Good Calories, Bad Calories

incidence of atherosclerosis in diabetics, quite aside from any other effects insulin might have on triglycerides, lipoproteins, or blood pressure. And if this is the case, then the excessive secretion of insulin—induced by the consumption of refined carbohydrates and sugars—might be responsible for causing or exacerbating atherosclerosis in those of us who are not diabetic.

This is another of those conceptions, like the ability of insulin to regulate blood pressure, that have been mostly neglected for decades, despite the profound implications if it’s true. The specter of this atherogenic effect of insulin is noted briefly, for example, in the fourteenth edition (2005) of Joslin’s Diabetes Mellitus. The Harvard diabetologist Edward Feener and Victor Dzau, president of the Duke University Health System, write that “the effects of insulin on [cardiovascular disease] in diabetes and insulin resistance are related to both systematic metabolic abnormalities and the direct effects of insulin action on the vasculature [blood vessels; my italics].” The second mention, by two Harvard cardiologists, acknowledges the association between insulin resistance, hyperinsulinemia, and heart disease and suggests that if insulin resistance is not the problem, then “another possibility” is that insulin itself “has direct cardiovascular effects.” Nothing more is said.

The first evidence of the potential atherogenicity of insulin emerged from precisely the kind of experiments in rabbits that initially gave credibility to the cholesterol hypothesis a century ago. Rabbits fed high-cholesterol diets develop plaques throughout their arteries, but diabetic rabbits (Type 1) will not suffer this atherosclerotic fate no matter how cholesterol-rich their diet. Infuse insulin along with the cholesterol-laden diet, however, and plaques and lesions will promptly blossom everywhere. This phenomenon was first reported in 1949 in rabbits, and then, a few years later, in chickens, by Jeremiah Stamler and his mentor Louis Katz, and later in dogs, too. Hence, insulin itself may be “one factor in the pathogenesis of the frequent, premature, severe atherosclerosis of diabetic patients,” as Stamler and his colleagues suggested.

In the late 1960s, Robert Stout of Queen’s University in Belfast published a series of studies reporting that insulin enhances the transport of cholesterol and fats into the cells of the arterial wall and stimulates the synthesis of cholesterol and fat in the arterial lining. Since a primary role of insulin is to facilitate the storage of fats in the fat tissue, Stout reasoned, it was not surprising that it would have the same effect on the lining of blood vessels. In 1969, Stout and the British diabetologist John Vallance-Owen pre-empted Reaven’s Syndrome X hypothesis by suggesting that the “ingestion of large quantities of refined carbohydrate” leads first to hyperinsulinemia and insulin resistance, and then to atherosclerosis and heart disease. In certain individuals, they suggested, the insulin secretion after eating these carbohydrates would be “disproportionately large.” “The carbohydrate is disposed of in three sites—adipose [fat] tissue, liver and arterial wall,” Stout wrote. “Obesity is produced. In the liver, triglyceride and cholesterol are synthesized and find their way into the circulation. Lipid synthesis is also stimulated in the arterial wall and is augmented by deposition of [triglycerides and cholesterol]…which in a few decades would reach significant proportions.” In 1975, Stout and the University of Washington pathologist Russell Ross reported that insulin also stimulates the proliferation of the smooth muscle cells that line the interior of arteries, a necessary step in the thickening of artery walls characteristic of both atherosclerosis and hypertension.

This insulin-atherogenesis hypothesis is the simplest possible explanation for the intimate association of diabetes and atherosclerosis: the excessive secretion of insulin accelerates atherosclerosis and perhaps other vascular complications. It also implies, as Stout suggested, that any dietary factor—refined carbohydrates in particular—that increases insulin secretion will increase risk of heart disease. This did not, however, become the preferred explanation. Even Reaven chose to ignore it.^*54 But Reaven’s hypothesis proposed that heart disease was caused primarily by insulin resistance through its influence on triglycerides. He considered hyperinsulinemia to be a secondary phenomenon. Stout considered hyperinsulinemia the primary cause of atherosclerosis.

Most diabetologists have believed that diabetic complications are caused by the toxic effects of high blood sugar.^*55 The means by which high blood sugar induces damage in cells, arteries, and tissues are indeed profound, and the consequences, as the carbohydrate hypothesis implies, extend far beyond diabetes itself. This line of research is pursued by only a few laboratories. As a result, its ultimate implications and validity remain to be ascertained. But it should be considered as yet another potential mechanism by which the consumption of refined carbohydrates could cause or exacerbate the entire spectrum of the chronic diseases of civilization.

In particular, raising blood sugar will increase the production of what are known technically as reactive oxygen species and advanced glycation end-products, both of which are potentially toxic. The former are generated primarily by the burning of glucose (blood sugar) for fuel in the cells, in a process that attaches electrons to oxygen atoms, transforming the oxygen from a relatively inert molecule into one that is avid to react chemically with other molecules. This is not an ideal situation biologically. One form of reactive oxygen species is those known commonly as free radicals, and all of them together are known as oxidants, because what they do is oxidize other molecules (the same chemical reaction that causes iron to rust, and equally deleterious). The object of oxidation slowly deteriorates. Biologists refer to this deterioration as oxidative stress. Antioxidants neutralize reactive oxygen species, which is why antioxidants have become a popular buzzword in nutrition discussions.

The potential of advanced glycation end-products (AGEs) for damage is equally worrisome. Their formation can take years, but the process (glycation) begins simply, with the attachment of a sugar—glucose, for instance—to a protein without the benefit of an enzyme to orchestrate the reaction. That absence is critical. The role of enzymes in living organisms is to control chemical reactions to ensure that they “conform to a tightly regulated metabolic program,” as the Harvard biochemist Frank Bunn explains. When enzymes affix sugars to proteins, they do so at particular sites on the proteins, for very particular reasons. Without an enzyme overseeing the process, the sugar sticks to the protein haphazardly and sets the stage for yet more unintended and unregulated chemical reactions.

The term glycation refers only to this initial step, a sugar molecule attaching to a protein, and this part of the process is reversible—if blood-sugar levels are low enough, the sugar and protein will disengage, and no damage will be done. If blood sugar is elevated, however, then the process of forming an advanced glycation end-product will move forward. The protein and its accompanying glycated sugars will undergo a series of reactions and rearrangements until the process culminates in the convoluted form of an advanced glycation end-product. These AGEs will then bind easily to other AGEs and to still more proteins through a process known as cross-linking—the sugars hooked to one protein will bridge to another protein and lock them together. Now proteins that should ideally have nothing to do with each other will be inexorably joined.

In the mid-1970s, Rockefeller 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 initially motivated by the observation that diabetics have high levels of an unusual form of hemoglobin—the oxygen-carrying protein of red blood cells—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 all glycated proteins in the body. (The best determination of whether diabetics are successfully controlling their blood sugar comes from measuring hemoglobin A1c, because it reflects the average blood sugar over a month or more.)