The obvious implication is that obesity and Type 2 diabetes are two sides of the same physiological coin, two consequences, occasionally concurrent, of the same underlying defects—hyperinsulinemia and insulin resistance. This was precisely what von Noorden had suggested in 1905 with his diabetogenous-obesity hypothesis, even down to the notion that obesity would naturally result when muscle tissue becomes resistant to taking up glucose from the circulation before fat tissue does. Now the science had caught up to the speculation. “We generally accept that obesity predisposes to diabetes; but does not mild diabetes predispose to obesity?” as Yalow and Berson wrote in 1965. “Since insulin is a most lipogenic agent, chronic hyperinsulinism would favor the accumulation of body fat.”

When Yalow and Berson measured individual insulin and blood-sugar responses to the consumption of carbohydrates, they reported that even lean, healthy subjects exhibit “great biologic variation” in what they called the “insulin-secretory responses.” In other words, we secrete more or less insulin in response to the same amount of carbohydrates, or our insulin is more or less effective at lowering blood sugar or at promoting fat accumulation, or it remains elevated in the circulation for longer or shorter periods of time. And because variations of less than 1 percent in the partitioning of calories either for fuel or for storage as fat could lead to the accumulation of tens of pounds of excess fat over a decade, it would take only infinitesimal variations in these “insulin-secretory responses” to mark the difference between leanness and obesity, and between health and diabetes.

Over the years, prominent diabetologists and endocrinologists—from Yalow and Berson in the 1960s through Dennis McGarry in the 1990s—have speculated on this train of causation from hyperinsulinemia to Type 2 diabetes and obesity. Anything that increases insulin, induces insulin resistance, and induces the pancreas to compensate by secreting still more insulin, will also lead to an excess accumulation of body fat.

One of the more insightful of these analyses was by the geneticist James Neel in 1982, when he “revisited” his thrifty-gene hypothesis and rejected the idea (which has since been embraced so widely by public-health authorities and health writers) that we evolved through periods of feast and famine to hold on to fat.*118 Neel suggested three scenarios of these insulin-secretory responses that could constitute a predisposition to obesity and/or Type 2 diabetes—each of which, he wrote, would be a physiological “response to the excessive glucose pulses that result from the refined carbohydrates/over-alimentation of many civilized diets.” Genetic variations in these responses would determine how long it would be before obesity or diabetes appears, and which of the two appears first. The one important caveat about these three scenarios, Neel added, is that they “should not be thought of as mutually exclusive or as exhausting the possible biochemical and physiological sequences” that might induce obesity and/or diabetes once populations take to eating modern Western diets.