Good Calories, Bad Calories (34 page)

One key fact to remember in this discussion is that LDL and LDL cholesterol are not one and the same. The LDL carries cholesterol, but the amount of cholesterol in each LDL particle wil vary. Increasing the LDL cholesterol is not the same as increasing the number of LDL particles.

There are two ways to increase the amount of cholesterol in LDL. One is to increase the amount of cholesterol secreted to begin with; the other is to decrease the rate of disposal of cholesterol once it’s been created (which is apparently what happens when we eat saturated fat). Either method wil eventual y result in elevated LDL cholesterol. Joseph Goldstein and Michael Brown worked out the details of the clearance-and-disposal mechanism in the 1970s, and this work won them the Nobel Prize.

As for secretion, the key point is that most low-density lipoproteins, LDL, begin their lives as very low-density lipoproteins, VLDL. (This was one implication of the observation that both LDL and VLDL are composed of the same apo B protein, and it was established beyond reasonable doubt in the 1970s.) This is why VLDL is now commonly referred to as a precursor of LDL, and LDL as a remnant of VLDL. If the liver synthesizes more cholesterol, we end up with more total cholesterol and so more LDL cholesterol, although apparently not more LDL particles. If the liver synthesizes and secretes more VLDL, we wil also end up with more LDL cholesterol but we have more LDL particles as wel , and they’l be smal er and denser.

This process is easier to understand if we picture what’s actual y happening in the liver. After we eat a carbohydrate-rich meal, the bloodstream is flooded with glucose, and the liver takes some of this glucose and transforms it into fat—i.e., triglycerides—for temporary storage. These triglycerides are no more than droplets of oil. In the liver, the oil droplets are fused to the apo B protein and to the cholesterol that forms the outer membrane of the bal oon.

The triglycerides constitute the cargo that the lipo-proteins drop off at tissues throughout the body. The combination of cholesterol and apo B is the delivery vehicle. The resulting lipoprotein has a very low density, and so is a VLDL particle, because the triglycerides are lighter than either the cholesterol or the apo B. (In the same way, the more air in the hold of a ship, the less dense the ship and the higher it floats in the water.) For this reason, the larger the initial oil droplet, the more triglycerides packaged in the lipoprotein, the lower its density.

The liver then secretes this triglyceride-rich VLDL into the blood, and the VLDL sets about delivering its cargo of triglycerides around the body.

Throughout this process, known poetical y as the delipidation cascade, the lipoprotein gets progressively smal er and denser until it ends its life as a low-density lipoprotein—LDL. One result is that any factor that enhances the synthesis of VLDL wil subsequently increase the number of LDL particles as wel . As long as sufficient triglycerides remain in the lipoprotein to be deposited in tissues, this evolution to progressively smal er and denser LDL

continues. It’s this journey from VLDL to LDL that explains why most men who have high LDL cholesterol wil also have elevated VLDL triglycerides. “It’s the overproduction of VLDL and apo B that is the most common cause of high LDL in our society,” says Ernst Schaefer, director of the lipid-metabolism laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. None of this, so far, is controversial; the details are described in recent editions of biochemistry textbooks.

How this process is regulated is less wel established. In Krauss’s model, based on his own research and that of the Scottish lipid-metabolism researcher Chris Packard and others, the rate at which triglycerides accumulate in the liver controls the size of the oil droplet loaded onto the lipoprotein, and which of two pathways the lipoprotein then fol ows. If triglycerides are hard to come by, as would be the case with diets low in either calories or carbohydrates, then the oil droplets packaged with apo B and cholesterol wil be smal ones. The ensuing lipoproteins secreted by the liver wil be of a subspecies known as intermediate-density lipoproteins—which are less dense than LDL but denser than VLDL—and these wil end their lives as relatively large, fluffy LDL. The resulting risk of heart disease wil be relatively low, because the liver had few triglycerides to dispose of initial y.

If the liver has to dispose of copious triglycerides, then the oil droplets are large, and the resulting lipoproteins put into the circulation wil be triglyceride-rich and very low-density. These then progressively give up their triglycerides, eventual y ending up, after a particularly extended life in the circulation, as the atherogenic smal , dense LDL. This triglyceride-rich scenario would take place whenever carbohydrates are consumed in abundance. “I am now convinced it is the carbohydrate inducing this atherogenic [profile] in a reasonable percentage of the population,” says Krauss. “…we see a quite striking benefit of carbohydrate restriction.”

This model also explains, as Pete Ahrens suggested in 1961, why high-carbohydrate diets appear innocuous in populations that are chronical y undernourished. This was inevitably the case with those Southeast Asian populations extol ed by Keys and others for their low total-cholesterol levels and apparent absence of heart disease. Such populations lived on carbohydrate-rich diets out of economic necessity rather than choice. Their diets were predominantly unrefined carbohydrates because that’s what they cultivated and it was al they could afford. As Ahrens had noted, the great proportion of individuals in such populations barely eked out enough calories to survive. This was true not only of Japan in the years after World War I , but of Greece and other areas of the Mediterranean as wel . If these populations indeed had low cholesterol and suffered little from heart disease, a relative lack of calories and a near-complete absence of refined carbohydrates would have been responsible, not the low intake of saturated fat. In developed nations

—the United States, for example—where calories are plentiful, it would be the carbohydrates pushing our metabolisms toward the production of atherogenic lipoproteins. Here, too, the saturated fat in the diet is of little significance.

THE ROLE OF INSULIN

The suppression of inconvenient evidence is an old trick in our profession. The subterfuge may be due to love of a beautiful hypothesis, but often enough it is due to a subconscious desire to simplify a confusing subject. It is not many years ago that the senior physician of a famous hospital was distinctly heard to remark, sotto voce, “medicine is getting so confusing nowadays, what with insulin and things.” It is a sentiment with which almost everybody who qualified more than a quarter of a century ago is likely to sympathize…. But ignoring difficulties is a poor way of solving them.

RAYMOND GREENE, in a letter to The Lancet, 1953

Scientific progress is driven as much by the questions posed as by the tools available to answer them. In the 1950s, when Ancel Keys settled on dietary fat and cholesterol as causes of heart disease, he did so because he sought to understand the disparity in disease rates among nations and what he believed was a growing epidemic of coronary heart disease in the United States. Those investigators whose research would eventual y evolve into the science of metabolic syndrome—the physiological abnormalities common to obesity, diabetes, and heart disease—had different questions in mind. Why are the obese exceptional y likely to become diabetic and vice versa? Why is atherosclerosis so common with both diabetes and obesity? Are these coincidental associations, or do obesity, heart disease, and diabetes share a common cause?

In the decade after World War I , Jean Vague, a professor of medicine at the University of Marseil e in France, extended these associations to what he cal ed “android obesity,” where the excess fat sits predominantly around the waist. (“Beer bel ies” are the archetypal example.) Vague reported that android obesity was associated with atherosclerosis, gout, kidney stones, and adult-onset diabetes. He speculated that some type of hormonal overactivity led to overeating, and that, in turn, to an increased secretion of insulin to store away the excess calories in fat tissue. This excessive secretion of insulin might then, over the years, cause what he cal ed pancreatic depletion and thus diabetes. A similar hormonal overactivity, Vague suggested, might cause atherosclerosis, either directly or by inducing the secretion of “lipoprotein molecules,” as John Gofman was proposing, which would then cling to the artery wal s and begin the accumulation of fats and cholesterol that is characteristic of atherosclerotic plaques.

Gofman also sought out common mechanisms to explain the association between obesity and heart disease. Because weight gain was associated with both higher blood pressure and increased triglyceride-rich VLDL, he suggested, that alone could explain why the obese had an increased risk of heart disease. But Gofman did not speculate whether weight gain elevated blood pressure and triglycerides or whether the same mechanism increased our weight and raised our blood pressure and triglycerides.

It was Margaret Albrink who extended Gofman’s observations to diabetes and set the stage for the science that would eventual y evolve into our current understanding of metabolic syndrome. In 1931, Albrink’s advisers at Yale, John Peters and Evelyn Man, had set out to test the speculation voiced by El iot Joslin, among others, that the atherosclerosis that plagues diabetics is caused by the fat and cholesterol in their carbohydrate-restricted diets. Man and Peters measured cholesterol in seventy-nine diabetics treated at Yale and reported in 1935 that the high-fat diets then prescribed for diabetics did not increase cholesterol: only nine of the seventy-nine had abnormal y high cholesterol—the ones who “were extremely il and profoundly emaciated.” Man and Peters continued col ecting blood samples from diabetic patients for another quarter-century. In 1962, Albrink reported that the average triglycerides in these samples had increased by 40 percent over the years, and this was accompanied by a dramatic increase in the proportion of diabetics with atherosclerotic complications—from 10 percent in the early 1930s to 56 percent by the late 1950s. This coincided with a doubling of the proportion of carbohydrates in the prescribed diabetic diet and a reduction in fat calories from 60 percent to 40 percent, in accord with the increasing suspicion that fatty diets caused heart disease. (Joslin made a similar observation in 1959.) Albrink also confirmed Gofman’s observation that weight gain was accompanied by high triglyceride levels: adding ten pounds in middle age was associated with a 50 percent increase in triglycerides. Almost invariably, the greater the body fat, the higher the triglycerides in the circulation.

To Albrink, these associations implied that heart-disease research should not be guided by Keys’s model but, rather, by attempts to understand what she cal ed the “abnormal metabolic patterns” common to obesity, diabetes, and heart disease. High triglycerides characterized these abnormalities, Albrink said. She proposed that these patterns were caused or exacerbated in susceptible individuals by diets high in either calories or carbohydrates or just “purified carbohydrates.” But she offered no biological mechanism to explain it.

The potential explanation arrived in the form of two insulin-related conditions, insulin resistance and chronical y elevated levels of insulin in the circulation, hyperinsulinemia—a vital y important focus of our inquiry.

Through the first half of the twentieth century, little was understood of insulin beyond its role in diabetes, because no method existed to measure its concentration in the bloodstream with any accuracy. Insulin is a very smal protein, technical y known as a peptide, and it circulates in the blood in concentrations that are infinitesimal compared with those of cholesterol and lipoproteins. As a result, the measurement of insulin in human blood relied on a variety of arcane tests that depended on the ability of insulin to prompt the absorption of glucose by laboratory rats or even by fat or muscle tissue in a test tube. This situation changed in 1960 with the discovery by Rosalyn Yalow and Solomon Berson of a method capable of reliably measuring the concentration of insulin and other peptide hormones in human blood. In 1977, when Yalow was awarded the Nobel Prize for the discovery (Berson had died in 1972), the Nobel Foundation described Yalow and Berson’s measurement technology as bringing about “a revolution in biological and medical research.”

The impact on diabetes research had been immediate. Yalow and Berson showed that those who had developed diabetes as adults had levels of circulating insulin significantly higher than those of healthy individuals—a surprising finding. It had long been assumed that lack of insulin was the root of al diabetes. As Yalow and Berson among others also reported, the obese, too, had chronical y elevated insulin levels.

By 1965, Yalow and Berson had suggested why these adult-onset diabetics could appear to be lacking insulin—manifesting the symptoms of diabetes, high blood sugar, and sugar in their urine—while simultaneously having excessive insulin in their circulation: their tissues did not respond properly to the insulin they secreted. They were insulin-resistant, defined by Yalow and Berson as “a state (of a cel , tissue, system or body) in which greater-than-normal amounts of insulin are required to elicit a quantitatively normal response.” Because of their resistance to insulin, adult-onset diabetics had to secrete more of the hormone to maintain their blood sugar within healthy levels, and this would become increasingly difficult to achieve the longer they remained insulin-resistant.*51

A critical aspect of this insulin resistance, Yalow and Berson noted, is that some tissues might become resistant to insulin while others continued to respond normal y, and this would determine how the damage done by the insulin resistance would manifest itself in different individuals. So “it is desirable,” they wrote, “wherever possible, to distinguish generalized resistance of al tissues from resistance of only individual tissues.”