Adrian Vella, M.D.'s interest in diabetes predates his meeting with his cat, Luna. An elderly tabby, Luna was considered too frail to move to England with her owners who sold their house to Dr. Vella. The Mayo endocrinologist and diabetes researcher kindly adopted her and, ironically, Luna subsequently developed diabetes.

"We completely changed her diet, of course," Dr. Vella says. "And I gave her daily insulin injections for three months."

Luna no longer needs her daily shot and, unfortunately, feline diabetes doesn't shed much light on the human variety. But Dr. Vella's passion for helping people with diabetes is stronger than ever.

It's well known that overeating and lack of exercise generally put people at risk for diabetes. But that generalization isn't true for every individual.

"We see patients who have gained weight and never exercise, but never develop diabetes," says Dr. Vella. "And we also see people at the opposite end of the spectrum who have followed reasonable diets, aren't overweight, and yet develop type 2 diabetes. Why that is, we do not really know."

"Diabetes is a very common disease and it is becoming more common, unfortunately," says Robert Rizza, M.D., an endocrinologist and chair of research at Mayo Clinic. He adds that, with diabetes now accounting for roughly one-fifth of all health care spending in the United States, Mayo has prioritized finding a solution for the condition.

The Mechanics of Glucose Metabolism

Dr. Vella's research focuses on how certain genes might affect people's ability to metabolize glucose (sugar). Once these physiological processes are better understood, Mayo hopes to devise ways to prevent or delay the onset of diabetes, and its many complications.

Type 2 diabetes, once known as "adult-onset" diabetes, is a chronic condition that affects the way the body metabolizes glucose, its main source of fuel. In patients with type 2 diabetes, the effects of insulin - a hormone that regulates the absorption of glucose into the cells - are either defective, or the body doesn't produce enough insulin to maintain normal blood-glucose levels. Left uncontrolled, the consequences of type 2 diabetes can be life-threatening. They include heart and blood-vessel disease, and damage to the nerves, eyes, feet and kidneys.

According to Dr. Vella, variation in a human gene called TCF7 offers some explanation for why people develop diabetes - but not much. The TCF7 variants "increase the risk of developing diabetes two-fold," he explains. "But in reality, that's pretty weak. Smoking, for example, increases the risk of heart disease nine-or ten-fold." What's more, the variant of TCF7 that increases the risk of diabetes is carried by about 45 to 50 per cent of the population, Dr. Vella says - but not everyone in that group will develop the disease.

Previous studies have suggested that TCF7 alters insulin secretion. But most of those studies, Dr. Vella says, have used human populations studied for other reasons: "We, on the other hand, are actually conducting experiments designed specifically to measure insulin secretion."

The broader goal is to identify the physiological pathways of glucose regulation, and to discover why these break down. Mayo researchers have developed a unique method to map the complex process of glucose metabolism: Study participants -- who might be relaxing in front of a television -- receive intravenous injections of chemical tracers in one arm and have blood drawn from the other. The tracers leave a chemical "trail" that allows researchers to monitor glucose metabolism precisely.

"By using the right kind of tracers, we can probe all these pathways," Dr. Rizza says. "We can measure stuff that simply no one could measure before."

Mayo's studies involve three groups: healthy individuals; people with type 2 diabetes; and patients with "impaired" fasting glucose levels. Patients in this last group have a condition sometimes called "prediabetes," in which blood-glucose levels are higher than normal but not high enough to be classified as diabetes. In addition to insulin secretion, the research measures "insulin action" - its effectiveness in getting glucose into cells and thereby lowering blood-glucose levels.

Compared to healthy individuals, those with type 2 diabetes have both lower insulin secretion and lower insulin action. Mayo's experiments have shown that people with prediabetes secrete insulin in amounts similar to healthy patients, but have lowered insulin action. Compared to people with diabetes, those with prediabetes actually secrete more insulin - but not enough to compensate for the impaired insulin action.

In trying to figure out why people with prediabetes don't secrete enough insulin, Mayo researchers are looking at the beta-cells: the cells in the pancreas that make and release insulin. "It seems to us that the (insulin-secretion) failure occurs because the beta-cells cannot compensate for impaired insulin action by producing more insulin," Dr. Vella says. "Why is that so? We assume that the people who have the genetic variation which has been associated with type 2 diabetes are more likely to fail."

A clearer understanding of glucose regulation is essential to developing medications that might prevent or delay the onset of diabetes. Because of subtle differences in the mechanics of the disease, a medication might work for one patient, but not another.

"If you understand the 'why' of diabetes," says Dr. Rizza, "then instead of just rolling the dice and saying, 'Here, take this pill; let's see if it works,' you get some insight into why it might work."

The Role of the Digestive Tract in Diabetes

Dr. Vella's research is just one piece of Mayo's effort to decipher diabetes. Other endocrinologists are studying how fat and protein are metabolized, how the body stores fat, and how people become obese. Other investigators are studying which management systems deliver the best-possible information and health care to diabetes patients.

Another aspect of diabetes predisposition, and possible treatment, involves the gastro-intestinal tract. Digestion plays a key role in glucose metabolism. When food enters the small intestine, cells lining the intestine secrete hormones that, in turn, trigger the release of insulin.

"The rate at which food moves out of the stomach and into the intestine sets up a cascade of events that ultimately has an impact on the blood-glucose level," says Michael Camilleri, M.D., a Mayo gastroenterologist and 2007 Mayo Clinic Distinguished Investigator. "This is a very integrated physiological response."

Researchers already have shown that gastric-bypass surgery, which changes the anatomy of the digestive system to limit the amount of food that can be eaten and digested, improves patients' blood-glucose levels dramatically. It might seem obvious that eating less would lower blood glucose but, according to Dr. Camilleri, there may be more to it. He notes that although post-surgery weight loss can take months, patients' blood-glucose levels improve much more quickly.

"Isn't it interesting that the diabetes gets better before people lose an enormous amount of weight?" Dr. Camilleri says. "That suggests that these hormonal and reflex responses arising in the gastro-intestinal tract are probably just as important, if not more important, than the weight-loss itself."

Mayo's efforts to decode diabetes are particularly important in light of longer life spans. Dr. Vella points out that diabetes is more common nowadays partly because people are living longer.

"It's the nature of the beast that as we age, beta-cells are likely to fail, we are less likely to be active, and we are more likely to overeat," explains Dr. Vella. "Understanding the physiological processes enough to delay the onset of the disease might mean patients don't have to deal with diabetes until the last four years of life, rather than the last 20 years."

The collaboration of researchers from several medical specialties is typical of Mayo Clinic. With its strong commitment to a multi-disciplinary approach, Mayo is ideally suited for diabetes research.

"By combining forces, I think we get a more comprehensive understanding," says Dr. Camilleri.

Dr. Rizza agrees, adding that Mayo's physicians routinely conduct research and treat patients, resulting in "a very different mindset" from that found at other medical centers. Mayo doctors see first-hand how diseases affect patients' lives, and are able to take questions about symptoms and conditions back to their labs. That symbiosis benefits patients, and energizes physicians.

"It's just irresistible," Dr. Rizza says, "because it's so much fun."

- Barbara Toman, April 2008