Even without a comprehensive theory to explain the variability of diabetes, researchers are making headway in discovering how the disease works. Scientists have so far identified about 250 genes related to appetite, insulin resistance, metabolism, and fat storage. The number is growing as researchers apply ultrafast microarray technology (gene chips that scan for mutations for diseases) to search for relevant DNA. Efforts include the National Institutes of Health Diabetes Genome Anatomy Project and another NIH-sponsored venture, the International HapMap Project, which is creating a map of regions in the human genome called haplotypes, where the underlying DNA influences common diseases like diabetes.
For one out of 30 people with diabetes, genes are known to play a decisive role, particularly in a grouping of DNA known as maturity-onset diabetes of the young, which includes a mutation that causes the pancreas to produce less insulin. For everyone else, the genetic link is weak. No definitive diabetes gene has been found. At Joslin, researcher Andrzej Krolewski studied 140 families rife with diabetes and found mutations on two chromosomes. Only 40 percent of the 140 families had it. The others had no genes that could account for the disease. That suggests no primary gene for diabetes exists. But many genes could have a moderate impact on whether a person gets diabetes, and many others could have a minor impact.
The results of various gene combinations can be confusing: Some people can eat themselves into full-blown diabetes with nary a known gene to blame. Others are insulin resistant and crank out huge levels of insulin to compensate, yet they never develop diabetes. A few diabetics are not fat, eat healthfully, and exercise. "These people have a very strong genetic basis for the disease," Reaven says.
Laboratories trying to tease out molecular answers have made some progress. Last summer, Gerald Shulman of Yale University and the Howard Hughes Medical Institute implicated mitochondria—the parts of the cell that burn fat and glucose to produce energy. He suspects that the mitochondria in people predisposed to developing type 2 diabetes produce less energy, causing cells to demand less fuel, which triggers insulin resistance. Shulman used a magnetic resonance spectrometer to test older adults for mitochondrial output. He found that as people age, their cellular energy production declines, which may explain why diabetes is related to aging. Shulman more recently tested young, healthy, lean 20-year-olds whose parents have diabetes and discovered that they, too, have mitochondria that produce less energy and are somewhat insulin resistant—strong indicators they will get diabetes when they're older.
Researchers are also trying to tease out the role of fat in diabetes. "All the problems start with fat," says Osama Hamdy, director of Joslin's obesity clinical program. "It is such an irony that in the modern era we are finally feeding huge numbers of people," he says, "but our bodies were not designed to be satiated with so much food." Clinical studies reveal that all that extra sugar gets stuffed into the fat cells our ancestors used to store energy for times of hunger. But crammed with too much, the cells start to die at the center, causing a cascade of harmful reactions, including chronic inflammation as the immune system tries to deal with the rot and a buildup of toxins that further injure cells and add to insulin resistance.
"Imagine if you buy some food and you store it on a shelf, and then you go and buy more food," says Hamdy. "You need more space, so you expand the shelf space, but the food you originally bought doesn't get eaten, so it rots. That's essentially what happens to fat cells." As fat cells bulge, the body tries to store glucose in other tissues, including the liver, kidney, heart, muscles, and blood vessels, where the rotting process takes hold.
Medicines used to treat diabetes fall into four groups: those that stimulate the pancreas to put out more insulin; those that lower insulin resistance in cells; those that help the body use insulin; and those that slow down or block the breakdown of starches, which in turn keeps blood-glucose levels lower. Taken separately or in combination, these drugs work somewhat in some patients and not in others. They can only be taken in concert with a strict diet and require frequent blood tests to monitor glucose levels. None of the drugs cures anything. "They merely slow down the progression of the disease," says Paul Herrling, head of corporate research for Novartis, maker of Starlix, an insulin-cell booster.
Novartis is one of many drug companies with new medicines being tested in humans, according to Pharmaceutical Research and Manufacturers of America. Most of the new wave of drugs in development act to block the actions of specific proteins that bring on symptoms of diabetes, or they work to reduce obesity by dissolving fat or controlling appetite. Other companies offer ramped-up versions of drugs already on the market or ways either to increase the potency of insulin or ease its delivery. Several not on the list have failed in human tests, usually because of unacceptable side effects.
A recent contender in the drug wars is a chemical long known to reduce blood sugar—a relative of aspirin in the chemical family of salicylates. It is a version of aspirin that does not cause internal bleeding when taken in high doses. In 2002 Joslin researcher Steven Shoelson knew that salicylates block the action of a protein called NFkB, a genetic master switch in the liver that helps launch a cascade of genes that cause the chronic, low-grade inflammation associated with diabetes. Shoelson had already determined that weight gain and a Western diet trigger an increase in NFkB, long a culprit in the more severe inflammation and pain of rheumatoid arthritis. He thought of salicylates for diabetes after reading a study demonstrating that they block NFkB in arthritis patients. He reasoned that if high blood sugar activates NFkB, which causes inflammation, then blocking NFkB might not only reduce inflammation but also reduce blood-sugar levels. Amazingly, he found that another researcher had the idea more than 100 years ago. Searching the literature, he found a paper written by Wilhelm Ebstein, a German physician, in 1876.
Ebstein reported that he gave a patient large amounts of an extract of willow bark, or sodium salicylate, the primary component in aspirin. (Adding acetic acid, or common vinegar, to sodium salicylate produces aspirin.) The amount of sugar in the urine of the 58-year-old man with "diabetes mellitus," now known as diabetes, was significantly reduced. Ebstein gave him 10 grams of salicylate a day, more than 10 times the normal dose for a headache. Shoelson says his team is using about half that dosage. He and Allison Goldfine have tested salicylates on 36 patients at Joslin—including Jerry Silva. The results have not been tabulated, but earlier trials proved that salicylates not only lower blood glucose but also triglycerides. Silva does not yet know his results, but he suspects he was in the control group that got a placebo because he didn't notice a reaction. The downside for salicylates is the large dosage, says Goldfine, the equivalent of 20 aspirins a day. "We don't know if using these large doses is safe over a long time."
No medicine is as effective for treating diabetes as exercising seven days a week and following a healthy diet. Osama Hamdy likes to talk about the Diabetes Prevention Program, a national study at Joslin and elsewhere that tested the impact of exercise and diet versus that of drugs. The study split prediabetics into a control group and two experimental groups—one in which subjects exercised and watched their weight and another in which people took metformin, a drug that improves insulin sensitivity in the liver. People in the first group lost 7 percent of their body weight on average and reduced their risk by 58 percent. Those on metformin lost about four pounds and reduced their risk by 31 percent. "Losing even this small amount of weight," Hamdy says, "5 to 7 percent, substantially reduces the risk of getting diabetes."
Silva is counting on that being true. When his diabetes was diagnosed last winter, his doctor gave him glyburide. But the drug made him hypoglycemic—too little blood sugar. He felt woozy, so he opted for taking long strolls on a home treadmill and bicycling. On a recent Sunday, he watched his favorite football team, the Patriots. But he didn't sit on a couch "drinking beer like I used to." He walked seven miles on a treadmill, simulating the more active way of life of his ancestors. So far, Silva has lost 25 pounds, and his blood sugar has tumbled by 65 percent, to just above normal. He is still at risk, but he hopes that keeping the weight off will ease possible complications from his disease. "I have a 7-year-old daughter," he says, "and I want to live to see her grow up."