An epidemic in the making

For a nation obsessed with fitness, it’s a small wonder that so many Americans manage to keep gaining weight. Despite an ever-growing choice of diet products and weight-loss programs, more and more Americans are losing the struggle against an expanding girth—or not fighting it at all. According to the Centers for Disease Control and Prevention, rates of obesity surged 60 percent during the past decade and, today, one in five Americans is considered obese, or 30 percent above his or her ideal weight.

People who are serious about effectively battling obesity have generally turned to fitness instructors or nutritionists. But at Yale, fat is also the stuff of serious science, pursued by nearly 100 epidemiologists, pediatricians, endocrinologists, biologists, nurses, biochemists and psychologists, among others. They are all part of the Yale Diabetes Endocrinology Research Center, led by Robert S. Sherwin, M.D., the C.N.H. Long Professor of Medicine and past president of the American Diabetes Association. Founded in 1993 with a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, the Yale diabetes center provides the infrastructure for an active interdisciplinary team representing 16 departments. Its mission is not to trim the American waistline but to find ways to prevent and treat an often-serious consequence of obesity, type 2 diabetes mellitus.

Type 2 diabetes occurs when beta cells in the pancreas lose their ability to produce enough insulin to compensate for defects in glucose metabolism. Unlike type 1 diabetes, an autoimmune disease that destroys the beta cells and all of the body’s insulin-making ability, type 2 diabetes leaves patients capable of producing insulin but unable to use it effectively. This can result in kidney and heart disease, stroke, blindness, nerve damage and loss of limbs. In 1997, the American Diabetes Association (ADA) estimated that 16 million Americans had diabetes. According to Sherwin, the number has increased by at least 6 percent a year since then, largely in tandem with the rise in obesity.

Worse, type 2 diabetes, long thought of as an adults-only illness, is now striking increasing numbers of young people, particularly Native Americans, African-Americans, Asians and Latinos. “We are seeing obesity running rampant, particularly in young adults,” says Sherwin. “It’s a major health problem that has gotten increasingly worse in the past five years.”

The Yale group has focused its efforts on understanding the biology of type 2 diabetes and on crafting strategies to prevent its occurrence in key groups of patients at risk for the disease. These approaches draw in a diverse group of investigators who are interested in everything from the biochemical pathways of glucose metabolism to the best ways to encourage at-risk children and older adults to exercise and follow a healthy diet.

In vivo biochemistry

Gerald I. Shulman, M.D., Ph.D., has spent the past 15 years exploring the cellular mechanisms of insulin resistance, the defect in the body’s ability to use insulin that characterizes type 2 diabetes. Insulin resistance has been shown to be the best predictor for whether or not an individual with a family history of type 2 diabetes will go on to develop diabetes. Recently, his team proposed a new mechanism to explain how an excess of fatty acids in the bloodstream increases the risk of diabetes by interfering with glucose metabolism. “Clearly too much fat is bad for you and somehow it interferes with insulin’s ability to stimulate glucose uptake into skeletal muscle. We wanted to know how,” says Shulman. To find out, he and collaborators including Douglas L. Rothman, Ph.D., Kitt F. Petersen, M.D., Robert G. Shulman, Ph.D. (no relation to Gerald) and Gary W. Cline, Ph.D., have used the tools of nuclear magnetic resonance (NMR) spectroscopy to perform what Shulman calls “in vivo biochemistry in real time.” Their techniques allow researchers to measure metabolic changes noninvasively and with much greater sensitivity than was possible before.

“In the old days, we would have had to perform muscle biopsies to assess the concentration of a metabolite in a particular tissue. Even then we wouldn’t have had nearly as clear a picture of what was going on inside the cell because a cell doesn’t behave the same once you remove it from the body,” says Shulman, the associate director of the Yale Diabetes Endocrinology Research Center, professor of medicine and of cellular and molecular physiology, and a Howard Hughes Medical Institute investigator.

An example of the power of the NMR technique was recently demonstrated in a study in which his group used it to measure the amount of fat inside the muscle cells of normal volunteers. They found that higher levels of such intracellular fat are the best indicator of whether or not an individual is insulin resistant.

In order to determine the way in which fatty acids trigger the chemical defects that interfere with insulin’s ability to stimulate glucose transport, the Yale researchers infused fatty acids into healthy volunteers and found that they could induce insulin resistance temporarily within five to six hours—demonstrating an inverse link between the presence of fatty acids and the body’s ability to metabolize glucose. In subsequent studies the Yale team found that excess fatty acids block insulin’s ability to activate phosphoinositol 3-kinase, a key enzyme responsible for mediating insulin’s capacity to stimulate glucose transport. This is the same step that the Yale scientists, in a study published last year in The New England Journal of Medicine, found to be defective in patients with type 2 diabetes. Further research into this pathway could lead to the development of new drugs that are more precisely targeted and carry fewer side effects.

In another study, the Shulman group examined whether or not exercise training might be able to reverse the defect in insulin-stimulated glucose transport in the offspring of patients with type 2 diabetes. In 1995, Shulman’s team demonstrated that exercise alone can reduce or reverse this abnormality. In that study, also published in The New England Journal, the team examined 10 sedentary adults whose parents had both developed type 2 diabetes and who consequently faced a 40 percent lifetime risk of getting the disease themselves. All of the subjects were insulin resistant but none was obese. The exercise routine consisted of three 15-minute sessions on a stair-climbing machine, four times a week for six weeks. The researchers gave the volunteers glucose intravenously and took blood samples to monitor how well they processed sugar. After one workout, the muscle cells’ ability to store glucose improved by 69 percent; after six weeks, by 102 percent. At the end of the study, insulin sensitivity, the ability of the body to use its own insulin, improved by 43 percent. “It’s clear that exercise training can reverse the major defect responsible for insulin resistance in these individuals,” says Shulman, “and that it is likely to be an effective means in preventing or even reversing type 2 diabetes.”

An aggressive approach to treatment

While researchers including Shulman are doing the kind of basic research that leads to new drugs, clinicians are working directly with people vulnerable to the disease, especially children.

“There have never been so many obese children,” says Sonia Caprio, M.D., associate professor of pediatrics in the section of endocrinology. She has shown that excess weight clearly carries with it the risk of type 2 diabetes. Last year at the ada meeting in San Antonio, Caprio reported that 19 percent of 180 children she tested during the course of treatment for weight disorders had impaired glucose tolerance. “That is not to say that all these children will become diabetic—because it’s not too late,” she says. “If they do improve their weight and increase exercise, they can prevent it.”

Still, a decade ago it was rare for more than 5 percent of all pediatric diabetes cases to manifest themselves in the type 2 form of the disease; most children had type 1 diabetes. Today, in some clinics that number has soared as high as 40 percent, according to Caprio. The phenomenon is so new that epidemiologists haven’t yet compiled national statistics by age. To understand what is happening, Caprio began a five-year study last year to determine the metabolic reasons behind the explosion of new cases of type 2 diabetes in children. “We want to learn more about the pathway and where the defect is,” she says.

Meanwhile, the race is on to find better ways to treat this new subset of patients before complications set in. Because people with type 2 diabetes usually develop it in middle age, complications often do not arise until their 60s or 70s. For the pediatric patients, the prospect of kidney failure or cardiovascular disease may come decades earlier, in their 30s or 40s.

In August, Caprio was awarded a $3.5 million grant over seven years as the principal investigator at Yale for a multicenter trial to compare standard medical therapies such as insulin and glucophage to newer drugs that have not yet been used in children and adolescents. These include inhaled insulin, insulin sensitizers and insulin secretagogues such as nateglinide. “We propose to be very aggressive in treating the disease in children, rather than taking the usual, laid-back approach,” Caprio says. “It used to be the case that you would try to improve diet a little and try a little exercise. But in 10 years, the pancreas is out of shape and the damage is done.”

At the other end of the age spectrum are participants in studies conducted by Loretta A. di Pietro, M.P.H. ’85, Ph.D. ’88, an associate professor of epidemiology and public health and associate fellow at the John B. Pierce Laboratory in New Haven. Working with adults 60 and older, she is studying how fat is deposited and teasing out the differences between the physical changes caused by normal aging and those attributable to lack of exercise. Di Pietro is in the midst of a study including dozens of female volunteers at Heritage Village retirement community in Southbury, a 45-minute drive from her office at Yale. The aim is to study the impact of nine months of exercise training on hormonal regulation and sugar and fat metabolism. Participants agree to provide blood samples and muscle biopsies that will yield information about precisely how exercise seems to reverse or prevent insulin resistance.

The women are divided into three groups. One group does high-intensity aerobic training, jogging on mini-trampolines at about 85 percent of their maximum capacity as measured by heart rate. The second group jogs at moderate intensity. The third group, considered the placebo group, does stretching, tai chi or yoga. The mini-trampolines provide aerobic exercise without the jarring impact of running on the ground. About five women can work out at a time, which di Pietro says makes the routine more fun and motivates the women to continue exercising when the study is completed.

Fat in the abdominal area, which increases postmenopausally due to the drop in sex hormones, is linked to an increased risk of diabetes, says di Pietro, who is expanding the study to senior centers in New Haven and West Haven. These fat deposits, the deep kind that cover tissues within the abdominal cavity, are much more metabolically active than fat cells in the thighs and buttocks. In addition, there is a decline in both the quantity and quality of muscle mass with aging and disuse.

Researchers theorize that when abdominal fat is broken down, it goes directly to the liver, where it interferes with insulin function and glucose metabolism. di Pietro and research assistant Jodi Crimmins, M.S., are studying hormonal responses to exercise and, in particular, the effect of exercise on growth hormone, insulin-like growth factor and cortisol and how these hormonal changes relate to improvements in whole-body glucose metabolism. The goal is to study how much exercise a subject must perform to garner the anti-diabetes effects. Are there gains after one bout of exercise or is long-term training necessary? Is moderate-intensity exercise sufficient? Must one exercise a little bit every day or is one intense training session a week just as good?

Fighting evolution

As any dieter knows, gaining weight is a breeze compared to losing it. The reason, as is becoming increasingly apparent, has more to do with the evolution of the human species than with gluttony. Humans evolved into a sturdy species because of an inherited ability to prevent starvation, says Sherwin. “We evolved on a planet where food was scarce and you had to work hard to get it. You needed a gene pool to hold onto calories.” In other words, those who survived long enough to produce offspring were able to pass along their calorie-hoarding genes. Those who dropped pounds easily died young. That was good for the survival of the species but is frustrating for those trying to lose weight today.

Recent clues derived from studying the basic biology of the fat cell are lending credence to this theory. Several studies have shown that when individuals reduce their food intake, they also slow metabolism and increase their appetite, thereby negating the impact of fewer calories. Hunger and metabolism are controlled by an intricate system of hormonal signals to and from within the brain. A minor shift in this chemical balance can have a dramatic impact on weight loss or gain.

For instance, a slight change in the hormonal milieu could prompt a craving for, say, an extra hundred calories a day and lead to a gain of 10 pounds in one year. Multiply that by five years, and the average-sized person becomes obese. Sherwin and others at Yale have been studying how leptin, a protein signal released by fat cells, controls appetite. The name for leptin, identified in 1994 by scientists at Rockefeller University, comes from the Greek word leptos, which means thin, and its discovery prompted speculation that a better diet pill was on the way. Further research has revealed a much more complex picture, and many questions remain to be answered about leptin and its role in controlling appetite.

Sherwin has shown that leptin acts by binding to receptors in specific regions at the base of the hypothalamus, triggering a cascade of hormonal changes. The leptin cascade, he says, “is a complex system that seems to have an enormous impact on how much we eat.

“Theoretically, if a person has too much fat, the body would stop eating; if there is not enough, the body would increase feeding,” says Sherwin. The problem is that individuals who are obese appear to have an altered set point for leptin. “It takes more leptin to shut off feeding. Then you go on a diet and leptin drops, so you want to eat again.” Researchers hope these insights into the leptin receptor will lead to a new approach to weight loss, perhaps a drug that would latch onto the receptor and minimize appetite without slowing metabolism.

As for the genetically blessed—those annoyingly lean people who eat whatever they want without gaining an ounce—scientists have a hunch that they may be endowed with more so-called brown fat than white fat. According to this theory, supported by animal studies, brown fat cells, so named because they have a redder hue due to an increased blood supply, burn calories faster than do white fat cells. The goal, then, for drug-makers would be to somehow increase the proportion of brown cells, promoting fat burning rather than storage.

“We are trying to turn the tables on millions of years of evolution,” says Sherwin. “We are not doing too well yet, but at least we are beginning to understand and recognize the problem.”