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