Photo: Paul Thacker

by Whitley Hill

36 Spring/Summer 2004 Photo: Paul Thacker

he invisible epidemic: that’s “I was 29, working Jackson was admitted to what the American at the U-M Office Michigan’s comprehen- T Association calls the disease of Administrative sive, six-day inpatient that last year took the lives of 170,000 Systems as a techni- program where her blood Americans, a number that continues to cal writer. I was liv- glucose levels were stabi- rise. Each year, 25,000 new cases of ing alone and had a lized. She consulted with blindness are caused by diabetes. It is the boyfriend; I was dietitians, attended group most common cause of renal failure in playing a lot of fid- sessions with other newly the country. Today, diabetes is the fourth dle music. I can say diagnosed people, and leading cause of death by disease in the that I never even began to learn to accept U.S. Nearly 20 million Americans have mentioned the word the reality of life with a this disease. A third of them don’t even ‘diabetes’ in my life. Martha Funnell chronic, potentially seri- know. Then suddenly I ous disease. started to lose weight and was walking But it doesn’t have to be this way. Every “I felt overwhelmed,” she recalls. “I around with a water bottle, chips, candy day at the , some took every instruction very seriously. bars. I was always hungry but I kept los- of the world’s best and brightest scien- Eat at the same time every day. Follow ing weight, which I thought was great at tists work at the frontline of the fight the diet plan exactly, eating the pre- the time. I even began lifting weights at against diabetes and its devastating scribed amount of carbohydrates. Give the Y! complications. That battle is the work of two distinct centers at Michigan: the Michigan Diabetes Research and Train- ing Center, which supports research, U-M scientists are beginning to test a triple antioxidant training, education and community out- reach, and its sister center, the Juvenile therapy that could prevent . They are Diabetes Research Foundation Center exploring how cells react to oxidative stress, how growth for the Study of Complications in Diabetes, which brings together basic hormones contribute to complications, and how surrogate and clinical scientists to understand and islet cells could be implanted into people with diabetes. treat the complications of the disease. The Diabetes Informatics Core is taking the sharing of Together, the two centers fuel a power- ful environment that nurtures research, research findings to a new level. Michigan researchers are education and patient care, and targets asking tough questions about health care delivery and one of mankind’s most frustratingly pervasive and deadly diseases. At the making changes that save lives. core of it all are the patients treated here, people like Anne Jackson. Diagnosed with type 1 diabetes in 1986, “Soon I was feeling horrible — ‘spaced- your shot 20 minutes before eating. Jackson has received all her treatment at out’ and tired all the time. My vision Keep a detailed log — write down every Michigan, given birth to two beautiful, was getting blurry. I’d been seeing a psy- meal, every dose of insulin, your activ- healthy children, participated in clinical chiatrist and told him about it, and he ity level. It was painstaking. After all trials, and kept her doctors on their toes ordered a blood test. That night, he these years, I still get overwhelmed by with an insistent curiosity about new called me at home and said, ‘You’re all the monitoring I have to do to stay developments in research. But at the going to the emergency room. Pack healthy, but my ability to handle it is beginning, she was an exhausted, fright- your overnight bag, you’ll be there for a much better.” ened face in an ER waiting room, living while.’ My blood sugar was 890. proof of John Lennon’s adage, “Life is Normal is 80-120. In the ER, they told Helping people “handle” their diabetes what happens when you’re making other me, ‘Ms. Jackson, you’re going to be is the work of Martha Funnell. A clini- plans...” taking insulin for the rest of your life.’” cal nurse specialist for more than 30

Left: U-M Nurse practitioner Nugget Burkhart with diabetes patient Lydia. “When I first went on the pump, I was scared, but I learned that it isn’t as scary as I thought,” Lydia says of the insulin pump that regulates her diabetes. “Nurse Nugget helped me not to be scared.” Medicine at Michigan 37 years, she also is the admin- “We’ve come to realize that knowing what’s care. The sad part is that istrator for both of Mich- best for diabetes is not the same as knowing we’re often people’s last igan’s diabetes centers, a hope. They’ve been told diabetes educator, and a what’s best for someone with diabetes.” there’s not much that can be past president of Health —Martha Funnell, administrator for done to help them in terms Care and Education for the U-M’s diabetes centers of complications and other American Diabetes Associa- issues. They come here tion. Her work with patients because we treat patients and health professionals with respect; we recognize reflects a sea change in the clinical care knowing what’s best for diabetes is not their right to be involved in the decision- of people with diabetes. Gone are the the same as knowing what’s best for making process, and they respond posi- days of a didactic, one-size-fits-all someone with diabetes.” tively to that.” approach that obliged patients to “obey” ur work has been largely ometimes, it seems, research a rigid set of rules. Today, the patient is focused on helping health moves at a glacial pace. Basic recognized as the key to his or her own professionals let go of the old science must yield a molecular health. “O S idea of ‘getting people to change.’ It isn’t foundation for success. Then follow ani- “The concept of patient empowerment possible and it’s not our job or responsi- mal trials, then clinical trials that can last grew out of our work with patients here bility. Instead, our job is to help people for many years. Eva Feldman (M.D. at the center and with others around by creating a partnership — ‘you tell me 1983, Ph.D. 1979) is thrilled to make note the country,” says Funnell. “Empower- what you want, how hard you want to of a center study that is today making the ment is the recognition that people with work, and I’ll help you to reach those jump from basic science to clinical trials. diabetes give 99 percent of their own goals.’ This is a huge paradigm shift!” The center’s goal: understanding what causes the devastating complications that care and that each is the most important Funnell says that word of the care develop when blood glucose soars too person in determining their outcomes. patients receive at Michigan has high. What complex chain of chemical spread far and wide. “People “Professionals used to try to get events causes damage, heart disease, come here because they people to care for themselves in the kidney failure and a host of other prob- know they’re going way health professionals thought lems? Five years ago, the center received was best. We’ve come to realize that to get excellent

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

38 Spring/Summer 2004 DIABETES 101 Time-dependent changes in PET images of the left ventricle of the heart from a 26-year-old “Diabetes” is an umbrella term for two female with type 1 diabetes. Blood flow to the heart, shown in the top four panels by blood distinct diseases that yield similar out- vessels’ ability to take up N13-ammonia, is normal. Sympathetic innervation, shown in the bottom four panels, indicates extensive lack of neurotransmitter tracer uptake and loss of comes. Type 1 diabetes, or “juvenile dia- nerve endings in the heart, a characteristic of cardiac autonomic neuropathy. betes” strikes most often in childhood, though more and more adults are devel- oping it, for reasons doctors have been a landmark $6.6-million grant from the placebo. Each candidate undergoes a unable to explain. Type 1 is considered Juvenile Diabetes Research Foundation to PET scan at the beginning of the trial to an autoimmune disease, in which the work on answering these questions. It’s assess the innervation of the heart. We’ll body’s own T cells attack and destroy been money well spent. learn how well each subject’s heart is the insulin-producing islet cells in the innervated, then two years later, repeat pancreas. Without insulin in the blood- Says Feldman, a professor of the PET scan and look for damage. stream, the body cannot properly and director of the center, “We have a metabolize glucose; nerve-damaging unifying underlying hypothesis: that “Nearly all of us at the center are physi- toxins accumulate in the blood. People diabetes complications are caused by cians who see patients and are doing with type 1 diabetes are dependent on glucose-mediated oxidative stress. What basic science. Our goal is to take what insulin injections, often several times a we have shown is that high blood glu- we learn in the lab and apply it to our day. Approximately 2 million Americans cose levels damage the mitochondria — patient population, and now that’s have type 1 diabetes. the powerhouse in human cells that pro- starting to happen.” duces the energy required by cells to Type 2 diabetes usually develops in But this is just one of several intriguing function. High glucose causes the mito- adulthood. The body continues to pro- avenues of research at the center. Says chondria to become dysfunctional and duce insulin, but is unable to respond to Feldman, “We are looking at the antioxi- to produce toxic metabolic byproducts it. Often, it can be controlled with diet dant response element, a little piece in a called superoxides. These superoxides and/or oral medications. Approximately gene that, when triggered, allows the cell (also called “reactive oxygen species”) 18 million Americans have type 2 diabetes. to get stronger, to fight oxidative stress cause oxidative stress in cells that are more vigorously. Many natural com- Both types can cause diabetic neuropa- prone to diabetic injury: kidney, nerve pounds appear to increase the cell’s ability thy — the degeneration of — and retina.” to fight oxidative injury. Botanicals — the which can be manifested in many ways: Preliminary studies in tissue culture and active ingredients in broccoli and other urinary, digestive and heart problems, or mouse models of diabetes have paved plants and vegetables — appear to be very simply pain in the feet and legs. the way for a human clinical trial to test potent inducers of this antioxidant —WH a potential preventive treatment for dia- response element which then causes the betic neuropathy. “The idea is to use transcription of genes and the translation therapies that target multiple points of proteins used by the cells to fight off along the pathway that leads to oxida- oxidative injury. Theoretically, you could tive stress,” says Feldman. “We’re in the couple one of these potent botanical midst of a double-blind, placebo-con- agents with the amino acid taurine — trolled trial with three drugs. Partic- also a very potent antioxidant — and a ipants will receive alpha lipoic acid, more standard antioxidant, as a new nicotinamide, and allopurinol — each of triple therapy. Each component would which affects a different segment of the work on a different part of the pathway. oxidative stress pathway — or a Together, they’d be synergistic.”

Medicine at Michigan 39 In February of 2003, The New Yorker Arvan was recruited to U-M in 2003 The second area Arvan’s team is study- magazine published an article by from Albert Einstein College of Medicine ing involves potential gene therapies for Jerome Groopman, M.D., entitled in New York City. He brought with him type 1 diabetes. “Specifically, we’re “The Edmonton Protocol,” about seven coworkers without whom, he says, interested in trying to generate what’s advances in pancreatic islet cell trans- he never would have moved. known as a single-chain insulin analog plants. Subjects received donor islet — an artificial replacement gene. I see a “My lab is working on two main areas: cells via a tantalizingly simple proce- day when stem cells could be used that insulin secretion from cultured beta cell dure and were immediately freed from could differentiate into beta cells. lines,” says Arvan, “and from authentic insulin dependency. If it seemed too Surrogate cells, genetically engineered islets, from animal models — rats and good to be true, it was — for now at to generate insulin, could do the job and mice. We’re trying to understand how least. Michigan researchers are as anx- be implanted into an individual.” insulin gets packaged in an intracellular ious as anyone to find a cure for this compartment known as the secretory Ultimately, adds Arvan, the problem of disease, but transplant is not yet the granule. Ninety-nine percent of all insulin diabetes has to be attacked on multiple solution. For one thing, two or more is stored in this compartment. The for- levels. And at Michigan, that’s happening. pancreases are needed to harvest enough mation of this compartment in beta cells cells for a transplant. With a million Feldman concurs that although finding and the relationship of this insulin are Americans living with type 1 diabetes a lasting cure for diabetes is an ongoing crucial to glucose-regulated secretion of and only a few thousand acceptable goal, learning to prevent or control its insulin into the bloodstream.” donors per year, the barriers to equi- table distribution are daunting. Photo: Juliana Thomas – Reproduced by permission of the Juvenile Diabetes Research Foundation “There is an incipient program for islet International 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 treat- ment is still insulin, insulin, insulin. The single biggest advances in diabetes man- agement are still advances in insulin.”

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 medi- cine and of physiology back: Andrea Vincent, Ph.D., research investigator; Eva Feldman; Martin Stevens, M.D., associate professor of inter- nal medicine; James Russell, M.D., associate professor of neu- rology; Christin Carter-Su, Ph.D., professor of molecular and integra- tive physiology; Kelli A. Sullivan, assistant research scientist

40 Spring/Summer 2004 Photo: Paul Jaronski Photo: Paul 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., post- doctoral fellow; Ming Liu, M.D., Ph.D., research associate; Roberto Lara-Lemus, M.D., Ph.D., postdoctoral fellow complications will have the most imme- molecular and integrative physiology in sue is much more complex, and that it diate impact. And, she says, the discov- the U-M Medical School. acts as an endocrine organ that releases eries made here may be easily applied to hormones. The hormones regulate the Curious and intrepid, Saltiel is deter- a host of other neurological diseases. body’s response to insulin.” Further mined to understand how cells respond research into this area by Saltiel and oth- “There’s an underlying common thread to insulin’s signals. His team is looking ers may lead to a new generation of in nerve damage,” she says, “whether at what happens inside the cell’s intri- drugs to fight diabetes or burn fat. it’s in the brain — such as in Alzheimer’s, cate machinery to determine how so “Understanding problems with how we Parkinson’s and Huntington’s diseases — many signals can spring from one hor- handle fat might provide a valuable clue or in the peripheral nerves. In all these mone-receptor interaction. They’ve to developing new therapies for dia- disorders, it appears that cells undergo a found that each signal appears to travel betes,” he says, “but we first need a bet- similar process of programmed death. a different path through a cell, depend- ter understanding of how insulin works So if we understand and clearly treat ing on what it’s saying. Says Saltiel, on healthy people. one , such as dia- “The inside of the cell isn’t just a bag of betic neuropathy, there should be appli- gunk; it’s very well organized.” “Diabetes is a worldwide epidemic — cability to other neurological diseases as and a terrible epidemic in our state. Here Though no one knows what triggers it, well.” at the Life Sciences Institute, we’re build- the first stage of developing diabetes is a ing a matrix organization to focus on hat role does insulin play in cel- reduced sensitivity to insulin’s signaling, important problems like this. It’s a hub lular signaling? How is insulin he explains. The clues may lie in the for scientists working in different areas, able to “tell” a cell to open its physiology of , which is a hall- W but focused on common problems. That’s membrane to accept sugar, to burn up mark of type 2 diabetes. But why does the exciting part for me. The NIH sup- sugar, or to store it as glycogen or fat? an abundance of nutrition interfere port is great, but still inadequate. We’re with this system? Alan Saltiel, Ph.D., is trying to find out. looking to the Life Sciences Corridor, pri- “Fat cells were once thought of as merely vate industry, foundations and other You can’t talk about diabetes research a cargo space for energy storage,” says types of philanthropy, and hope to mount at the University of Michigan without Saltiel. “Now we know that adipose tis- a big effort in this area.” 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 “Diabetes at Michigan has a remarkable history. It truly John Jacob Abel Collegiate Professor of the Life Sciences, was the first principal makes you feel part of a scientific family. I’m very proud investigator to join the U-M Life to be part of this long tradition of diabetes research and Sciences Institute in 2001 — the latest chapter in the University of Michigan’s treatment at Michigan.” tradition of world-class biomedical — Eva Feldman, professor of neurology and director, research. He became the institute’s U-M Juvenile Diabetes Research Foundation Center director in 2002, and also serves as a professor of internal medicine and of

Medicine at Michigan 41 Photo: Paul Thacker Photo: Paul Thacker

he leading diabetes research taking place at Michigan every T 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, Alan Saltiel Stefan Fajans to a long line of battered, beige note- books dating back to 1950 and chroni- room learning from each other. Jason cling diabetes in one Michigan family there yet. The prevention and cure of asks Anne about her initial diagnosis, since 1958. Fajans’ careful observation diabetes isn’t going to happen overnight, how the news of her diabetes was broken of that and other families led to a star- but progress is being made at an to her, and how that felt. Suhani asks her tling discovery that has significantly astounding rate. I’m hoping that with about the different doctors she’s seen, affected medicine’s understanding of time, we’ll reach the stage where dia- how their styles of communication dif- type 2 diabetes by introducing the con- betes mellitus is no longer a worldwide fered. Then, the group completes an cept of MODY (mature-onset diabetes affliction.” exercise. All of them, including the stu- of the young). new program at U-M is dents, share a story of a personal loss, “See all those books up there?” he asks. designed to give medical stu- and how someone helped them cope “These are all records of individuals — A dents direct experience with with that loss. people who were completely asympto- people who are living with chronic dis- The students gain valuable interviewing matic and healthy. Most weren’t dia- eases. Says Arno Kumagai, M.D., who and listening skills, but beyond these betic at the time of their first conceived of and initiated the program, “The Family Centered Experience is a obvious things, they encounter patients examination. But they had a first-degree required course for first- and second-year on their home turf, seeing them as much family history of diabetes: a parent, a medical students. The purpose is to give sibling, a child. The conventional wis- more than just a collection of symptoms. them the opportunity to learn medicine dom in those days was that type 2 dia- betes 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 “The prevention and cure of diabetes isn’t going to and could be diagnosed in children as happen overnight, but progress is being made at an well. This familial predisposition was actually inherited in an autosomal dom- astounding rate.” inant fashion in some families to form a subtype of type 2 diabetes (MODY). By — Stefan Fajans, professor emeritus of internal medicine making the diagnosis early and treating young patients, we have avoided com- plications.” In 1991, he co-published the ‘from the other side of the stethoscope’ Says Bacha, “The program helps us first paper to describe a genetic marker by listening to the stories of individuals understand how the patient experiences for MODY; from this discovery, the gene with chronic or serious illnesses.” their illness outside of the doctor’s office, itself was found in 1996. In addition to and the profound effects that an illness Anne Jackson and her family are partici- that pioneering research into MODY, can have not only on a patient’s body, Fajans led the team in the 1960s that pating in the program. On an icy evening in January, medical students Jason Bacha but also on their sense of self, their emo- showed the involvement of amino acids in tions, their family, their beliefs, their insulin release. and Suhani Bora stand in the Jackson/ Held family’s front hall, stomping the relationships, their work ... in other “I love the discovery of new knowl- snow from their boots. Within a few words, their entire life. It’s one thing to edge,” he says, “and being able to help minutes the students and the entire fam- read about an illness in a textbook, but families with diabetes. But we’re not ily are sitting downstairs in the family it has been an entirely different experi-

42 Spring/Summer 2004 ence meeting, talking with and learning endocrinologist, Dr. Robert Lash. I’m with her colleague Bob Anderson helped from an individual who actually has the living proof of someone who has bene- coin the term “patient empowerment,” illness. fited from and the new is that while her involvement with her technologies and treatments for type 1 patients’ health yields immediate satis- “Getting to know Anne and her family diabetes. When I was diagnosed, I was faction, communicating the wide spec- has been an extraordinary experience told I’d be on insulin for the rest of my trum of diabetes research at Michigan for me. Not only has she taught me life. It’s been 18 years and, yes, I’m still stirs ongoing excitement. “It’s a thrill to more about diabetes than I’ve learned on insulin, but instead of four shots per be able to tell people about all the from lectures, but the entire family has day, my insulin is now delivered by an research that’s going on here. That’s also taught me, through their own per- insulin pump the size of a beeper. I’m where the hope comes from — it’s sonal experiences and stories, how to be a looking forward to the day the insulin important for anyone with an illness.” more caring and compassionate doctor.” pump will be so small that it can And Funnell confides she has a hope of It’s this balance between hard-line basic be implanted and deliver insulin auto- her own. “My fervent wish,” she says science and the immeasurable value of matically, acting much like a ‘normal’ with a smile, “is that one day I’ll be out personal interaction between patient pancreas.” and health professional that makes of a job .... ” Michigan’s approach to diabetes singu- sk anyone with diabetes about larly effective. Jackson concurs. hope and the answer will come A swiftly: a transplant. A cure. “I have the best of both worlds in my Or an end to diabetic complications. medical care — the latest knowledge and technology at my disposal, and car- Part of the joy of her job, says Funnell, ing, patient-focused clinicians, like my the nurse and diabetes educator who

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

Medicine at Michigan 43