Why do so many Pima Indians have diabetes? The question is simple, but the answers are not. They are part of a very complex puzzle that NIH researchers are trying to decode through genetic research.
There are approximately 100,000 genes packed into 23 pairs of chromosomes in each person. Within a gene, chemicals form individual codes, like words, which tell the cells of the body what to do. It is the code within a gene that directs the body to grow skin, and determines whether the skin is brown, yellow, black or white; to form hair and bone; to circulate blood and hormones such as adrenalin and insulin; and to perform every other biological process in the body.
Some diseases are caused by bacteria or viruses that infect the body and make it sick. Others, such as diabetes, occur because a gene's code causes it to function differently under some circumstances. For instance, if a person has a gene that makes that person likely to get diabetes, eating a lot of high fat food over time may increase that person's chance of getting sick. On the other hand, eating lower fat foods such as fruits and vegetables and exercising each day may help to prevent the disease. A person can't choose his or her genes, but can choose what to eat and whether or not to exercise.
Finding the gene or genes that may increase a person's risk for getting diabetes and obesity is the most effective way scientists have to learn what's wrong in a diabetic person.
With the help of the Pima Indians, NIH scientists have already learned that diabetes develops when a person's body doesn't use insulin effectively. They know that other genes probably influence some people's bodies to burn energy at a slow rate, and/or to want to eat more, making it more likely that they will become overweight. Being overweight, in turn, puts a person at even higher risk for diabetes. Because they have learned this over 30 years of working with the Pima Indians, NIH scientists now are able to test ways to prevent the disease with low-fat diets and regular exercise.
When scientists find the codes for the genes that contribute to diabetes and obesity, they will be able to study how the genes work, and how the changes that result might contribute to disease. Then they will have the best clues available to design treatments and cures.
DNA, each human being's personal collection of genes, is as individual as a thumbprint. Because the code for a particular gene can be slightly different in each person, tracking genes is difficult, time-consuming work. It is possible to do this work only when scientists have the cooperation of large families.
Mormon families in Salt Lake City helped researchers find a gene for colon cancer, and a large group of related families in Venezuela contributed their blood and skin samples so researchers could identify the gene for Huntington's disease. Now Pima families from the Gila River Indian Community are making it possible for NIDDK researchers to search for diabetes and obesity genes.
If it were not for families of Pima Indian volunteers and technology developed in the last 10 years, it would not be possible to search for the genetic causes of so complex a disease as diabetes, according to Dr. Clifton Bogardus of NIDDK.
"We got into this work because of Pima families," Dr. Bogardus says. "NIDDK scientists, including Drs. Bennett, Knowler, and Pettitt, have studied well over 90 percent of the people on the reservation at least once. We know the families, and DNA has been collected from them routinely since the mid 1980s."
Shortly after that, other scientists began to develop ways of creating maps that show where genes are located on chromosomes in cells. They learned how to cut a fragment of DNA, and find its code. Because fragments of DNA will naturally attach to complementary fragments like a zipper, scientists learned how to identify unfamiliar pieces of DNA by using familiar fragments that were electronically labeled. If the labeled DNA found a match, scientists were able to use x-ray film to make a "picture" of the unfamiliar DNA fragment.
When researchers have volunteers from large families of several generations whose medical and genetic history is well known to them, blood samples from those volunteers are extremely valuable in learning about a disease. Using laboratory techniques, they can separate the volunteers' DNA from their blood, and compare DNA from family members who have disease and those who do not.
The researchers look for a piece of DNA shared only by members of a family who have disease. When they find the same genetic variation in many people with disease, that variation is called a marker. Because a marker and a gene that helps cause disease are often inherited together, researchers can then use that marker like a signpost to search for the sought-after gene itself.
Beginning in 1983 and continuing for 10 years, NIDDK studied the genetic codes of almost 300 non-diabetic Pima Indians in great detail. "We looked at body composition, how well a person produced insulin, how well that person's cells responded to insulin, and other factors. After a number of years, some of the volunteers developed diabetes and we were able to determine that insulin resistance and obesity were major predictors of disease," Dr. Bogardus explains.
Because diabetes is such a complex disease, Dr. Bogardus and his staff are attempting to narrow their search by first looking for the genetic causes of physical conditions that can lead to diabetes, such as the genes that influence a person's cells to secrete less and respond less to insulin that is needed to regulate blood sugar.
In 1993, they identified a gene called FABP2 that may contribute to insulin resistance. This gene makes an intestinal fatty acid binding protein using one of two amino acids. When the gene makes the protein with threonine, one of those amino acids, the body seems to absorb more fatty acids from the fat in meals. NIH scientists think that could lead to a higher level of certain fats and fatty acids in the blood, which could contribute to insulin resistance.
Another group of NIH scientists, led by Dr. Michael Prochazka and Dr. Bruce Thompson, are developing a genetic map for the Pima Indians, a tool that could be very useful in defining what causes so much diabetes in the community. They have already identified a number of markers different from those in the white population.
Researchers sometimes get unexpected results leading to further work, even when they have carefully thought out a project. While studying how a person's cells respond to insulin, biochemist Dr. David Mott identified an enzyme called protein phosphatase 1 that seems to play a role in insulin resistance. "Now it turns out there are actually three of these protein phosphatase enzymes," Dr. Bogardus explains, "so we're trying to figure out which of the three is the most important. We're also trying to find out if there's a difference in one of those three genes in the Pima Indians," he adds.
The NIH gene-seekers hope to answer many questions that could make better health an expectation for diabetes-prone Pima Indians. How do these genes work? What switches these genes on and off? How does a person's life-style contribute to disease when these genes are present? Is one gene missing some important chemical? If so, is there a substitute for that chemical's activity?
When they have these answers, doctors may be able to say why the Pima Indians and other non-whites get diabetes so often. They will be better able to identify those who are likely to become diabetic. Most importantly, they will have the pieces of the diabetic puzzle that could be the key to preventing diabetes in new generations of Pima Indians.
- Jane DeMouy