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Blazing a research trail for diabetes

By Bill Zeeble, KERA 90.1FM reporter

Dallas, TX – Bill Zeeble, KERA 90.1 Reporter: In the dry, hot heart of Arizona lies the 372,000 acre Gila River reservation, home to the Native American Pima tribe. The local hospital, some telephone polls, and the occasional low-rise building interrupt the pale, flat desert vista of green, single story-tall cactus. Conditions appear so barren and harsh, one might conclude things haven't changed here for thousands of years, which is about as long as Native Americans have lived here.

Kristine Morago, Councilwoman, District 3, Gila River Government: We gathered, we went hunting.

Zeeble: Gila River Government Councilwoman Kristine Morago says life [(did)] changed after the federal government took the water rights away a hundred years ago. Then, in this century, the Gila River was dammed and diverted.

Morago: The moment the river stopped flowing, we relied on the government to provide food, shelter and other things. From that point on, you can see in documentation form how that one instance really changed this community.

Dr. Clifton Bogardus, Chief, Clinical Diabetes & Nutrition Section of the National Institute of Diabetes and Digestive Kidney Disease and the National Institutes of Health: They went from living off the land to having to live out of cans very abruptly.

Zeeble: Dr. Clifton Bogardus heads the Clinical Diabetes and Nutrition Section of the Phoenix office for the National Institutes of Health. The NIH has been studying the Pima for 37 years, because half the tribe has or will get diabetes. The numbers started rising after World War Two, when their diet and hardy farming lifestyle changed. Today, the Pima have the highest rate of diabetes in the world. They're also among the most obese. Bogardus and the NIH have tried for years to find out why. Solve the weight problem, and you might solve the Type 2 diabetes epidemic, because the two are linked. Bogardus thinks the Pima are genetically pre-disposed to obesity.

Bogardus: It may well be, and I think it's likely that there are genetic determinants. So some people are - based on what they've inherited - much more likely to overeat. I think the evidence is very solid in that respect. Some significant proportion of why people overeat has to do with their genetic makeup.

Zeeble: Medical experts chant the Type 2 diabetic mantra: eat less, exercise more, and keep your blood sugar normal, testing with a small, simple-to-use home monitor. Yet, doctors like Wesley Yamada, Podiatrist at the hospital in Sacaton, Arizona, find that message often goes unheeded.

Dr. Wesley Yamada, Podiatrist, Hu Hu Kam Memorial Hospital: If your blood sugars are 300 but you're coherent and happy and don't have any ills or pains that day, it's a successful day. There's a reluctance to accept the fact that there's an entity that is going to eventually accelerate their aging process and end up killing them. There's a reluctance to accept diabetes being here, ?cause why is it four generations ago we didn't have it and now we do?

Zeeble: Hospital board president Pete Jackson says decades of resentment and suspicion towards outsiders have contributed to the problem. For one thing, after nearly 40 years of NIH research and observation, many Pima now ask, "Why aren't we cured yet?" Jackson remembers asking one NIH doctor - years ago - whether there was a way to prevent Type 2 diabetes? The doctor said "diet and exercise."

Pete Jackson, Board President, Gila River Health Care Corporation: I told him, So why don't you go tell the people that? I accused him of using us in a fish bowl [(GUINEA PIGS - yes)] approach on research, ?cause we don't migrate as much as metropolitan populations do. So we're a likely candidate for projects - all you need to do is sit there and watch it take its toll.

Zeeble: Dr. Bogardus defends the research, saying the tribe and diabetics everywhere have benefitted tremendously.

Bogardus: The observation about the perinatal mortality of offspring of pregnant mothers, which was found here, led to huge reduction in perinatal mortality. That's one example. There are others about high blood pressure and its effect on complications of diabetes.

Zeeble: But some tribal leaders now want to end the decades-long relationship with the NIH. Four years ago, after amassing income from casinos, the tribe decided to build a hospital and set up its own non-profit health corporation in the community. Outside observers say so far, it's working. Taking ownership of the diabetes epidemic, which has killed thousands and taken limbs, kidneys, and eyesight from countless Pima members, is also important. In the meantime, other Pima members still volunteer to be tested at the Phoenix NIH facility. They undergo blood, bone and muscle tests, enter a metabolic chamber to gauge energy expenditure, and eat controlled diets.

[Ambient sound of knocking on a door and a person saying: John, [(me)] the brave volunteer.]

Zeeble: Researchers here also want to know which genes could be interfering with insulin use. Scientists know such inefficiencies are precursors to full-blown diabetes, which hinders the metabolism of sugars. Over time, the disease can claim eyesight, limbs, kidney, heart and nerve function. Dr. Craig Hanis, a professor of Human Genetics at the University of Texas Health Science Center in Houston, has been driving down to Starr County, Texas for years to study the diabetes-prone Mexican-American population there.

Dr. Craig Hanis, Professor of Human Genetics, University of Texas Health Science Center: If we can find the genes, then we can start to ask, "If an individual has the susceptibility form of the gene, what happens when they have a high fat diet vs. the low fat diet? What happens if they live a sedentary lifestyle vs. a more active lifestyle?" Perhaps, if I have a susceptibility gene, I'll need to watch what I do differently than somebody else, and that'll give us great hope.

Zeeble: Now, Hanis says he and Dr. Graeme Bell with the University of Chicago have found that gene, called CAPN 10, on Chromosome 2. The researchers claim it's responsible for 14% of Type 2 diabetics among Starr County's Mexican-Americans - a group with the highest percentage of diabetes in the state. They say another gene on Chromosome 15 also plays a big part. Between the two, the genes could account for half the genetic components for diabetes among the county's Mexican-Americans. Scientists are also holding out great hope on another genetic front dealing with Type 1 diabetics - those who must inject insulin to survive. Earlier this year, Canadian doctors successfully transplanted insulin-producing islet cells into 11 patients. For years they'd tried the procedure unsuccessfully. But this time, they did not use steroid-based immuno-suppressant drugs, which tend to attack islet cells. After months, patients remain off their insulin shots. That's the breakthrough. Dr. Chris Newgard, Professor of Diabetes Research and Biochemistry at the University of Texas Southwestern Medical Center in Dallas, says here's the problem.

Dr. Chris Newgard, Professor of Diabetes Research and Biochemistry at the University of Texas Southwestern Medical Center in Dallas: A minimum of two or, more likely, three pancreases are going to be required to generate enough islets for a transplant. So you can see, a million patients who need this tissue and only several thousand pancreases, and several needed for each transplant, generates a gap between what'll be a demand for this approach.

Zeeble: That leaves scientists like Newgard and others trying for the holy grail of genetics research.

Newgard: The whole ball game here is to create a source of cells that is replenishable. That is, that can be grown in unlimited quantity at relatively low cost.

[Ambient sound of a centrifuge.]

Zeeble: Newgard and colleagues have genetically engineered rat cells that produce insulin. But he says more time's needed for similar results with human cells.

Newgard: I honestly believe that ?cause there's a growing interest in this area - and the level of sophistication of molecular techniques has really skyrocketed in recent years - that we should be looking at a replenishable source of human cells that can deliver insulin somewhere in the next three to five years.

Zeeble: Until then, the Canadian experiment will be repeated over the next year at 10 sites around the world. Scientists will see if they can duplicate - and validate - the record of perfect islet cell transplants in diabetics. For KERA 90.1, I'm Bill Zeeble.