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 achievement. A year later, Reaven received the ADA’s Banting Medal for Scientific Achievement.*52 Reaven then gave the prestigious Banting Lecture at the ADA’s annual conference and took the opportunity to extend the implications of his research. For the first time, he laid out the hypothesis of what he called Syndrome X (metabolic syndrome) and the cluster of disorders—including insulin resistance, hyperinsulinemia, high triglycerides, low HDL cholesterol, and high blood pressure—that accompanies Type 2 diabetes and obesity and plays a critical role in the genesis of heart disease even in nondiabetics. “Although this concept may seem outlandish at first blush,” Reaven said, “the notion is consistent with available experimental data.” As Reaven described it, the condition of being resistant to insulin leads to both heart disease and diabetes. But not everyone with insulin resistance becomes diabetic; some continue to secrete sufficient insulin to overcome their insulin resistance, though this hyperinsulinemia causes havoc on its own, including elevating triglyceride levels, and also further exacerbating the insulin resistance—a vicious cycle.