Good Calories, Bad Calories (37 page)

In the mid-1970s, Rockefel er University biochemist Anthony Cerami and Frank Bunn independently recognized that AGEs and glycation play a major role in diabetes.*56 Both Cerami and Bunn were initial y motivated by the observation that diabetics have high levels of an unusual form of hemoglobin

—the oxygen-carrying protein of red blood cel s—known as hemoglobin A1c, a glycated hemoglobin. The higher the blood sugar, the more hemoglobin molecules undergo glycation, and so the more hemoglobin A1c can be found in the circulation. Cerami’s laboratory then developed an assay to measure hemoglobin A1c, speculating correctly that it might be an accurate reflection of the diabetic state. Diabetics have two to three times as much hemoglobin A1c in their blood as nondiabetics, a ratio that apparently holds true for nearly al glycated proteins in the body. (The best determination of whether diabetics are successful y control ing their blood sugar comes from measuring hemoglobin A1c, because it reflects the average blood sugar over a month or more.)

Since 1980, AGEs have been linked directly to both diabetic complications and aging itself (hence the acronym). AGEs accumulate in the lens, cornea, and retina of the eye, where they appear to cause the browning and opacity of the lens characteristic of senile cataracts. AGEs accumulate in the membranes of the kidney, in nerve endings, and in the lining of arteries, al tissues typical y damaged in diabetic complications. Because AGE

accumulation appears to be a natural y occurring process, although it is exacerbated and accelerated by high blood sugar, we have evolved sophisticated defense mechanisms to recognize, capture, and dispose of AGEs. But AGEs stil manage to accumulate in tissues with the passing years, and especial y so in diabetics, in whom AGE accumulation correlates with the severity of complications.

One protein that seems particularly susceptible to glycation and cross-linking is col agen, which is a fundamental component of bones, cartilage, tendons, and skin. The col agen version of an AGE accumulates in the skin with age and, again, does so excessively in diabetics. This is why the skin of young diabetics wil appear prematurely old, and why, as the Case Western University pathologist Robert Kohn first suggested, diabetes can be thought of as a form of accelerated aging, a notion that is slowly gaining acceptance. It’s the accumulation and cross-linking of this col agen version of AGEs that causes the loss of elasticity in the skin with age, as wel as in joints, arteries, and the heart and lungs.

The process can be compared to the toughening of leather. Both the meat and hide of an old animal are tougher and stiffer than those of a young animal, because of the AGE-related cross-linking that occurs inevitably with age. As Cerami explains, the aorta, the main artery running out of the heart, is an example of this stiffening effect of accumulated and cross-linked AGEs. “If you remove the aorta from someone who died young,” says Cerami, “you can blow it up like a bal oon. It just expands. Let the air out, it goes back down. If you do that to the aorta from an old person, it’s like trying to inflate a pipe.

It can’t be expanded. If you keep adding more pressure, it wil just burst. That is part of the problem with diabetes, and aging in general. You end up with stiff tissue: stiffness of hearts, lungs, lenses, joints…. That’s al caused by sugars reacting with proteins.”

AGEs and the glycation process also appear to play at least one critical role directly in heart disease, by causing the oxidation of LDL particles and so causing the LDL and its accompanying cholesterol to become trapped in the artery wal , which is an early step in the atherosclerotic process. Oxidized LDL also appears to be resistant to removal from the circulation by the normal mechanisms, which would also serve to increase the LDL levels in the blood. As it turns out, LDL is particularly susceptible to oxidation by reactive oxygen species and to glycation.*57 In this case, both the protein portion and the lipid portion (the cholesterol and the fats) of the lipoprotein are susceptible. These oxidized LDL particles appear to be “markedly elevated” in both diabetics and in nondiabetics with atherosclerosis, and are particularly likely to be found in the atherosclerotic lesions themselves.

That glycation and AGEs are critical factors in diabetic complications and in heart disease has recently been demonstrated by experiments with compounds known as anti-AGE compounds or AGE breakers. These wil reverse arterial stiffness, at least in laboratory animals, and, as one recent report put it, ameliorate “the adverse cardiovascular and [kidney-related] changes associated with aging, diabetes and hypertension.” Whether these or similar compounds wil work in humans remains to be seen.

When biochemists discuss oxidative stress, glycation, and the formation of advanced glycation end-products, they often compare what’s happening to a fire simmering away in our circulation. The longer the fire burns and the hotter the flame, the more damage is done. Blood sugar is the fuel. “Current evidence points to glucose not only as the body’s main short-term energy source,” as the American Diabetes Association recently put it, “but also as the long-term fuel of diabetes complications.”

But there is no reason to believe that glucose-induced damage is limited only to diabetics, or to those with metabolic syndrome, in whom blood sugar is also chronical y elevated. Glycation and oxidation accompany every fundamental process of cel ular metabolism. They proceed continuously in al of us.

Anything that raises blood sugar—in particular, the consumption of refined and easily digestible carbohydrates—wil increase the generation of oxidants and free radicals; it wil increase the rate of oxidative stress and glycation, and the formation and accumulation of advanced glycation end-products. This means that anything that raises blood sugar, by the logic of the carbohydrate hypothesis, wil lead to more atherosclerosis and heart disease, more vascular disorders, and an accelerated pace of physical degeneration, even in those of us who never become diabetic.

SUGAR

M. Delacroix, a writer as charming as he is prolific, complained once to me at Versail es about the price of sugar, which at that time cost more than five francs a pound. “Ah,” he said in a wistful, tender voice, “if it can ever again be bought for thirty cents, I’l never more touch water unless it’s sweetened!” His wish was granted….

JEAN ANTHELME BRILLAT-SAVARIN, The Physiology of Taste, 1825

WHEN BIOCHEMISTS TALK ABOUT “SUGAR,” they’re referring to a whole host of very simple carbohydrate molecules, al of which are characterized, among other things, by their sweet taste and ability to dissolve in water. Their chemical names al end in “-ose”—glucose, fructose, and lactose, among others.

When physicians talk about blood sugar, they’re typical y talking about glucose, although other sugars can be found in the bloodstream at very much lower concentrations. Then there’s the common usage of “sugar,” meaning the sweet, powdered variety that we put in our coffee or tea. This is sucrose, which in turn is constituted of equal parts glucose and fructose. In the discussion to come, when we refer to “sugar” we’l always be talking about sucrose. When we use the term “blood sugar,” we’l be talking about glucose.

When nutritionists in the 1960s discussed the pros and cons of sugar and starches, their concern was whether simple carbohydrates were somehow more deleterious than complex carbohydrates of starches. Chemical y, simple carbohydrates, as in sugar and highly refined flour, are molecules of one or two sugars bound together, whereas the complex carbohydrates of starches are chains of sugars that can be tens of thousands of sugars long. Complex carbohydrates break down to simple sugars during the process of digestion, but they take a while to do so, and if the carbohydrate is bound up with fiber

—i.e., indigestible carbohydrates—the digestion takes even longer. Since the early 1980s, both simple and complex carbohydrates have played a role in determining the glycemic index, which is a measure of how quickly carbohydrates are digested and absorbed into the circulation and so converted into blood sugar. This concept of a glycemic index has had profound consequences on the official and public perception of the risks of starches and sugar in the diet. But it has done so by ignoring the effect of fructose—in sugar and high-fructose corn syrup—on anything other than its ability in the short term to elevate blood sugar and elicit an insulin response.

In the mid-1970s, Gerald Reaven initiated the study of glycemic index to test what he cal ed the “traditional y held tenet” that simple carbohydrates are easier to digest than more complex carbohydrates “and that they therefore produce a greater and faster rise” in blood sugar and insulin after a meal.

Reaven’s experiments confirmed this proposition, but he was less interested in blood sugar than in insulin, and so left this research behind. It was taken up a few years later by David Jenkins and his student Thomas Wolever, both of whom were then at Oxford University. Over the course of a year, Wolever and Jenkins tested sixty-two foods and recorded the blood-sugar response in the two hours after consumption. Different individuals responded differently, and the variation from day to day was “tremendous,” as Wolever says, but the response to a specific food was stil reasonably consistent. They also tested a solution of glucose alone to provide a benchmark, which they assigned a numerical value of 100. Thus the glycemic index became a comparison of the blood-sugar response induced by a particular carbohydrate food to the response resulting from drinking a solution of glucose alone. The higher the glycemic index, the faster the digestion of the carbohydrates and the greater the resulting blood sugar and insulin. White bread, they reported, had a glycemic index of 69; white rice, 72; corn flakes, 80; apples, 39; ice cream, 36. The presence of fat and protein in a food decreased the blood-sugar response, and so decreased the glycemic index.

One important implication of Jenkins and Wolever’s glycemic-index research is that it provided support for Cleave’s speculations on the saccharine disease. The more refined the carbohydrates, the greater the blood-sugar and insulin response. Anything that increases the speed of digestion of carbohydrates—polishing rice, for instance, refining wheat, mashing potatoes, and particularly drinking simple carbohydrates in any liquid form, whether a soda or a fruit juice—wil increase the glycemic response. Thus, the addition of refined carbohydrates to traditional diets of fibrous vegetables or meat and milk, or even fish and coconuts, could be expected to elevate blood-sugar and insulin levels in the population. And this would conceivably explain the appearance of both atherosclerosis and diabetes as diseases of civilization, through the physiological abnormalities of metabolic syndrome—glucose intolerance, hyperinsulinemia, insulin resistance, high triglycerides, low HDL, and smal , dense LDL.

Jenkins and Wolever’s research, first published in 1981, led to a surprisingly vitriolic debate among diabetologists on the value of the glycemic index as a guide to control ing blood sugar. Reaven argued that the concept was worthless if not dangerous: saturated fat, he argued, has no glycemic index, and so adding saturated fat to sugar and other carbohydrates wil lower their glycemic index and make the combination appear benign when that might not quite be the case. “Ice cream has a great glycemic index, because of the fat,” Reaven observed. “Do you want people to eat ice cream?” Reaven also disparaged the glycemic index for putting the clinical focus on blood sugar, whereas he considered insulin and insulin resistance the primary areas of concern. The best way for diabetics to approach their disease, Reaven insisted, was to restrict al carbohydrates.

Paradoxical y, the glycemic index appears to have had its most significant influence not on the clinical management of diabetes but on the public perception of sugar itself. The key point is that the glycemic index of sucrose is lower than that of flour and starches—white bread and potatoes, for instance—and fructose is the reason why. The carbohydrates in starches are broken down upon digestion, first to maltose and then to glucose, which moves directly from the smal intestine into the bloodstream. This leads immediately to an elevation of blood sugar, and so a high glycemic index. Table sugar, on the other hand—i.e., sucrose—is composed of both glucose and fructose. To be precise, a sucrose molecule is composed of a single glucose molecule bonded to a single fructose molecule. This bond is broken upon digestion. The glucose moves into the bloodstream and raises blood sugar, just as if it came from a starch, but the fructose can be metabolized only in the liver, and so most of the fructose consumed is channeled from the smal intestine directly to the liver. As a result, fructose has little immediate effect on blood-sugar levels, and so only the glucose half of sugar is reflected in the glycemic index.

That sugar is half fructose is what fundamental y differentiates it from starches and even the whitest, most refined flour. If John Yudkin was right that sugar is the primary nutritional evil in the diet, it would be the fructose that endows it with that singular distinction. With an eye toward primitive diets transformed by civilization, and the change in Western diets over the past few hundred years, it can be said that the single most profound change, even more than the refinement of carbohydrates, is the dramatic increase in fructose consumption that comes with either the addition of fructose to a diet lacking carbohydrates, or the replacement of a large part of the glucose from starches by the fructose in sugar.

Because fructose barely registers in the glycemic index, it appeared to be the ideal sweetener for diabetics; sucrose itself, with the possible exception of its effect on cavities, appeared no more harmful to nondiabetics, and perhaps even less so, than starches such as potatoes that were being advocated as healthy substitutes for fat in the diet. In 1983, the University of Minnesota diabetologist John Bantle reported in The New England Journal of Medicine that fructose could be considered the healthiest carbohydrate. “We see no reason for diabetics to be denied foods containing sucrose,” Bantle wrote.