The Diabetes Dilemma

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The Diabetes Dilemma
Monday May 01, 2006
by MEGHAN HOLOHAN

Millions of Americans -- including more and more Appalachians -- are diagnosed with diabetes. While some physicians and patients work hard to change diet and exercise to address the disease, researchers are investigating new treatments for a complex condition.

The aluminum soda pop cans shimmered in the fridge. Ruth Brooks opened the door, grasped one of the shiny cans, cracked open the top, and tipped it back so the sugary liquid slid down her throat.

Ruth padded through her family’s home outside of Athens, Ohio, beverage in hand, ready to tackle her chores. The 40-year-old redhead lives with her parents, helping them care for their home and shuttling them to doctor’s appointments and other errands. Twelve times a day, or more, Ruth walked to the fridge, thrust her hand inside, and the ritual started again. She didn’t think about it. She just did it.

Soda pop accompanied her meals and quenched her thirst when she woke. She sustained this habit for many years. Drinking soda doesn’t seem that bad. It’s not booze or drugs. But it is full of sugar, which spikes glucose in the bloodstream and contributes to obesity.

Ruth had been heavyset all her life. When she lost 30 pounds, she was overjoyed and looked good. One morning in July 2005, however, she woke with dozens of little bumps on her stomach. They prickled and itched, but she figured they were some sort of bug bite. She smothered the bumps with Neosporin and took some Advil hoping she would feel better in a few days.

Every three months or so, Ruth took her mother, Freda, to see physician Jay Shubrook in his office at Ohio University’s medical center. It just so happened that they visited him right after the bites appeared.

During her exam, Freda showed Shubrook a bump on her leg. It resembled the pockmarks on Ruth’s stomach. You need to go to the hospital, Shubrook insisted. Well if you think that’s bad, you should see my daughter’s stomach, Freda said.

During the usual battery of tests at the hospital, doctors discovered that Ruth’s blood sugar was extremely high. She was diabetic and did not know—she might have had the disease for months or even years before Shubrook found it. Her days of skipping breakfast and slurping soda were over.

“My sugar was up, but I thought, ‘Why don’t I just watch what I eat,’” Ruth explains, but adds that the doctors told her watching what she ate wasn’t enough.

Even though Ruth’s parents both have type 2 diabetes, she never suspected that she also had the disease. Ruth’s story is not uncommon. An estimated 20.8 million adults and children in the United States have diabetes. While 14.6 million of those have been diagnosed with the condition, the American Diabetes Association estimates that 6.2 million do not know that they have the disease.

According to the Centers for Disease Control, diabetes was the sixth leading cause of death in the United States in 2000, and people who suffer from the disease are twice as likely to die prematurely as those without diabetes. Currently, the United States spends $132 billion to treat diabetes, and experts say that by 2020 the cost of managing it will be close to $200 billion.

As grim as the national statistics are, the problem is even worse in Appalachian Ohio, according to Ohio University researchers. About 12 percent of the population — almost double the national average of 7 percent — is diabetic, says Frank Schwartz, associate professor of endocrinology and director of the university’s Appalachian Rural Health Institute Diabetes/Endocrine Center, which aligns physicians who perform clinical research with scientists. Together they look for genetic and molecular causes of the disease in the hope of developing new methods to prevent, early diagnose, and treat diabetes more effectively.

The 122 Minute Challenge

These days Ruth awakes and opens the fridge, looking past the aluminum soda cans. She pulls out milk for her breakfast or low-fat soup for lunch. Since her diagnosis, Ruth forces herself to eat breakfast. Though never much of a morning person, she knows that eating breakfast helps to regulate her blood sugar levels.

After breakfast, Ruth pulls out a lancet, pricking her finger. A tiny blood drop falls on the testing strip, and in moments she knows what the sugar levels are in her blood. For Ruth, a good reading runs about 135. Anyone with a fasting blood sugar reading of 126 or higher is considered diabetic. Next, she pulls out a syringe and plunges it into her skin. No matter how healthfully Ruth eats, she needs insulin.

Caring for diabetes consumes a lot of patient and doctor time. Patients who are not insulin dependent spend on average between 122 to 144 minutes per day managing their diabetes, according to one study, and must see their physician every three months. The American Diabetes Association recommends that physicians check 26 different criteria to properly treat diabetic patients, which easily doubles the amount of time a doctor spends with a patient. Shubrook spends much of his patient visits on education.

“It’s an 18-month plan to make major changes,” says Schwartz, who is one of the few endocrinologists in the region. “Patients have to hear what they need to do several times, they have to want to change, and then they have to develop a plan to change. It takes a number of visits to the physician, dietitian, and diabetes educator to really understand the importance of making these changes.”

Ruth says it doesn’t take too much time to care for her diabetes, but as she describes how her routine has changed since her diagnosis, it’s clear that she at least thinks more about eating and exercising. Since July she’s managed a maximum of three root beers a day. For lunch, she’ll have a can of soup and a sandwich, and for dinner, she eats with her family—just smaller portions. Sometimes she snacks on microwave popcorn, and she suddenly says, “Maybe I should eat smaller portions of that.”

“I think I’m doin’ okay,” she adds. “That’s what Dr. Shubrook says at least.”

Cultural Challenges

Many patients struggle, however, says Schwartz. Only 25 percent of diabetic patients fully comply with their doctors’ orders, while 5 to 10 percent do not comply at all. The remaining 65 percent of people try hard to adhere, but do not always follow doctor recommendations.

As an endocrinologist in Appalachia, Schwartz has treated many obese and diabetic patients. He’d often explain that by eating more healthfully and exercising, they could lose weight and better manage their type 2 diabetes. Many patients on the exam room table looked at Schwartz and said, “I can’t afford healthy food.”

Schwartz contends that his patients could afford fresh veggies and fruits, but they think that potato chips, sugary sodas, and juice are less expensive. A candy bar or a burger from a fast food joint seems more convenient and more enticing, but is also much more expensive calorie for calorie, he notes.

That’s not just an Appalachian problem. People get diabetes because they are obese, sedentary, and genetically predisposed to the condition. But geographic, economic, and cultural factors in this region make it harder for physicians to diagnose and treat diabetes earlier in the process.

Brooke Hallowell, an Ohio University associate professor of hearing, speech, and language sciences and co-director of the Appalachian Rural Health Institute, has helped conduct several surveys about public health issues that suggest that diabetes is particularly problematic in this region. Some residents don’t have health insurance, or don’t use it if they do, she explains. Others don’t have transportation to reach a doctor. Low incomes and poor diets in this region also contribute to the problem.

Schwartz also notes that his Appalachian patients often do not visit physicians for preventative measures and take days off from work only if the symptoms of the illness are severe. And since diabetes has few significant symptoms, people don’t realize they are creating permanent damage to important organs until it is too late. By the time people show symptoms, their diabetes is so severe that these patients are on their way to permanent eye damage, kidney damage, or circulation problems that result in amputation.

That’s unfortunate, Hallowell adds, as there are many things that can be done these days to control blood sugar, blood pressure, and abnormal lipid problems that contribute to the complications of diabetes. “But if people aren’t even getting the help soon enough,” she says, “it’s hard to make a difference.”

Appalachians can be wary of medical professionals or of coming to the unfamiliar Ohio University campus where many of them practice, Hallowell and Schwartz point out. “We developed all these diabetes education classes for our patients in the region and very few came because they don’t trust the government, didn’t trust health care, didn’t trust
doctors,” Schwartz says. “They need to know us and develop a trust for us.”

Health care professionals need to better understand, however, how to talk to these patients, he notes. “When a patient is noncompliant and you say, ‘You know, George, if you don’t do what I say, you’ll be blind,’ you’re not encouraging him,” Schwartz says. Instead, it’s important to give them positive examples of how a family should deal with diabetes or how lifestyle changes can easily be made.

Another key issue is training more physicians to specialize in diabetes. Throughout the United States there is a shortage of endocrinologists at a time when endocrine disorders like diabetes are rising — especially in rural areas like Southeast Ohio. According to Schwartz, fewer than 8 percent of patients with diabetes see an endocrinologist. Family medicine physicians and internal medicine doctors treat the bulk of diabetic patients.

To address the problem in Appalachian Ohio, Schwartz created the Diabetology Fellowship at the College of Osteopathic Medicine — the first in the nation to take primary care physicians and train them as diabetes specialists. Shubrook, assistant professor of family medicine, is the first physician to finish the fellowship, which teaches family practice physicians how to best treat diabetes. He now serves as the program director of the fellowship.

Medical Interventions

Many physicians are resigned to the fact that it’s easier to give patients a pill than to get them to change their lifestyle. While insulin has been the standard treatment for diabetes since 1923, researchers and physicians know that it isn’t a cure or a method to ward off the disease’s effects on the body. And while most evidence is anecdotal, moderate weight gain is associated with insulin use.

The wide scope of the problem and the debilitating effects of the disease have prompted more and more scientists to examine new treatments that could aid millions of people with diabetes.

At Ohio University’s Edison Biotechnology Institute, senior scientist John Kopchick has been investigating endocrine disorders, including diabetes, for almost 20 years. In the late 1980s, Kopchick, a Goll Ohio Eminent Scholar and professor of molecular and cellular biology, discovered a growth hormone inhibitor or antagonist that since has been developed into a drug to treat acromegaly. The disorder occurs when the pituitary gland produces an excess of growth hormone, most likely due to a tumor on the gland. The condition causes adults’ bones and internal organs to grow, prompting a variation of gigantism. In addition to radically changing physical appearances, this disorder causes great pain and an increased chance of diabetes and other diseases.

The drug, called pegvisomant, inhibits growth hormones from attaching to the sites that cause abnormal growth. After his serendipitous discovery, Kopchick wondered if it could treat similar disorders. He investigated kidney disease in type 1 diabetic mice and found that over production of growth hormone contributes to the problem. Because pegvisomant tapers the amount of growth hormone in the body, it could also reduce the occurrence of kidney disease as well, according to his studies.

Pegvisomant seems to have yet another use. Patients whose acromegaly caused diabetes are now reporting that symptoms of their diabetes have disappeared. Pfizer, which owns and markets pegvisomant as Somavert, is conducting clinical trials with
diabetic patients to see if Kopchick’s compound be used to treat diabetes or could cure some of the problems associated with it, including kidney disease, he says. At the very least, Kopchick’s drug prevents diabetic mice from getting kidney disease, leading researchers to believe that pegvisomant could prohibit kidney disease in diabetic humans.

In the years since Kopchick’s initial discovery, several other researchers at Edison Biotechnology Institute have been focused on addressing diabetes and other endocrine disorders. To provide them with a new tool in their research, Schwartz started a biorepository for blood from people with diabetes to investigate treatments for the condition. Many hospitals and medical centers have similar repositories for tumors that allow researchers easy access to the human variation of the disease they are studying, he says. Researchers at Ohio University and elsewhere will use the storehouse of samples to study treatments that aim to address obesity as it relates to diabetes.

Combating Obesity

Ruth vigilantly monitors her blood sugar and sticks to her diet. She also tries to be more active in her household chores after Shubrook advised her that exercise will help her manage diabetes. After heaving an ax for an hour on a crisp fall day chopping wood to heat the house, Ruth feels better. The additional exercise seems to pay off; her blood sugar has been so good that she takes eight units of insulin in the morning and 18 units of insulin at night instead of 15 units and 25 units, respectively. But when she steps on the scale, she is disheartened — her weight is rising slightly. It’s hard to imagine Ruth being sad for too long, though, because she is so optimistic about her diabetes.

Though obesity is a common precursor to type 2 diabetes, it also can be a side effect. One of the pitfalls of using insulin or glucose-lowering drugs to treat both type 1 or type 2 diabetes is that they usually cause additional weight gain, which can complicate the condition, says Ohio University researcher Xiaozhou Chen, who has witnessed the problem firsthand both in his adopted home of Southeast Ohio and his native China.

“We have an obesity epidemic,” Chen says. “Up to 90 percent of people with type 2 diabetes in the U.S. are either overweight or obese.”

As a child and young man living during the Cultural Revolution in China, Chen and his peers went to work in the countryside on a farm after completing middle school. Chairman Mao Tse-Tung resented intellectuals, and while in power he outlawed higher education and made manual labor compulsory for all middle school graduates.

When Mao died in 1976, Chen was among the first group of Chinese to enter the university. He came to Ohio University in 1983 and earned his PhD in biochemistry in 1988. He’s now a principal investigator at Edison Biotechnology Institute and associate professor of molecular and cellular biology in the College of Osteopathic Medicine.

When he’d return to China, Chen noticed that the normally slender Chinese were gaining more and more weight. Soon he learned that China suffered from an obesity epidemic as well. Everywhere Chen looked, he saw obesity and diabetes as an area that needed new research.

In the late 1990s, Chen read a research paper by a group of Japanese scientists who investigated the effects of the banaba plant. Since his days of farming, he has always been interested in how plants could be used for medicinal purposes. During World War II, the Japanese army invaded the Philippines, where soldiers discovered this plant and brought it back to Japan. Ever since then, Japanese people have enjoyed banaba tea, and doctors claimed it helps regulate body weight and glucose levels in the bloodstream.

The Japanese researchers used the banaba plant in a diabetic animal model, proving that banaba indeed lowers body weight and glucose levels. They identified a compound that they thought was responsible for the anti-diabetic effects. Chen thought that these researchers selected the wrong compound by using incorrect methodology of focusing on tumor cells, which are not natural target cells in diabetes. He decided to replicate the study, but used a different cell model than his Japanese colleagues.

By looking at fat cells, Chen discovered that Tannic acid was the compound with the real anti-diabetic effects. Tannic acid is already present in our daily diets in many vegetables, fruit, beer, and red wine. Scientists and doctors already knew that this compound improved cardiovascular health, and the additional anti-diabetic and anti-fat effects make it more appealing.

Like insulin, Tannic acid binds to and activates individual insulin receptors located on the fat and muscle cells, which moves blood glucose into these cells and reduces blood glucose levels. Tannic acid also suppresses fat cell growth. As a result, the compound improves glucose uptake in cells without causing excessive weight gain. Chen’s compound is unique because it treats diabetes effectively in a way similar to insulin, but doesn’t cause the weight gain that insulin or other diabetic drugs do.

Chen has filed several patent applications for his technological inventions and compounds. He now is working with a company to develop the banaba extract as a dietary supplement for the U.S. market and hopes to develop Tannic acid and its more potent and efficacious derivatives into anti-diabetic therapeutics.

Blocking Diabetes

While Chen examines the weight gain caused by insulin, another researchers, Leonard Kohn, is examining how to combat obesity before it can trigger diabetes.

Before joining Ohio University in 2000 as the J.O. Watson, D.O. Endowed Research Chair in the College of Osteopathic Medicine and a senior scientist at Edison Biotechnology Institute, Kohn spent 36 years at the National Institutes of Health, where his work focused on Graves’ disease, the most common form of hyperthyroidism. In the early 1990s, Kohn and a colleague investigated one of the therapies for Graves’ disease, methimazole, which effectively treated the disorder because it not only blocked thyroid hormone development, but also suppressed abnormal major histocompatibility (MHC) gene expression. Abnormal MHC gene expression was associated with autoimmune diseases in general — including diabetes.

This discovery was exciting to Kohn and his colleagues because it seemed that this class of drugs potentially could treat other kinds of inflammatory autoimmune diseases by blocking signaling receptors. The researchers added a ring of phenyl to the original drug and used the compound phenylmethimazole on lupus. The new compound worked 50 to 100 fold better than methimazole, but Kohn needed to know how it worked. He started to dig deeper.

Around the same time, Kohn and others in the scientific community proposed the idea that type 2 diabetes is an inflammatory autoimmune disorder — a break from conventional thought. Kohn and others noticed that diabetes isn’t just a breakdown in the pancreas function. Patients with diabetes also have abnormal visceral fat, which is found deeper in the body surrounding internal organs. This abnormal visceral fat causes the overproduction of adipokines.

Adipokines are proteins found mostly in fat tissue that have signaling properties —
meaning they communicate to other proteins to help with body functions. Adipokines often control appetite, energy, and insulin resistance, among other functions. Adipokines also are related to cytokines, which are substances secreted by the cells of the immune system. Cytokines are produced when toll-like receptors (TLR) in the body are activated. These receptors reduce the influx of signals from environmental insults much like a tollbooth slows the flow of cars onto a highway. As a result, a TLR would generally protect a person from something like cigarette smoke because it recognizes the invader and prevents it from entering.

Because the body produces adipokines and cytokines as an immune response, the presence of a high concentration of adipokines in obese and diabetic patients supports the idea that type 2 diabetes is an inflammatory autoimmune disease. When the adipokines are mass produced by non-immune protective cells, such as fat cells, they are pathological and cause the body to become resistant to insulin, contributing to type 2 diabetes. Instead of attacking outside assailants, the adipokines turn on the body.

Kohn’s compound phenylmethimazole blocks the adipokine production (blocking TLR-4 specifically) so that the body doesn’t have too many adipokines. By blocking the production of adipokines, phenylmethimazole reduces the chances of developing type 2 diabetes.

There’s still more work to do, though, before Kohn’s compound could be on the market. After laboratory work is complete, the potential drug must be tested in humans, which can take years or decades.

Though Kohn’s potential drug may help prevent the development of diabetes, he notes that it also may help someone like Ruth, who already has the disease. It might hinder complications such as blindness and the need for amputation, he says, and even reduce the risk of cancer — such as colon cancer — which occurs more frequently in people with diabetes.

Reaching Out to Patients and Families

While scientists work on new treatments that could eventually aid millions of people with diabetes, other Ohio University researchers and medical professionals are asking how they can help patients and families deal with the disease today.

Sharon Denham, a professor of nursing at Ohio University, and her colleagues have taken a closer look at the type of information doctors and nurses offer patients, as well as how patients — and more importantly, their families — translate that advice to managing diabetes in everyday life.

In one recent project, Denham and Ann Rathbun, an assistant professor of health sciences, studied medical brochures and pamphlets distributed to patients in four Southeast Ohio counties. They found that the majority were written at 10th and 12th grade reading levels, which is significantly higher than the average newspaper article, which is written at a 6th grade level.

“That’s especially a problem for people living in this area, where literacy and education issues are prevalent,” Denham notes.

The findings caught the attention of the Centers for Disease Control, which recently funded Denham’s proposal to develop the “Diabetes Community Kit for Appalachia.” The kit will contain health care information that’s more culturally appropriate for the region and written at a lower reading level, she says. And in a separate but related project, the College of Health and Human Services has developed new brochures to reach children — a growing demographic for type 2 diabetes in Appalachia and elsewhere in America — through its Kids on Campus program for underserved, at-risk youth.

Clinicians also must keep family dynamics in mind when treating diabetes patients. Denham conducted another study about family health routines and type 2 diabetes with Ohio University researchers Margaret Manoogian and Mary de Groot. After conducting focus groups with diabetics and their families, the researchers discovered that patients with diabetes may not always share information on how they should be making changes in grocery shopping, eating, exercise, and medication with family members; other times family members don’t truly understand or support the changes.

Gender also makes a big difference, Denham notes. Wives of men with diabetes are more likely to assist with health care by attending doctor visits, buying healthy groceries, and cooking appropriate meals. A woman with diabetes, however, may never establish new routines if her family members aren’t agreeable to lifestyle changes.

The initial study suggests that medical professionals should put greater emphasis on family-focused care. “Most of oureducation is pretty much pointed to the individual and doesn’t take into account that people live in a household with others — that’s where they spend most of their time. If they don’t know what to do, they make it up as they go along,” says Denham, who is gathering further data with de Groot on the impact of family intervention in type 2 diabetes.

De Groot, an assistant professor of psychology, points to another aspect of diabetes management that should get more attention: mental health. Recent studies have shown that people with diabetes are twice as likely as the average person to also suffer from depression, she says, and people with diabetes are even more prone to the problem than other patients with chronic illness. The researcher has studied the problem in Appalachia with doctors Shubrook and Schwartz, and found that about one-third of 200 patients surveyed had moderate to severe depression. Only about 25 percent of people with diabetes are ever screened for depression by their physicians, however, she says.

The good news about depression and diabetes, de Groot notes, is that anti-depression medications and cognitive behavioral therapy can lessen symptoms of depression and lower blood sugars. The researcher also is studying how a program of counseling and exercise can help address the problem and is tailoring it for rural residents who might not have easy access to sidewalks or other amenities available in suburban or urban areas.

“One thing I value about diabetes research,” she says, “is that it’s able to give something back to people with diabetes.”

Other outreach initiatives spearheaded by the Appalachian Rural Health Institute’s Diabetes/Endocrine Center — which is part of the NanoBioTechnology Initiative, one of three major Ohio University research priorities — include free pre-diabetes classes that offer tips on weight management, exercise, and monitoring blood sugar to reduce the risk of developing the disease, and a mobile van that travels throughout Southeast
Ohio, reaching people with diabetes who can’t easily make it to their doctors, according to Schwartz.

The center recently received a boost for these programs from Governor Bob Taft’s Healthy Ohioans Initiative, which provided $200,000 to establish and bolster diabetes treatment and education services in 11 Appalachian counties. The money will be used for more patient screenings, surveys, and to recruit county health leaders — those in health departments, school systems, etc. — who can help build and implement the overall diabetes initiative outreach plans, says Schwartz, who adds that the Centers for Disease Control sees the center’s initiative potentially as a model for a 13-state program.

The wide number of programs spearheaded by the Diabetes/Endocrine Center aim to not only treat and support today’s diabetics, but help prevent the problem in future generations of Americans who are facing grim statistics. One in three people born in 2000 will develop diabetes; the statistics rise to one in two for people of color, Shubrook says. “We expect this to only increase,” he adds.

As for Shubrook’s patient Ruth, she is resigned to the fact that she has high sugar. Sometimes Ruth opens the fridge and gazes at the tantalizing aluminum soda cans and grabs one. She cracks open the top, allowing the familiar liquid to slide down her throat. She’s afraid if she doesn’t have soda when she craves one, she’ll have a soda binge. But Ruth also is sure of another thing: With diabetes, she can never return to her old ways.

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