by Whitley Hill

The invisible epidemic: that's what the American Diabetes Association calls the disease that last year took the lives of 170,000 Americans, a number that continues to rise. Each year, 25,000 new cases of blindness are caused by diabetes. It is the most common cause of renal failure in the country. Today, diabetes is the fourth leading cause of death by disease in the U.S. Nearly 20 million Americans have this disease. A third of them don't even know.

But it doesn't have to be this way. Every day at the University of Michigan, some of the world's best and brightest scientists work at the frontline of the fight against diabetes and its devastating complications. That battle is the work of two distinct centers at Michigan: the Michigan Diabetes Research and Training Center, which supports research, training, education and community outreach, and its sister center, the Juvenile Diabetes Research Foundation Center for the Study of Complications in Diabetes, which brings together basic and clinical scientists to understand and treat the complications of the disease.

Together, the two centers fuel a powerful environment that nurtures research, education and patient care, and targets one of mankind's most frustratingly pervasive and deadly diseases. At the core of it all are the patients treated here, people like Anne Jackson.

Anne Jackson with son, Charlie Held, daughter, Alice Held, and husband, Peter Held Photo: D.C. Goings

Diagnosed with type 1 diabetes in 1986, Jackson has received all her treatment at Michigan, given birth to two beautiful, healthy children, participated in clinical trials, and kept her doctors on their toes with an insistent curiosity about new developments in research. But at the beginning, she was an exhausted, frightened face in an ER waiting room, living proof of John Lennon's adage, "Life is what happens when you're making other plans..."

"I was 29, working at the U-M Office of Administrative Systems as a technical writer. I was living alone and had a boyfriend; I was playing a lot of fiddle music. I can say that I never even mentioned the word 'diabetes' in my life. Then suddenly I started to lose weight and was walking around with a water bottle, chips, candy bars. I was always hungry but I kept losing weight, which I thought was great at the time. I even began lifting weights at the Y!

"Soon I was feeling horrible — 'spaced-out' and tired all the time. My vision was getting blurry. I'd been seeing a psychiatrist and told him about it, and he ordered a blood test. That night, he called me at home and said, 'You're going to the emergency room. Pack your overnight bag, you'll be there for a while.' My blood sugar was 890. Normal is 80-120. In the ER, they told me, 'Ms. Jackson, you're going to be taking insulin for the rest of your life.'"

Jackson was admitted to Michigan's comprehensive, six-day inpatient program where her blood glucose levels were stabilized. She consulted with dietitians, attended group sessions with other newly diagnosed people, and began to learn to accept the reality of life with a chronic, potentially serious disease.

"I felt overwhelmed," she recalls. "I took every instruction very seriously. Eat at the same time every day. Follow the diet plan exactly, eating the prescribed amount of carbohydrates. Give your shot 20 minutes before eating. Keep a detailed log — write down every meal, every dose of insulin, your activity level. It was painstaking. After all these years, I still get overwhelmed by all the monitoring I have to do to stay healthy, but my ability to handle it is much better."

Martha Funnell Photo: Paul Thacker

Helping people "handle" their diabetes is the work of Martha Funnell. A clinical nurse specialist for more than 30 years, she also is the administrator for both of Michigan's diabetes centers, a diabetes educator, and a past president of Health Care and Education for the American Diabetes Association. Her work with patients and health professionals reflects a sea change in the clinical care of people with diabetes. Gone are the days of a didactic, one-size-fits-all approach that obliged patients to "obey" a rigid set of rules. Today, the patient is recognized as the key to his or her own health.

"The concept of patient empowerment grew out of our work with patients here at the center and with others around the country," says Funnell. "Empowerment is the recognition that people with diabetes give 99 percent of their own care and that each is the most important person in determining their outcomes.

"Professionals used to try to get people to care for themselves in the way health professionals thought was best. We've come to realize that knowing what's best for diabetes is not the same as knowing what's best for someone with diabetes."

"Our work has been largely focused on helping health professionals let go of the old idea of 'getting people to change.' It isn't possible and it's not our job or responsibility. Instead, our job is to help people by creating a partnership — 'you tell me what you want, how hard you want to work, and I'll help you to reach those goals.' This is a huge paradigm shift!"

Funnell says that word of the care patients receive at Michigan has spread far and wide. "People come here because they know they're going to get excellent care. The sad part is that we're often people's last hope. They've been told there's not much that can be done to help them in terms of complications and other issues. They come here because we treat patients with respect; we recognize their right to be involved in the decision-making process, and they respond positively to that."

Sometimes, it seems, research moves at a glacial pace. Basic science must yield a molecular foundation for success. Then follow animal trials, then clinical trials that can last for many years. Eva Feldman (M.D. 1983, Ph.D. 1979) is thrilled to make note of a center study that is today making the jump from basic science to clinical trials. The center's goal: understanding what causes the devastating complications that develop when blood glucose soars too high. What complex chain of chemical events causes nerve damage, heart disease, kidney failure and a host of other problems? Five years ago, the center received a landmark $6.6-million grant from the Juvenile Diabetes Research Foundation to work on answering these questions. It's been money well spent.

Says Feldman, a professor of neurology and director of the center, "We have a unifying underlying hypothesis: that diabetes complications are caused by glucose-mediated oxidative stress. What we have shown is that high blood glucose levels damage the mitochondria — the powerhouse in human cells that produces the energy required by cells to function. High glucose causes the mitochondria to become dysfunctional and to produce toxic metabolic byproducts called superoxides. These superoxides (also called "reactive oxygen species") cause oxidative stress in cells that are prone to diabetic injury: kidney, nerve and retina."

Preliminary studies in tissue culture and mouse models of diabetes have paved the way for a human clinical trial to test a potential preventive treatment for diabetic neuropathy. "The idea is to use therapies that target multiple points along the pathway that leads to oxidative stress," says Feldman. "We're in the midst of a double-blind, placebo-controlled trial with three drugs. Participants will receive alpha lipoic acid, nicotinamide, and allopurinol — each of which affects a different segment of the oxidative stress pathway — or a placebo. Each candidate undergoes a PET scan at the beginning of the trial to assess the innervation of the heart. We'll learn how well each subject's heart is innervated, then two years later, repeat the PET scan and look for damage.

"Nearly all of us at the center are physicians who see patients and are doing basic science. Our goal is to take what we learn in the lab and apply it to our patient population, and now that's starting to happen."

But this is just one of several intriguing avenues of research at the center. Says Feldman, "We are looking at the antioxidant response element, a little piece in a gene that, when triggered, allows the cell to get stronger, to fight oxidative stress more vigorously. Many natural compounds appear to increase the cell's ability to fight oxidative injury. Botanicals — the active ingredients in broccoli and other plants and vegetables — appear to be very potent inducers of this antioxidant response element which then causes the transcription of genes and the translation of proteins used by the cells to fight off oxidative injury. Theoretically, you could couple one of these potent botanical agents with the amino acid taurine — also a very potent antioxidant — and a more standard antioxidant, as a new triple therapy. Each component would work on a different part of the pathway. Together, they'd be synergistic."

Eva Feldman and her team front: Tracy Schwab, Ph.D., research investigator; Arno Kumagai, M.D., clinical assistant professor of internal medicine; Frank C. Brosius, M.D. (Residency 1983), professor of internal medicine and of physiology back: Andrea Vincent, Ph.D., research investigator; Eva Feldman; Martin Stevens, M.D., associate professor of internal medicine; James Russell, M.D., associate professor of neurology; Christin Carter-Su, Ph.D., professor of molecular and integrative physiology; Kelli A. Sullivan, assistant research scientist Photo: Juliana Thomas – Reproduced by permission of the Juvenile Diabetes Research Foundation International

In February of 2003, The New Yorker magazine published an article by Jerome Groopman, M.D., entitled "The Edmonton Protocol," about advances in pancreatic islet cell transplants. Subjects received donor islet cells via a tantalizingly simple procedure and were immediately freed from insulin dependency. If it seemed too good to be true, it was — for now at least. Michigan researchers are as anxious as anyone to find a cure for this disease, but transplant is not yet the solution. For one thing, two or more pancreases are needed to harvest enough cells for a transplant. With a million Americans living with type 1 diabetes and only a few thousand acceptable donors per year, the barriers to equitable distribution are daunting.

"There is an incipient program for islet transplantation at U-M, but so far none have taken place here," says Peter Arvan, M.D., chief of endocrinology at the U-M Medical School. "The mainstay of diabetes treatment is still insulin, insulin, insulin. The single biggest advances in diabetes management are still advances in insulin."

Arvan was recruited to U-M in 2003 from Albert Einstein College of Medicine in New York City. He brought with him seven coworkers without whom, he says, he never would have moved.

"My lab is working on two main areas: insulin secretion from cultured beta cell lines," says Arvan, "and from authentic islets, from animal models — rats and mice. We're trying to understand how insulin gets packaged in an intracellular compartment known as the secretory granule. Ninety-nine percent of all insulin is stored in this compartment. The formation of this compartment in beta cells and the relationship of this insulin are crucial to glucose-regulated secretion of insulin into the bloodstream."

The second area Arvan's team is studying involves potential gene therapies for type 1 diabetes. "Specifically, we're interested in trying to generate what's known as a single-chain insulin analog — an artificial replacement gene. I see a day when stem cells could be used that could differentiate into beta cells. Surrogate cells, genetically engineered to generate insulin, could do the job and be implanted into an individual."

Ultimately, adds Arvan, the problem of diabetes has to be attacked on multiple levels. And at Michigan, that's happening.

Peter Arvan and his team front: Young-nam Park , Ph.D., research associate; Peter Arvan; Xiang Zhao, graduate student back: Jaemin Lee, graduate student; Yukihiro Yamaguchi, Ph.D., postdoctoral fellow; Jose Ramos-Castaneda, Ph.D., postdoctoral fellow; Ming Liu, M.D., Ph.D., research associate; Roberto Lara-Lemus, M.D., Ph.D., postdoctoral fellow Photo: Paul Jaronski

Feldman concurs that although finding a lasting cure for diabetes is an ongoing goal, learning to prevent or control its complications will have the most immediate impact. And, she says, the discoveries made here may be easily applied to a host of other neurological diseases.

"There's an underlying common thread in nerve damage," she says, "whether it's in the brain — such as in Alzheimer's, Parkinson's and Huntington's diseases — or in the peripheral nerves. In all these disorders, it appears that cells undergo a similar process of programmed death. So if we understand and clearly treat one neurological disorder, such as diabetic neuropathy, there should be applicability to other neurological diseases as well."

What role does insulin play in cellular signaling? How is insulin able to "tell" a cell to open its membrane to accept sugar, to burn up sugar, or to store it as glycogen or fat?

Alan Saltiel, Ph.D., is trying to find out.

You can't talk about diabetes research at the University of Michigan without mentioning this affable scientist. With an international reputation as an expert on insulin, and well over 200 papers and 12 patents in his wake, Saltiel, the John Jacob Abel Collegiate Professor of the Life Sciences, was the first principal investigator to join the U-M Life Sciences Institute in 2001 — the latest chapter in the University of Michigan's tradition of world-class biomedical research. He became the institute's director in 2002, and also serves as a professor of internal medicine and of molecular and integrative physiology in the U-M Medical School.

Curious and intrepid, Saltiel is determined to understand how cells respond to insulin's signals. His team is looking at what happens inside the cell's intricate machinery to determine how so many signals can spring from one hormone-receptor interaction. They've found that each signal appears to travel a different path through a cell, depending on what it's saying. Says Saltiel, "The inside of the cell isn't just a bag of gunk; it's very well organized."

Alan Saltiel Photo: Paul Thacker

Though no one knows what triggers it, the first stage of developing diabetes is a reduced sensitivity to insulin's signaling, he explains. The clues may lie in the physiology of obesity, which is a hallmark of type 2 diabetes. But why does an abundance of nutrition interfere with this system?

"Fat cells were once thought of as merely a cargo space for energy storage," says Saltiel. "Now we know that adipose tissue is much more complex, and that it acts as an endocrine organ that releases hormones. The hormones regulate the body's response to insulin." Further research into this area by Saltiel and others may lead to a new generation of drugs to fight diabetes or burn fat. "Understanding problems with how we handle fat might provide a valuable clue to developing new therapies for diabetes," he says, "but we first need a better understanding of how insulin works on healthy people.

"Diabetes is a worldwide epidemic — and a terrible epidemic in our state. Here at the Life Sciences Institute, we're building a matrix organization to focus on important problems like this. It's a hub for scientists working in different areas, but focused on common problems. That's the exciting part for me. The NIH support is great, but still inadequate. We're looking to the Life Sciences Corridor, private industry, foundations and other types of philanthropy, and hope to mount a big effort in this area."

The leading diabetes research taking place at Michigan every day owes a profound debt to every dedicated investigator who has come before. Stefan Fajans (pronounced "fi-yuns") (M.D. 1942, Residency 1949) has researched and treated diabetes at the University of Michigan since 1946. Now retired, he still comes to his office every day to continue deciphering the fascinating puzzles of this disease. Fajans points to the top shelf of his bookcase, to a long line of battered, beige notebooks dating back to 1950 and chronicling diabetes in one Michigan family since 1958. Fajans' careful observation of that and other families led to a startling discovery that has significantly affected medicine's understanding of type 2 diabetes by introducing the concept of MODY (mature-onset diabetes of the young).

Stefan Fajans Photo: Paul Thacker

"See all those books up there?" he asks. "These are all records of individuals — people who were completely asymptomatic and healthy. Most weren't diabetic at the time of their first examination. But they had a first-degree family history of diabetes: a parent, a sibling, a child. The conventional wisdom in those days was that type 2 diabetes occurred only in middle age, but by doing these family studies, and by testing not only adults but also kids, I found that type 2 diabetes developed and could be diagnosed in children as well. This familial predisposition was actually inherited in an autosomal dominant fashion in some families to form a subtype of type 2 diabetes (MODY). By making the diagnosis early and treating young patients, we have avoided complications." In 1991, he co-published the first paper to describe a genetic marker for MODY; from this discovery, the gene itself was found in 1996. In addition to that pioneering research into MODY, Fajans led the team in the 1960s that showed the involvement of amino acids in insulin release.

"I love the discovery of new knowledge," he says, "and being able to help families with diabetes. But we're not there yet. The prevention and cure of diabetes isn't going to happen overnight, but progress is being made at an astounding rate. I'm hoping that with time, we'll reach the stage where diabetes mellitus is no longer a worldwide affliction."

A new program at U-M is designed to give medical students direct experience with people who are living with chronic diseases. Says Arno Kumagai, M.D., who conceived of and initiated the program, "The Family Centered Experience is a required course for first- and second-year medical students. The purpose is to give them the opportunity to learn medicine 'from the other side of the stethoscope' by listening to the stories of individuals with chronic or serious illnesses."

Anne Jackson and her family are participating in the program. On an icy evening in January, medical students Jason Bacha and Suhani Bora stand in the Jackson/ Held family's front hall, stomping the snow from their boots. Within a few minutes the students and the entire family are sitting downstairs in the family room learning from each other. Jason asks Anne about her initial diagnosis, how the news of her diabetes was broken to her, and how that felt. Suhani asks her about the different doctors she's seen, how their styles of communication differed. Then, the group completes an exercise. All of them, including the students, share a story of a personal loss, and how someone helped them cope with that loss.

The students gain valuable interviewing and listening skills, but beyond these obvious things, they encounter patients on their home turf, seeing them as much more than just a collection of symptoms.

Says Bacha, "The program helps us understand how the patient experiences their illness outside of the doctor's office, and the profound effects that an illness can have not only on a patient's body, but also on their sense of self, their emotions, their family, their beliefs, their relationships, their work ... in other words, their entire life. It's one thing to read about an illness in a textbook, but it has been an entirely different experience meeting, talking with and learning from an individual who actually has the illness.

"Getting to know Anne and her family has been an extraordinary experience for me. Not only has she taught me more about diabetes than I've learned from lectures, but the entire family has also taught me, through their own personal experiences and stories, how to be a more caring and compassionate doctor."

It's this balance between hard-line basic science and the immeasurable value of personal interaction between patient and health professional that makes Michigan's approach to diabetes singularly effective. Jackson concurs.

Suhani Bora, Jason Bacha and Anne Jackson Photo: D.C. Goings

"I have the best of both worlds in my medical care — the latest knowledge and technology at my disposal, and caring, patient-focused clinicians, like my endocrinologist, Dr. Robert Lash. I'm living proof of someone who has benefited from medical research and the new technologies and treatments for type 1 diabetes. When I was diagnosed, I was told I'd be on insulin for the rest of my life. It's been 18 years and, yes, I'm still on insulin, but instead of four shots per day, my insulin is now delivered by an insulin pump the size of a beeper. I'm looking forward to the day the insulin pump will be so small that it can be implanted and deliver insulin automatically, acting much like a 'normal' pancreas."

Ask anyone with diabetes about hope and the answer will come swiftly: a transplant. A cure. Or an end to diabetic complications.

Part of the joy of her job, says Funnell, the nurse and diabetes educator who with her colleague Bob Anderson helped coin the term "patient empowerment," is that while her involvement with her patients' health yields immediate satisfaction, communicating the wide spectrum of diabetes research at Michigan stirs ongoing excitement. "It's a thrill to be able to tell people about all the research that's going on here. That's where the hope comes from — it's important for anyone with an illness."

And Funnell confides she has a hope of her own. "My fervent wish," she says with a smile, "is that one day I'll be out of a job .... "

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