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Living with Diabetes:
UK Research Offers New Hope

Diabetes is a silent killer. The Centers for Disease Control and Prevention estimates 16 million Americans have diabetes, and 5.4 million of those people don't even know it yet.

Many people learn they have diabetes when they develop one of its life-threatening complications—blindness, kidney disease, nerve disease and amputations, or heart attack and stroke. For others, it's a routine insurance exam or pre-operative test that reveals the insidious disease. In any case, the diabetes diagnosis is the beginning of a lifelong battle, and researchers at the University of Kentucky are hard at work to discover new ways to prevent blindness and control diabetes through exercise and a change in eating habits.

Seeing Is Believing

Fannie Miller's eyesight had been deteriorating for years. The 61-year-old Owen County resident, who had suffered from diabetes for 20 years, had been living with diabetic macular edema (DME), a condition that occurs when damaged blood vessels leak and cause retinal swelling.

DME is common in diabetics, because over time the disease often damages the retina, the structure in the eye that receives visual images. In fact, about 40 percent of the 10.3 million people in the United States diagnosed with diabetes will develop DME. Ultimately, DME can lead to blindness.

Back in Owen County, Miller was bumping into doors and walls. "I was on the verge of going blind," she says.

Miller had lost virtually all vision in her right eye, and now her left eye was deteriorating as well. That was making it difficult for her to live in her own home and care for her handicapped daughter. Miller had repeatedly undergone the standard therapy—laser photocoagulation, which uses lasers to reduce leakage into the retina or new blood vessels. This procedure was no longer effective, and there were no more treatments to try.

Diabetes is the leading cause of blindness in people between the ages of 20 and 74, and if not for a new treatment developed by UK researchers, Miller might now be counted among this group. But hope came Miller's way in the form of a tiny implant device developed in part by P. Andrew Pearson, an associate professor of ophthalmology in the College of Medicine.

Called Envision TD, the implant was developed by Pearson and former UK researchers Paul Ashton and Thomas Smith. Much of the initial work on the technology was conducted at the UK Chandler Medical Center, and the device is now licensed by Bausch & Lomb.

Photo of Envision TDEnvision TD, pictured here, is a tiny polymer shell containing two milligrams of a drug placed on the end of a plastic strip. Once implanted, the device slowly releases the drug into the eye, reducing retinal inflammation.

The implant is a tiny polymer shell containing about two milligrams of a drug, in this case fluocinolone, placed on the end of a plastic strip. While the patient is awake and under local anaesthetic, the device is inserted during a 15-minute procedure through an incision in the white of the eye and sutured in place. Once the device is secure, a tiny port in the polymer shell slowly releases a drug into the eye, reducing retinal inflammation.

The patient cannot feel the implant. And since the drug goes directly into the eye, only a small amount is needed. The implant delivers medication for up to three years. By that time, it is hoped that macular edema will have run its course.

Miller underwent the procedure in November of 1999, and her vision improved gradually.

She was one of five patients with DME who were part of an initial test of the device. The implants not only halted vision loss but produced measurable improvements for four of the patients, including Miller. At nine months, the patients' mean visual acuity (clarity or sharpness of vision) was dramatically improved—from 20/158 to 20/82. (20/20 vision is a term used to express normal visual acuity measured at a distance of 20 feet. If you have 20/100 vision, it means that you must be as close as 20 feet to see what a person with normal vision can see at 100 feet.) These results compare favorably to the control group, whose visual acuity remained essentially unchanged.

"The results of this study are encouraging, especially because these patients had failed standard treatment, making their cases very difficult to treat," Pearson says. The idea of sustained drug delivery to the eye is an approach Pearson has been working on since 1988.

Photo of P. Andrew PearsonOphthalmologist P. Andrew Pearson was part of a UK research team that developed Envision TD.

"In most of the eye diseases we treat, the problem is on the surface of the eye," says Pearson. "The simple ways of treating these problems such as drops or ointments don't work for conditions in the back of the eye. Therefore, the mainstay of treatment has been systematic therapy (sending a drug through the entire bloodstream to reach the eye), but then you are saddled with high dosages of a drug to reach a therapeutic level."

In December 2000, Pearson began a Phase III trial of the device to treat uveitis, a severe inflammatory condition in the eye caused by a problem in the immune system. The trial will be conducted at 30 centers across the United States.

Clinical trials are also continuing on the device and its use for DME. Beginning in early 2001, 90 patients were enrolled at four sites: UK, the University of California-Davis, the Kresge Eye Institute in Detroit, and the University of Wisconsin-Madison.

"The results with diabetics are exciting, and the results are dramatic," Pearson says, "but there is still a lot of work to do. We need to demonstrate effectiveness in a much larger trial."

For now, Fannie Miller is living proof to the possibilities.

"I was going blind," she says. "Now I can do what I want to. I can read and pay my own bills. I can live in my own house. I can watch television without sitting right in front of it. I am very thankful."

Teaching Lifestyle Change

The link between diabetes and obesity is so strong that L. Raymond Reynolds, an associate professor of internal medicine in the College of Medicine's endocrinology division, often uses the term "diabesity" to convey how interrelated they are. And the bad news for diabetics is that all but one of the medications used to treat the disease cause weight gain.

"Insulin is a hormone that builds fat," Reynolds says. "So for the Type 1 diabetic who's recently been diagnosed and is underweight, it does wonders. But if you give too much insulin to the overweight Type 2 diabetic, it's a double-edged sword. It lowers blood sugar, but they gain weight and their blood pressure goes up."

Eighty percent of people with Type 2 diabetes are obese, and 80 percent of people with Type 2 diabetes die of heart disease. "We hear about things like cholesterol, blood pressure and smoking as risk factors for heart disease, but obesity just blows all those away," says James W. Anderson, a professor of medicine and clinical nutrition in the College of Medicine. "In people with diabetes, men have a threefold increased risk of heart disease and women have a fivefold increased risk."

Photo of James W. Anderson and L. Raymond ReynoldsJames W. Anderson (left) and L. Raymond Reynolds are testing a lifestyle program that's proven successful in helping people with diabetes lose weight.

Anderson says losing 10 kilograms (22 pounds) has a bigger impact on blood sugar than any of the current drugs for diabetes, except insulin. And Reynolds and Anderson's work has already shown that diabetics who lose weight can reduce, and sometimes eliminate, their insulin intake.

A recent six-month study, which Reynolds presented at the Endocrine Society meeting in Denver in June, showed that 21 obese patients (with Type 2 diabetes taking insulin) who underwent a targeted lifestyle program gained dramatic health benefits. The program was based on a 1,500 calorie/day diet (consisting of three packaged entrees, two low-calorie shakes, and five servings of fruits and vegetables) and exercise (40 minutes of moderate walking each day). Patients kept daily diaries of food intake and physical activity, attended weekly behavioral classes, were weighed weekly, and had blood drawn at eight, 16 and 24 weeks.

"When we started, their average weight was over 200 pounds," Reynolds says. "At 12 weeks, they'd already lost over 15 pounds, and by 24 weeks, 18 to 20 pounds. They weren't losing huge amounts of weight, but were losing enough to bring their blood pressure, blood sugars, cholesterol, and triglycerides down, and these were people who had diabetes for about 15 years."

"People with diabetes have more difficulty losing weight than people without diabetes," Anderson adds. "And that may have something to do with diet fatigue. They've been on a restrictive diet for years and it's hard to intensify that diet." But the beauty of this study, say Anderson and Reynolds, is that it's not a starvation diet.

"They aren't just on a liquid diet," Reynolds says. "People are eating real food like fruits and vegetables." And the boxed entrees include chicken pasta parmesan and chili. These pre-packed meal replacements come from Health Management Resources (HMR), a national health-care company in Boston that specializes in programs for weight and health management. HMR provides programs to health-care professionals who have established more than 400 medically supervised weight-management programs nationwide. Anderson heads UK's HMR program, which began in 1985.

Photo of HMR boxed meals and shakesThis study was funded by a grant from the drug company GlaxcoSmithKline. "The reason they funded this research is that we elected to give their drug Rosiglitazone to half the patients in this study," Reynolds says. Rosiglitazone is an insulin sensitizer known to promote weight gain in some patients. The weight loss, blood sugar, blood pressure and lipid numbers at the end of the study for the people taking Rosiglitazone and the people who took a placebo were almost identical. "So what that told me is that the effect of the lifestyle change was really much more powerful than the effect of the drug," Reynolds says.

"I think obesity is an area where there's a lot of bias about treatment, just like there is about mental illness," says Reynolds. "What we try to do with an approach like this is show people obesity is not necessarily a personal weakness or failure, it's a cultural problem, particularly when 60 percent of Americans are overweight."

"We used to say Type 2 diabetics were people over 40, but now we're alarmed at how many adolescents are developing Type 2," Anderson says, and he attributes this to the fact that 25 percent of children and a third of adolescents are obese.

Anderson's next goal is to provide a low-cost weight-loss alternative for people with obesity and diabetes. "Our HMR program can be expensive, and people with diabetes have a lot of medical bills: test materials, co-pays on six or seven medications," he says. "So what we're trying to do is develop a strategy that provides weight-loss intensity without the expense of hands-on medical supervision. I think that if we can train diabetics to use products like HMR entrees and shakes or Healthy Choice or even Slim Fast, get modest amounts of exercise and eat fruits and vegetables, we can change the way they manage their diabetes and improve their outcome.

"Last Thursday I saw a Methodist minister who enrolled in one of our first research projects 10 years ago. He lost about 40 pounds and went off insulin," Anderson says. "Now he's 79 years old, he swims three times a week, and he's still off insulin. He's on only one drug for diabetes. The 10-week program we introduced him to, with intermittent follow-up and an intensive one-year follow-up, has sustained him for 10 years. He believes this program saved his life."

Zyban: The New Fat Fighter

Zyban, the prescription drug used to treat depression and nicotine addiction, is an effective tool in the fight against obesity, according to a new study by James W. Anderson, professor of medicine and clinical nutrition in the UK College of Medicine.

Zyban, or Bupropion SR, has been on the market for about 10 years but available in the United States only since 1998.

Anderson led a year-long study, funded by a grant from GlaxcoSmithKline, the drug's manufacturer. In the first six months of the study, 327 people between the ages of 18 and 65 who were considered obese took either a placebo, 300 milligrams of bupropion, or 400 milligrams of the drug daily. Each participant was also on a restricted diet, ate two meal replacements per day, recorded miles walked, and kept a lifestyle diary.

Those who weren't taking the drug still lost weight—an average of 11 pounds over the six-month period—but study participants who took the drug lost, on average, twice as much weight—22 pounds.

In the second six months of the study, all participants received bupropion. Anderson says the drug reduces the flow of norepinephrine and dopamine, chemicals in the brain that regulate appetite.

"There are no magic bullets for treating obesity, but this does give us another tool in the toolbox. Diet and exercise are still the biggest keys to weight loss," Anderson says, who presented the findings at the national meeting of the American Diabetes Association in Philadelphia in June.

Alicia P. Gregory and Debra Gibson