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.