Good Calories, Bad Calories (72 page)

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 cal ed 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 stil more insulin, wil 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 mutual y 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 cal ed a “quick insulin trigger.” By this Neel meant that the insulin-secreting cel s 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 wil 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 cel s eventual y become insulin-resistant. When the “overworked” pancreatic cel s “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 normal y 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 wil 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 cel s to the insulin is also appropriate.

The defect is in the relative sensitivity of muscle and fat cel s to the insulin. The muscle cel s 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 cel s 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 clinical y, because when these investigators measure insulin resistance in humans they invariably do so on a whole-body level, which is al the existing technology al ows. 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 initial y reported in 1971, by the University of Washington endocrinologists Edwin Bierman and John Brunzel ,*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 cel s specifical y, while the muscle tissue remains insulin-resistant.

One of the few attempts, if not the only one, to measure the insulin sensitivity of fat cel s and muscle cel s 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 col eagues surgical y 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 cel s, and particularly so in fat cel s 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 cel s 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. Brunzel 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 al the vagaries of what Julius Bauer had cal ed lipophilia, or the “exaggerated tendency of some tissues to store fat.”

A critical enzyme in this fat-distribution process is known technical y as lipoprotein lipase, LPL, and any cel 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 wil 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 cel s—either to be fixed as triglycerides if these cel s are fat cel s, or oxidized for fuel if they’re not. The more LPL activity on a particular cel type, the more fatty acids it wil 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 al 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 cel s decreases and the LPL activity on the muscle cel s increases—the fat cel s release fatty acids, and the muscle cel s 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 wil 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 more common in women than in men. In men, the activity of LPL is higher in the fat tissue of the abdominal region than in the fat tissue below the waist, which would explain why the typical male obesity takes the form of the beer bel y. Women have more adipose-tissue LPL activity in the hips and buttocks than in the abdominal region, although after menopause the LPL activity in their abdominal region catches up to that of men.

These various fat deposits are also regulated over time by the changing flux of sex hormones, so LPL can be considered the point at which insulin and sex hormones interact to determine how and when we fatten. The male sex hormone testosterone, for instance, suppresses LPL activity in the abdominal fat, but has little or no effect on the LPL in the fat of the hips and buttocks. Increasing fat accumulation in the abdomen as men age may therefore be a product of both increasing insulin and decreasing testosterone. The female sex hormone progesterone increases the activity of LPL, particularly in the hips and buttocks, but estrogen, another female sex hormone, decreases LPL activity.*120 It’s the decrease in estrogen secretion during menopause

—and so the increase in LPL activity—that may explain why women frequently gain weight as they pass through menopause. The effect of decreasing estrogen secretion on LPL activity would also explain why women typical y fatten after the removal of the uterus in a hysterectomy. The change in hormonal regulation of LPL also explains how and why fat deposition changes during pregnancy and, after birth, with nursing.

In 1981, M. R. C. Greenwood, who was a student of Jules Hirsch and was then at Vassar Col ege, proposed what she cal ed the “gatekeeper hypothesis” of obesity, based on the hormonal regulation of LPL. “Conditions which favor increases in adipose tissue LPL,” Greenwood wrote, “result in increased fat accumulation and, when food intake is constant, lead to alterations in body composition.” Greenwood proposed the hypothesis based on her studies of the obese strain of rats known as Zucker rats, in which LPL activity in the fat tissue is elevated in the womb—apparently the effect of fetal hyperinsulinemia, though it then persists wel into adulthood. As a result, Zucker rats grow monstrously obese. But they wil actual y lay down more fat, Greenwood reported, if they’re kept to a strict diet than they wil if they’re al owed to eat freely to satisfy their hunger. The less they’re al owed to eat, however, the smal er their muscles wil be; their brains and kidneys wil also be “significantly reduced” in size. “In order to develop this obese body composition in the face of calorie restriction,” Greenwood wrote, “several developing organ systems in the obese rats were compromised.”

Since Greenwood proposed this LPL gatekeeper hypothesis, researchers have reported that obese humans have increased LPL activity in their fat tissue. They’ve also reported that LPL activity in fat tissue increases with weight loss on a calorie-restricted diet and it decreases in muscle tissue; both reactions wil work to maintain fat in the fat tissue, regardless of any negative energy balance that may be induced by the semi-starvation diet. During exercise, LPL activity increases in muscle tissue, enhancing the absorption of fatty acids into the muscles to be burned as fuel. But when the workout is over, LPL activity in the fat tissue increases. The sensitivity of fat cel s to insulin wil also be “sufficiently altered,” as the University of Colorado physiologist Robert Eckel has described it, so as to restock the fat tissue with whatever fat it might have surrendered.

The open question, as Eckel wrote, is whether the particular hormonal environment that leads us to regain weight once we’ve lost it—elevated LPL

activity on the fat cel s and decreased LPL activity in the skeletal muscle—is the same as the one that leads us to grow fat to begin with. If insulin drives obesity, then this is an obvious hypothesis. There is no evidence to refute it, so it must be taken seriously. It has to be noted, too, that carbohydrate-rich meals increase LPL activity in the fat tissue, which would be expected, because they increase insulin secretion as wel . Fat-rich meals do not. And so, as Eckel, a recent president of the American Heart Association, has put it, “habitual dietary carbohydrate intake may have a stronger effect on subcutaneous fat storage than does dietary fat intake.”