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.
The first of these scenarios was what Neel called a “quick insulin trigger.” By this Neel meant that the insulin- secreting cells in the pancreas are hypersensitive to the appearance of glucose in the bloodstream. They secrete too much insulin in response to the rise in blood sugar during a meal; that encourages fat deposition and induces a compensatory insulin resistance in the muscles. The result will be a vicious circle: excessive insulin secretion stimulates insulin resistance, which stimulates yet more insulin secretion. In this scenario, we gain weight until the fat cells eventually become insulin-resistant. When the “overworked” pancreatic cells “lose their capacity to respond” to this insulin resistance, Type 2 diabetes appears.
In Neel’s second scenario, there is a tendency to become slightly more insulin-resistant than would normally be the case when confronted with a given amount of insulin in the circulation. So even an appropriate insulin response to the waves of blood sugar that appear during meals will result in insulin resistance, and that in turn requires a ratcheting up of the insulin response. Once again, the result is the vicious cycle.
Neel’s third scenario is slightly more complicated, but there’s evidence to suggest that this one comes closest to reality. Here an appropriate amount of insulin is secreted in response to the “excessive glucose pulses” of a modern meal, and the response of the muscle cells to the insulin is also appropriate. The defect is in the relative sensitivity of muscle and fat cells to the insulin. The muscle cells become insulin-resistant in response to the “repeated high levels of insulinemia that result from excessive ingestion of highly refined carbohydrates and/or over-alimentation,” but the fat cells fail to compensate. They remain stubbornly sensitive to insulin. So, as Neel explained, the fat tissue accumulates more and more fat, but “mobilization of stored fat would be inhibited.” Now the accumulation of fat in the adipose tissue drives the vicious cycle.
This scenario is the most difficult to sort out clinically, because when these investigators measure insulin resistance in humans they invariably do so on a whole-body level, which is all the existing technology allows. Any disparities between the responsiveness of fat and muscle tissue to insulin cannot be measured. This is critical, because for the past thirty-five years the American Diabetes Association has recommended that diabetics eat a diet relatively rich in carbohydrates based on the notion that this makes them more sensitive to insulin, at least temporarily, so the diet appears to ameliorate the diabetes. This effect was initially reported in 1971, by the University of Washington endocrinologists Edwin Bierman and John Brunzell,*119 who then waged a lengthy and successful campaign to persuade the American Diabetes Association to recommend that diabetics eat more carbohydrates rather than less. If Neel’s third scenario is correct, however, a likely explanation for why carbohydrate-rich diets appear to facilitate blood-sugar control after meals is that they increase the insulin sensitivity of the fat cells specifically, while the muscle tissue remains insulin-resistant.
One of the few attempts, if not the only one, to measure the insulin sensitivity of fat cells and muscle cells separately in human subjects was made by the University of Vermont investigator Ethan Sims, in his experimental obesity studies of the late 1960s. Sims and his colleagues surgically removed fat samples from their subjects before, during, and after the periods of forced overeating and weight gain. They reported that high-carbohydrate diets had the unique ability to increase the insulin sensitivity of fat cells, and particularly so in fat cells that were already large and overstuffed. They had no similar effect, however, on the insulin resistance of the muscle tissue.
If this observation is correct, it means carbohydrates are uniquely capable of prolonging this lipid-trapping condition by keeping the fat cells sensitive to insulin when they might otherwise become insulin-resistant. This might lower blood-sugar levels temporarily and delay or improve the appearance of diabetes—or “mask” the diabetes, as von Noorden put it—but would do so at the cost of increasing fat accumulation and obesity. Sims’s observation suggests that Neel’s third scenario for the genesis of obesity and diabetes was astute, and it suggests that a carbohydrate-rich diet might temporarily improve the symptoms of diabetes only by furthering the fattening process. Sims’s studies have not been repeated in humans, but they have been reproduced and confirmed in animals. Brunzell says he refuses to believe that Sims got this measurement correct, but he also says that he has never tried to do the measurements himself because they’re too difficult. But the question of whether Sims got it right requires a definitive answer. Without one, there’s no way to know if the ADA recommendations have been helping diabetics or hurting them, let alone to understand the pathology of obesity and diabetes. The impact on the public health could be immense.
Through the 1970s, physiologists and biochemists worked out the mechanisms by which insulin and other hormones regulate not just the amount of fat we carry, but its distribution throughout the body, independent of how much we might happen to eat or exercise. By the end of the decade, they could explain at both a hormonal and an enzymatic level all the vagaries of what Julius Bauer had called lipophilia, or the “exaggerated tendency of some tissues to store fat.”
A critical enzyme in this fat-distribution process is known technically as lipoprotein lipase, LPL, and any cell that uses fatty acids for fuel or stores fatty acids uses LPL to make this possible. When a triglyceride-rich lipoprotein passes by in the circulation, the LPL will grab on, and then break down the triglycerides inside into their component fatty acids. This increases the local concentration of free fatty acids, which flow into the cells—either to be fixed as triglycerides if these cells are fat cells, or oxidized for fuel if they’re not. The more LPL activity on a particular cell type, the more fatty acids it will absorb, which is why LPL is known as the “gatekeeper” for fat accumulation.
Insulin, not surprisingly, is the primary regulator of LPL activity, although not the only one. This regulation functions differently, as is the case with all hormones, from tissue to tissue and site to site. In fat tissue, insulin increases LPL activity; in muscle tissue, it decreases activity. As a result, when insulin is secreted, fat is deposited in the fat tissue, and the muscles have to burn glucose for energy. When insulin levels drop, the LPL activity on the fat cells decreases and the LPL activity on the muscle cells increases—the fat cells release fatty acids, and the muscle cells take them up and burn them.
It’s the orchestration of LPL activity by insulin and other hormones that accounts for why some areas of the body will accumulate more fat than others, why the distribution of fat is different between men and women, and how these distributions change with age and, in women, with reproductive needs. Women have greater LPL activity in their adipose tissue than men do, for example, and this may be one reason why obesity and overweight are now
