The less common approach to this synchronicity of diseases has been to assume, as Peter Cleave did, that related diseases have related or common causes; that they are manifestations of a single underlying disorder. Cleave called it the saccharine disease because he believed sugar and other refined carbohydrates were responsible. By this philosophy, if diabetes, coronary heart disease, obesity, gout, and hypertension appear simultaneously in populations, as they did in the Tokelauan experience, and are frequently found together in the same patients, then they are very likely to be manifestations of a single underlying pathology. If nothing else, Cleave argued, this common-cause hypothesis was the simplest possible explanation for the evidence, and thus the one that should be presumed true until compelling evidence refuted it. This was Occam’s razor, and it should be the guiding principle of all scientific endeavors.

In the early 1950s, clinical investigators began to characterize the physiological mechanisms that would underlie Cleave’s saccharine-disease hypothesis of chronic disease, and that could explain the appearance of diseases of civilization going back over a century—the basis, in effect, of this carbohydrate hypothesis. The research evolved in multiple threads that resulted in some of the most fundamental discoveries in heart-disease and diabetes research. Only in the late 1980s did they begin to come together, when the Stanford diabetologist Gerald Reaven proposed the name Syndrome X to describe the metabolic abnormalities common to obesity, diabetes, and heart disease, all, at the very least, exacerbated by the consumption of sugar, flour, and other easily digestible carbohydrates. Syndrome X included elevated levels of the blood fats known as triglycerides; low levels of HDL cholesterol, now known as the good cholesterol; it included hypertension, and three phenomena that are considered precursors of adult-onset diabetes—chronically high levels of insulin (hyperinsulinemia), a condition known as insulin resistance (a relative insensitivity of cells to insulin), and the related condition of glucose intolerance (an inability to metabolize glucose properly). Over the years, other abnormalities have been added to this list: the presence of predominantly small, dense LDL particles, and high levels of a protein called fibrinogen that increases the likelihood of blood-clot formation. Elevated uric-acid concentrations in the blood, a precursor of gout, have been linked to Syndrome X, as has a state of chronic inflammation, marked by a high concentration in the blood of a protein known as C-reactive protein.