Good Calories, Bad Calories

John Peters and Evelyn Man, had set out to test the speculation voiced by Elliot 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 abnormally high cholesterol—the ones who “were extremely ill and profoundly emaciated.” Man and Peters continued collecting 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 called 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 chronically elevated levels of insulin in the circulation, hyperinsulinemia—a vitally 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 small protein, technically 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 all diabetes. As Yalow and Berson among others also reported, the obese, too, had chronically 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 cell, 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 normally, 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 all tissues from resistance of only individual tissues.”

From the mid-1960s onward, our understanding of the role of insulin resistance in both heart disease and diabetes was driven by the work of Stanford University diabetologist Gerald Reaven. Reaven began his investigations by measuring triglycerides and glucose tolerance in heart-attack survivors. A glucose-tolerance test is a common test given by physicians to determine if a patient is either diabetic or on the way to becoming so. The patient drinks a solution of glucose and water, and then, two hours later, the physician measures his or her blood sugar. If the blood sugar is higher than what’s considered normal, it means the patient has been unable to metabolize the glucose properly—hence, glucose intolerance—and so either lacks sufficient insulin to deal with the glucose, or is resistant to the insulin that is secreted. In 1963, Reaven reported that heart-attack survivors invariably had both high triglycerides and glucose intolerance, and this suggested that the two conditions had a common cause. Reaven considered insulin resistance to be the obvious suspect.

Working with John Farquhar, who had studied with Pete Ahrens at Rockefeller, Reaven developed a two-part hypothesis.

The first part explained why most, if not virtually all individuals with high triglycerides had what Ahrens had called carbohydrate-induced lipemia. In other words, their triglyceride levels increased with carbohydrate-rich diets and decreased when fat replaced the carbohydrates. The crucial factor, Reaven explained, is that, the more carbohydrates consumed, the more insulin is needed to transport the glucose from the carbohydrates into cells where it can be used as fuel. This insulin, however, also prompts the liver to synthesize and secrete triglycerides for storage in the fat tissue. If someone who is already insulin-resistant consumes a carbohydrate-rich diet, according to Reaven’s hypothesis, the person will have to secrete even more insulin to deal with the glucose, prompting in turn even greater synthesis and secretion of triglycerides by the liver, and so even higher triglyceride levels in the blood.

This, in turn, implied part two of the hypothesis: if eating a carbohydrate-rich diet in the presence of insulin resistance will abnormally elevate triglyceride levels, then it’s hard to avoid the implication that eating a carbohydrate-rich diet increases the risk of heart disease. Insulin resistance and carbohydrates will also exacerbate Type 2 diabetes, according to Reaven’s hypothesis, and this would explain, as well, why these diabetics inevitably have high triglycerides. By 1967, Reaven and Farquhar had reported that triglyceride levels, insulin resistance, and insulin levels moved up and down in concert even in healthy individuals: the more insulin secreted in response to carbohydrates, the greater the apparent insulin resistance and the higher the triglycerides.

Reaven and Farquhar spent the next twenty years working to establish the validity of the hypothesis. Much of the progress came with the development, once again, of new measuring techniques: in this case, tests that allowed investigators to measure insulin resistance directly. In 1970, Reaven and Farquhar published the details of the first such insulin-resistance test, which was then followed by a half-dozen more. The best of these—the “gold standard”—was developed at the NIH in the late 1960s and then refined over the next decade by a young endocrinologist named Ralph DeFronzo. It wasn’t until 1979, after DeFronzo joined the faculty at Yale Medical School and began measuring insulin resistance in human patients, that he published the details. It would take another decade for Reaven, Farqhuar, and DeFronzo, along with Eleuterio Ferrannini of the University of Pisa, among others, to convince diabetologists that resistance to insulin was the fundamental defect in Type 2 diabetes.

In 1987, the American Diabetes Association honored DeFronzo with its award for outstanding scientific