacks even though they eat a low-fat, high-carbohydrate diet?

A: In developing countries like China and India, and in Southeast Asia, the goal has been getting enough food to maintain weight. They ride bicycles, not cars. They work extremely hard and are very physically active. But when they move to more affluent countries and begin to live longer and to gain weight and get less active, the insulin resistance, which has been reasonably well-controlled, goes out of control. And suddenly there's an epidemic of heart attacks.

Q: Does insulin resistance cause obesity, as many diet books claim?

A: Absolutely not. Years ago, we put people with different degrees of insulin resistance on dramatically different diets--in one study, carbohydrates were either 85 or 17 percent of calories.[4] The only thing that affected their weight was how many calories they ate. More recently, we've published long-term studies showing that weight gain is unrelated to how insulin-resistant people were when the studies began.[5] And weight loss with low-calorie diets is also unrelated to the degree of insulin resistance.[6]

So there's not one shred of evidence that insulin resistance causes obesity.

Q: Would you expect it to?

A: No. If you think about it, the notion that insulin resistance causes obesity is unreasonable. Insulin resistance means that insulin isn't acting correctly. So if you don't have enough insulin of if your cells aren't responding to insulin, you can't deposit glucose into cells. If anything, you would lose weight.

Q: Theory aside, is it possible that low-carbohydrate diets help people lose weight by curbing appetite?

A: There isn't a great deal of evidence that any given diet will make you eat more of less. There are such enormous psychosocial effects on appetite that it's hard to separate out changes caused by what's in the diet.

WHAT TO DO

Q: What should you do if you suspect that you have Syndrome X?

A: Go to a doctor who knows about it and have tests done [see "What's Your Risk?"]. Even if you don't have all the signs, you may still have Syndrome X. Insulin resistance is the basic abnormality. But other things influence triglycerides, HDL, blood pressure, etc. Let's say you and I are equally insulin-resistant and our livers are making equal amounts of triglycerides, but you're more efficient at getting triglycerides out of the bloodstream, so your triglycerides are 160 and mine are 210. You're still insulin-resistant, but it doesn't show up in your triglyceride level.

Q: What would the doctor tell you?

A: He or she might tell you to lose weight if you're overweight, start exercising, watch your diet, and stop smoking. If all those lifestyle changes don't work, there are medicines that can help.

Q: Which lifestyle changes ate most important?

A: The most powerful are how much you weigh and how fit you are. If you're insulin-resistant and over-weight and you lose weight, you become less insulin-resistant. And you stay that way as long as you keep the weight off. The average over-weight person would benefit by losing only ten or 15 pounds.

Whether or not you lose weight, exercise also makes you less insulin-resistant. But if you stop exercising, you lose the benefit. So it's relatively transitory compared to the benefit of weight loss.

Q: What kind of diet is best for people with Syndrome X?

A: Not a high-carbohydrate diet, because you have to secrete more insulin to handle the carbs if you're insulin-resistant. I recommend limiting carbohydrates to 45 percent of calories. So if you're eating a 2,000-calorie diet, that's 225 grams of carbohydrate a day.

DIET BOOKS

Q: How does your diet compare to the Dr. Atkins diet?

A: The Atkins diet is dangerous because Atkins doesn't care how much saturated fat you eat. There's no doubt that the major determinant of LDL cholesterol--other than genes--is the amount of saturated fat in your diet. So it doesn't make much sense to have anybody eating large amounts of meat, cheese, butter, and other sources of saturated fat.

Q: What if you lose weight on the Atkins diet?

A: You'll make Syndrome X better, but the high LDL you get from eating so much saturated fat is bad, too. In fact, the people at worst risk by far for heart disease are people who have combined dyslipidemia, which is high LDL and Syndrome X.

Q: But if people lose weight on the Atkins diet, wouldn't their cholesterol drop?

A: Your total cholesterol might fall if you had high triglycerides and you lost weight, because your triglyceride-rich VLDL cholesterol would fall, and it's part of your total cholesterol. But LDL has very little relation to anything except saturated fat. So losing weight or exercise wouldn't lower your LDL.

Q: How much saturated fat do you recommend?

A: Five to ten percent of calories. That's similar to what the American Heart Association recommends. The difference is that, on our diet, you're replacing carbs with mono- and polyunsaturated fat.

Q: What do you think about The Zone diet?

A: Carbs don't make you fat, and insulin doesn't make you fat, as the book claims. Calories make you fat. It's like a bankbook. It's a matter of how much you put in and how much you take out. The more you eat and the fewer calories you burn up, the heavier you'll get. The law of thermodynamics, to the best of my knowledge, hasn't been repealed recently. What's more, the physiology behind The Zone's good and bad eicosanoids has no scientific basis.

Q: How is your diet different from The Zone diet?

A: The fundamental difference is that we substitute unsaturated fat for the carbs you give up. The Zone substitutes protein for carbohydrate. That's inappropriate because protein stimulates insulin secretion, and the protein is often accompanied by saturated fat and cholesterol. Fat doesn't stimulate insulin secretion.

Q: What about a very-low-fat diet like Dean Ornish's?

A: Ornish's program puts people on a very-low-fat diet, but it also includes exercise and weight loss. So his diet lowers LDL and, if you get active and lose weight, it's going to improve insulin resistance. But I think people who are insulin-resistant would do even better if they exercised, lost weight, and followed my diet, because mine raises HDL and lowers triglycerides.

Q: What about people who aren't insulin-resistant?

A: They can eat a low-fat diet and not worry about limiting carbs.

Q: To many people, a high-fat diet means pizza, hamburgers, and ice cream. Yours is like a low-fat diet plus oil.

A: Yes, it's got fish, poultry, fruits, vegetables, and the usual foods that you'd eat on a low-fat diet, plus unsaturated fats like nuts, peanut butter, mayonnaise, and salad dressing. It's not the Atkins message that you can eat all the fat you want--saturated of not--and still lose weight.

Q: Even unsaturated fat is largely empty calories. If people aren't careful, might they miss out on some nutrients?

A: Yes, but if people follow our advice, the nutrients are all there, except calcium. We tell people to take a daily calcium supplement because our diet supplies only 500 milligrams a day.

[1] J. Clin. Endocrin. Metab. 83: 2773, 1998.

[2] Metabolism 48: 989, 1999.

[3] New Eng. J. Med. 334: 952, 1996.

[4] J. Crin. Invest. 45: 1648, 1966.

[5] J. Clin. Endocrin. Metab. 83: 3498, 1998.

[6] J. Crin. Endocrin. Metab. 84: 578, 1999.

RELATED ARTICLE: OBESITY IN AMERICA: INEVITABLE?

As suggested by the intense interest in Syndrome X and low-carbohydrate diets (see cover story), America has one of the highest rates of obesity in the world. According to the Centers for Disease Control and Prevention (CDC), 46 percent of all U.S. adults were overweight of obese in the late 1970s. By the early 1990s the figure had climbed to 55 percent. During the same period, rates in teens almost doubled.

While obesity may be great for certain businesses--weight-loss franchises, the diet-book industry, and makers of exercise equipment, to name a few--it increases the risk of diabetes, hypertension, and heart disease. Also, it can undermine self-esteem and social and business success.

The rising rates of obesity certainly don't reflect new genetic mutations or something in the air we breathe. Rather, they reflect human ingenuity--the ingenuity that has led to three-car households, the movement of jobs from farms and mines to offices, and 670-calorie Cinnabons. As a result, it is easier than ever to consume more--and expend fewer--calories. The U.S. has become hothouse for obesity. While diet books, weight-loss counseling, and other approaches might help some people lose weight (at least temporarily), the real challenge is to adopt a lifestyle that helps us maintain a normal weight throughout our lives.

Serious efforts to prevent obesity would involve getting people out of cars and on to mass transit, bike paths, and sidewalks; having daily physical education in every school; and encouraging couch potatoes to become bikers, hikers, and joggers. Nutritionists would encourage people to cut calories by eating more fruits and vegetables and fewer burgers, fries, pizzas, sweets, and junk foods. Restaurants would offer cheaper half portions, and menus would list calories for standard meals. Major mass-media campaigns (perhaps funded in part by small taxes on junk foods) would encourage the public to make physical activity and sensible eating a daily habit.

On May 30 and 31, the federal government will sponsor a National Nutrition Summit, which will explore ways to prevent obesity and other chronic diseases. I hope that the meeting focuses on the systemic changes that are needed to promote the public's health and serves as a springboard for bold government programs.

Time will tell whether our nation chooses a lifestyle built around fitness--or gluttony and sloth.

Michael F. Jacobson Executive Director Center for Science in the Public Interest

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RELATED ARTICLE: DIET VS. DIET

Few people calculate the percentage of calories they get from protein, carbs, or fat, but this chart should give you some idea of how several diets vary. What the chart doesn't show is that most diets also restrict calories. The chart also omits other key features--like fruits, vegetables, fiber, and sodium--that can make or break a diet.

                                           Mono &
                           Saturated   Polyunsaturated
                 Protein      Fat            Fat

American Heart
Association         15%      5-10%            20%

Dr. Atkins       22%(*)     25%(*)         35%(*)

Dean Ornish      15-20%         3%             7%

Syndrome X          15%      5-10%         30-35%

The Zone            30%         6%            24%

                                Cholesterol
                 Carbohydrate    (mg/day)

American Heart
Association         55-60%            300

Dr. Atkins          18%(*)            880(*)

Dean Ornish         70-75%              5

Syndrome X             45%      below 300

The Zone               40%            210

(*) This diet makes no specific recommendation; recommended menu plans were used to calculate proportions.

Source: Syndrome X: Overcoming the Silent Killer That Can Give You a Heart Attack and NAH.

RELATED ARTICLE: WHAT'S YOUR RISK?

Some signs of Syndrome X--including insulin resistance itself--aren't worth measuring unless you're in a research study. The following seven signs, on the other hand, can be measured in any doctor's office.

They're not the only risk factors for a heart attack. Others include LDL cholesterol over 130, smoking, having diabetes, age (over 45 for men; over 55 for women), and being male.

If Your                                        Give Yourself

1. Fasting glucose level is greater than          3 points
   110, or your glucose at two hours
   into the Glucose Tolerance Test is
   greater than 140

2. Fasting triglyceride level is greater          3 points
   than 200

3. Fasting HDL cholesterol level is               3 points
   lower than 35

4. Blood pressure is greater than                 3 points
   145 over 90

5. Weight check reveals that you are more          1 point
   than 15 pounds overweight

6. Family has a history of heart disease,          1 point
   high blood pressure (hypertension),
   or diabetes

7. Lifestyle is characterized by physical        1/2 point
   inactivity in both work and leisure hours

   Total Score--
                    Your Risk of
                    Heart Attack
                    Triggered by
If You Scored       Syndrome X is

0-4 points          Low
5-8 points          Moderate
9-12 points         High
13 points or more   Very High

Source: Syndrome X: Overcoming the Silent Killer That Can Give You a Heart Attack.

RELATED ARTICLE: THE SYDROME X DIET

Here's a sample day's menu for Reaven's 1,800-calorie diet. It gets 45 percent of its calories from carbohydrates, 40 percent from (mostly unsaturated) fat, and 15 percent from protein. If you try to follow the diet, make sure you take a calcium supplement and don't eat extra fat (more fat means more calories).

The Syndrome X diet has about five servings of fruits and vegetables a day, but eating eight to ten a day may help lower your risk of high blood pressure and cancer.

BREAKFAST

1/2 cup cooked oatmeal with cinnamon, topped with 2 tsp.
  sliced almonds
1/2 cup low-fat milk
1/2 grapefruit
1 slice whole-wheat toast with 2 tsp. margarine*
1 slice Canadian bacon
Non-caloric beverage (water, coffee, tea, diet soda, etc.)

LUNCH

Peanut butter sandwich (2 Tbs. peanut butter, 1 Tbs. honey,
  1/3 cup seedless grapes cut in halves, between two slices
  of buttermilk white toast)
Green salad (1 cup lettuce, 4 tomato wedges, cucumber
  slices, 3 Tbs. small cooked shrimp, and 2 tsp. vinaigrette
  dressing)
1 Nabisco Ginger Snap
Non-caloric beverage

DINNER

2.5 oz. roasted turkey breast with no skin
1/4 cup cranberry sauce
3/4 cup mashed potatoes with 2 tsp. margarine(*)
1/4 baked sweet potato with 2 tsp. margarine(*)
1/2 cup fresh peas with I heaping tsp. margarine(*)
1/8 of a pumpkin pie
Non-caloric beverage

(*) Choose a margarine that is low in both saturated and trans fat.

Source: Syndrome X: Overcoming the Silent Killer That Can Give You a Heart Attack.

Gerald Reaven, M.D., has served as director of the Division of Endocrinology and Metabolism and the Division of Gerontology at Stanford University School of Medicine. He is now professor of medicine at Stanford and vice president of clinical development at Shaman Pharmaceuticals of South San Francisco, California. Reaven is the author of more than 500 scientific papers. His new book, Syndrome X: Overcoming the Silent Killer that Can Give You a Heart Attack, is scheduled to be published this month by Simon & Schuster. Nutrition Action Healthletter's Bonnie Liebman spoke to him by phone in Palo Alto, California.