Good Calories, Bad Calories

Grundy’s explanation allows both Keys and Cleave to be right—by suggesting that their hypotheses addressed two different but relevant nutrition transitions—and therefore does not require that we question the credibility of our public-health authorities. His explanation might be valid, but it relies on a number of disputable assumptions and a selective interpretation of the evidence. It could also be true that we faced very much the same problem fifty years ago that we do today, and that a continuing accumulation of evidence exonerates the fats in the diet and incriminates refined, easily digestible carbohydrates and starches instead. The implications are profound.

The appropriate response to any remarkable proposition in science is extreme skepticism, and the carbohydrate hypothesis of chronic disease offers no exception. But looking at the hypothesis in the context of a concept called homeostasis, which is of fundamental importance for understanding the nature of living organisms, gives us great insight. Much of the progress in physiology in the mid-twentieth century could be described as the transferral of this “concept of the nature of the wholeness,” as the Nobel Laureate chemist Hans Krebs suggested in 1971, “from the realm of philosophy and theory of knowledge to that of biochemical and physiological experimentation.” Though physiologists were aware of this paradigmatic shift, clinical investigators studying chronic disease have paid little attention, which means that the greater implications of the fundamental idea of homeostasis have been slighted.

In the mid-nineteenth century, the legendary French physiologist Claude Bernard observed that the fundamental feature of all living organisms is the interdependence of the parts of the body to the whole. Living beings are a “harmonious ensemble,” he said, and so all physiological systems have to work together to assure survival. The prerequisite for this survival is that we maintain the stability of our internal environment, the milieu interieur, as Bernard famously phrased it—including a body temperature between 97.3°F and 99.1°F and a blood-sugar level between 70 mg/dl and 170 to 180 mg/dl—regardless of external influences. “All the vital mechanisms, however varied they may be,” Bernard wrote, “have only one object, that of preserving constant the conditions of life in the internal environment.” (As the British biologist J.B.S. Haldane noted a half-century later, “No more pregnant sentence was ever framed by a physiologist.”) And this stability of the milieu interieur is accomplished, Bernard said, by a continual adjustment of all the components of this living ensemble “with such a degree of perfection that external variations are instantly compensated and equilibrated.”

In 1926, Bernard’s concept was reinvented as homeostasis by the Harvard physiologist Walter Cannon, who coined the term to describe what he called more colloquially “the wisdom of the body.” “Somehow the unstable stuff of which we are composed,” Cannon wrote, “had learned the trick of maintaining stability.” Although “homeostasis” technically means “standing the same,” both Cannon and Bernard envisioned a concept more akin to what systems engineers call a dynamic equilibrium: biological systems change with time, and change in response to the forces acting on them, but always work to return to the same equilibrium point—the roughly 98.6°F of body temperature, for instance. The human body is perceived as a fantastically complex web of these interdependent homeostatic systems, maintaining such things as body temperature, blood pressure, mineral and electric-charge concentration (pH) in the blood, heartbeat, and respiration, all sufficiently stable so that we can sail through the moment-to-moment vicissitudes of the outside world. Anything that serves to disturb this harmonic ensemble will evoke instantaneous compensatory responses throughout that work to return us to dynamic equilibrium.

All homeostatic systems, as Bernard observed, must be amazingly interdependent to keep the body functioning properly. Maintaining a constant body temperature, for example, is critical because biochemical reactions are temperature-sensitive—they will proceed faster in hotter temperatures and slower in colder ones. But not all biochemical reactions are equally sensitive, so their rates of reaction will not change equally with changes in temperature. A biological system like ours that runs ideally at 98.6°F can spin out of control when this temperature changes and all the myriad biochemical reactions on which it depends now proceed at different rates. Our body temperature is the product of the heat released from the chemical reactions that constitute our metabolism. It is balanced in turn by the cooling of our skin in contact with the outside air. On cold days, we will metabolically compensate to generate more heat, and so more of the calories we consume go to warming our bodies than they would on hot days. Thus, the ambient temperature immediately affects, among other things, the regulation of blood-sugar and of carbohydrate and fat metabolism. Anything that increases body heat (like exercise or a hot summer day) will be balanced by a reduction of heat generated by the cells, and so there is a decrease in fuel use by the cells. It will also be balanced by dehydration, increased sweating, and the dilation of blood vessels near the surface of the skin. These, in turn, will affect blood pressure, so another set of homeostatic mechanisms must work, among other things, to maintain a stable concentration of salts, electric charge, and water volume. As the volume of water in and around the cells decreases in response to the water lost from sweating or dehydration, our bodies respond by limiting the amount of water the kidneys excrete as urine and inducing thirst, so we drink water and replenish what we’ve lost. And so it goes. Any change in any one homeostatic variable results in compensatory changes in all of them.

This whole-body homeostasis is orchestrated by a single, evolutionarily ancient region of the brain known as the hypothalamus, which sits at the base of the brain. It accomplishes this orchestral task through modulation of the nervous system—specifically, the autonomic nervous system, which controls involuntary functions—and the endocrine system, which is the system of hormones. The hormones control reproduction, regulate growth and development, maintain the internal environment—i.e., homeostasis—and regulate energy production, utilization, and storage. All four functions are interdependent, and the last one is fundamental to the success of the other three. For this reason, all hormones have some effect, directly or indirectly, on fuel utilization and what’s known technically as fuel partitioning, how fuel is used by the body in the short term and stored for the long term. Growth hormone, for example, will stimulate the mobilization of fat from fat cells to use as energy for cell repair and tissue growth.

All other hormones, however, are secondary to the role of insulin in energy production, utilization, and storage. Historically, physicians have viewed insulin as though it has a single primary function: to remove and store away sugar from the blood after a meal. This is the most conspicuous function impaired in diabetes. But the roles of insulin are many and diverse. It is the primary regulator of fat, carbohydrate, and protein metabolism; it regulates the synthesis of a molecule called glycogen, the form in which glucose is stored in muscle tissue and the liver; it stimulates the synthesis and storage of fats in fat depots and in the liver, and it inhibits the release of that fat. Insulin also stimulates the synthesis of proteins and of molecules involved in the function, repair, and growth of cells, and even of RNA and DNA molecules, as well.

Insulin, in short, is the one hormone that serves to coordinate and regulate everything having to do with the storage and use of nutrients and thus the maintenance of homeostasis and, in a word, life. It’s all these aspects of homeostatic regulatory systems—in particular, carbohydrate and fat metabolism, and kidney and liver functions— that are malfunctioning in the cluster of metabolic abnormalities associated with metabolic syndrome and with the chronic diseases of civilization. As metabolic syndrome implies, and as John Yudkin observed in 1986, both heart disease and diabetes are associated with a host of metabolic and hormonal abnormalities that go far beyond elevations in cholesterol levels and so, presumably, any possible effect of saturated fat in the diet.

This suggests another way to look at Peter Cleave’s saccharine-disease hypothesis, or what I’ll call, for simplicity, the carbohydrate hypothesis of chronic disease. As Cleave pointed out, species need time to adapt fully to changes in their environment—whether shifts in climate, the appearance of new predators, or changes in food supply. The same is true of the internal environment of the human body—Bernard’s milieu interieur. By far the most dramatic change to this internal environment over the past two million years is due to the introduction of diets high in sugar and refined and other easily digestible carbohydrates. Blood-sugar levels rise dramatically after these meals; insulin levels rise in response and become chronically elevated— hyperinsulinemia—and tissues become resistant to insulin. And because half of every molecule of table sugar (technically known as sucrose) is a molecule of the sugar known as