36 Spring/Summer 2004

by Whitley Hill

Photo: Paul Thacker

Jackson was admitted toMichigan’s comprehen-sive, six-day inpatientprogram where her bloodglucose levels were stabi-lized. She consulted withdietitians, attended groupsessions with other newlydiagnosed people, andbegan to learn to acceptthe reality of life with achronic, potentially seri-ous disease.

“I felt overwhelmed,” she recalls. “Itook every instruction very seriously.Eat at the same time every day. Followthe diet plan exactly, eating the pre-scribed amount of carbohydrates. Give

your shot 20 minutes before eating.Keep a detailed log — write down everymeal, every dose of insulin, your activ-ity level. It was painstaking. After allthese years, I still get overwhelmed byall the monitoring I have to do to stayhealthy, but my ability to handle it ismuch better.”

Helping people “handle” their diabetesis the work of Martha Funnell. A clini-cal nurse specialist for more than 30 �

“I was 29, workingat the U-M Officeof AdministrativeSystems as a techni-cal writer. I was liv-ing alone and had aboyfriend; I wasplaying a lot of fid-dle music. I can saythat I never evenmentioned the word‘diabetes’ in my life.Then suddenly Istarted to lose weight and was walkingaround with a water bottle, chips, candybars. I was always hungry but I kept los-ing weight, which I thought was great atthe time. I even began lifting weights atthe Y!

“Soon I was feeling horrible — ‘spaced-out’ and tired all the time. My visionwas getting blurry. I’d been seeing a psy-chiatrist and told him about it, and heordered a blood test. That night, hecalled me at home and said, ‘You’regoing to the emergency room. Packyour overnight bag, you’ll be there for awhile.’ My blood sugar was 890.Normal is 80-120. In the ER, they toldme, ‘Ms. Jackson, you’re going to betaking insulin for the rest of your life.’”

Medicine at Michigan 37

T he invisible epidemic: that’swhat the American DiabetesAssociation calls the disease

that last year took the lives of 170,000Americans, a number that continues torise. Each year, 25,000 new cases ofblindness are caused by diabetes. It is themost common cause of renal failure inthe country. Today, diabetes is the fourthleading cause of death by disease in theU.S. Nearly 20 million Americans havethis disease. A third of them don’t evenknow.

But it doesn’t have to be this way. Everyday at the University of Michigan, someof the world’s best and brightest scien-tists work at the frontline of the fightagainst diabetes and its devastatingcomplications. That battle is the work oftwo distinct centers at Michigan: theMichigan Diabetes Research and Train-ing Center, which supports research,training, education and community out-reach, and its sister center, the JuvenileDiabetes Research Foundation Centerfor the Study of Complications inDiabetes, which brings together basicand clinical scientists to understand andtreat the complications of the disease.

Together, the two centers fuel a power-ful environment that nurtures research,education and patient care, and targetsone of mankind’s most frustratinglypervasive and deadly diseases. At thecore of it all are the patients treatedhere, people like Anne Jackson.

Diagnosed with type 1 diabetes in 1986,Jackson has received all her treatment atMichigan, given birth to two beautiful,healthy children, participated in clinicaltrials, and kept her doctors on their toeswith an insistent curiosity about newdevelopments in research. But at thebeginning, she was an exhausted, fright-ened face in an ER waiting room, livingproof of John Lennon’s adage, “Life iswhat happens when you’re making otherplans...”

U-M scientists are beginning to test a triple antioxidanttherapy that could prevent diabetic neuropathy. They areexploring how cells react to oxidative stress, how growth hormones contribute to complications, and how surrogate

islet cells could be implanted into people with diabetes.The Diabetes Informatics Core is taking the sharing of

research findings to a new level. Michigan researchers areasking tough questions about health care delivery and

making changes that save lives.

Martha Funnell

Photo: Paul Thacker

Left: U-M Nurse practitioner Nugget Burkhart with diabetes patient Lydia. “When I firstwent on the pump, I was scared, but I learned that it isn’t as scary as I thought,” Lydiasays of the insulin pump that regulates her diabetes. “Nurse Nugget helped me not tobe scared.”

years, she also is the admin-istrator for both of Mich-igan’s diabetes centers, adiabetes educator, and apast president of HealthCare and Education for theAmerican Diabetes Associa-tion. Her work with patientsand health professionalsreflects a sea change in the clinical careof people with diabetes. Gone are thedays of a didactic, one-size-fits-allapproach that obliged patients to “obey”a rigid set of rules. Today, the patient isrecognized as the key to his or her ownhealth.

“The concept of patient empowermentgrew out of our work with patients hereat the center and with others aroundthe country,” says Funnell. “Empower-ment is the recognition that people withdiabetes give 99 percent of their owncare and that each is the most importantperson in determining their outcomes.

“Professionals used to try to getpeople to care for themselves in theway health professionals thoughtwas best. We’ve come to realize that

knowing what’s best for diabetes is notthe same as knowing what’s best forsomeone with diabetes.”

“O ur work has been largelyfocused on helping healthprofessionals let go of the old

idea of ‘getting people to change.’ It isn’tpossible and it’s not our job or responsi-bility. Instead, our job is to help peopleby creating a partnership — ‘you tell mewhat you want, how hard you want towork, and I’ll help you to reach thosegoals.’ This is a huge paradigm shift!”

Funnell says that word of the carepatients receive at Michigan hasspread far and wide. “Peoplecome here because theyknow they’re goingto get excellent

care. The sad part is thatwe’re often people’s lasthope. They’ve been toldthere’s not much that can bedone to help them in termsof complications and otherissues. They come herebecause we treat patientswith respect; we recognize

their right to be involved in the decision-making process, and they respond posi-tively to that.”

S ometimes, it seems, researchmoves at a glacial pace. Basicscience must yield a molecular

foundation for success. Then follow ani-mal trials, then clinical trials that can lastfor many years. Eva Feldman (M.D.1983, Ph.D. 1979) is thrilled to make noteof a center study that is today making thejump from basic science to clinical trials.The center’s goal: understanding whatcauses the devastating complications thatdevelop when blood glucose soars toohigh. What complex chain of chemicalevents causes nerve damage, heart disease,kidney failure and a host of other prob-

lems? Five years ago, the center received

“We’ve come to realize that knowing what’sbest for diabetes is not the same as knowing

what’s best for someone with diabetes.”—Martha Funnell, administrator for

U-M’s diabetes centers

Phot

o: D

.C.G

oing

s

Anne Jackson with son, CharlieHeld, daughter, Alice Held, andhusband, Peter Held

38 Spring/Summer 2004

DIABETES 101“Diabetes” is an umbrella term for twodistinct diseases that yield similar out-comes. Type 1 diabetes, or “juvenile dia-betes” strikes most often in childhood,though more and more adults are devel-oping it, for reasons doctors have beenunable to explain. Type 1 is consideredan autoimmune disease, in which thebody’s own T cells attack and destroythe insulin-producing islet cells in thepancreas. Without insulin in the blood-stream, the body cannot properlymetabolize glucose; nerve-damagingtoxins accumulate in the blood. Peoplewith type 1 diabetes are dependent oninsulin injections, often several times aday. Approximately 2 million Americanshave type 1 diabetes.

Type 2 diabetes usually develops inadulthood. The body continues to pro-duce insulin, but is unable to respond toit. Often, it can be controlled with dietand/or oral medications. Approximately18 million Americans have type 2 diabetes.

Both types can cause diabetic neuropa-thy — the degeneration of nerves —which can be manifested in many ways:urinary, digestive and heart problems, orsimply pain in the feet and legs.

—WH

placebo. Each candidate undergoes aPET scan at the beginning of the trial toassess the innervation of the heart. We’lllearn how well each subject’s heart isinnervated, then two years later, repeatthe PET scan and look for damage.

“Nearly all of us at the center are physi-cians who see patients and are doingbasic science. Our goal is to take whatwe learn in the lab and apply it to ourpatient population, and now that’sstarting to happen.”

But this is just one of several intriguingavenues of research at the center. SaysFeldman, “We are looking at the antioxi-dant response element, a little piece in agene that, when triggered, allows the cellto get stronger, to fight oxidative stressmore vigorously. Many natural com-pounds appear to increase the cell’s abilityto fight oxidative injury. Botanicals — theactive ingredients in broccoli and otherplants and vegetables — appear to be verypotent inducers of this antioxidantresponse element which then causes thetranscription of genes and the translationof proteins used by the cells to fight offoxidative injury. Theoretically, you couldcouple one of these potent botanicalagents with the amino acid taurine —also a very potent antioxidant — and amore standard antioxidant, as a newtriple therapy. Each component wouldwork on a different part of the pathway.Together, they’d be synergistic.” �

a landmark $6.6-million grant from theJuvenile Diabetes Research Foundation towork on answering these questions. It’sbeen money well spent.

Says Feldman, a professor of neurologyand director of the center, “We have aunifying underlying hypothesis: thatdiabetes complications are caused byglucose-mediated oxidative stress. Whatwe have shown is that high blood glu-cose levels damage the mitochondria —the powerhouse in human cells that pro-duces the energy required by cells tofunction. High glucose causes the mito-chondria to become dysfunctional andto produce toxic metabolic byproductscalled superoxides. These superoxides(also called “reactive oxygen species”)cause oxidative stress in cells that areprone to diabetic injury: kidney, nerveand retina.”

Preliminary studies in tissue culture andmouse models of diabetes have pavedthe way for a human clinical trial to testa potential preventive treatment for dia-betic neuropathy. “The idea is to usetherapies that target multiple pointsalong the pathway that leads to oxida-tive stress,” says Feldman. “We’re in themidst of a double-blind, placebo-con-trolled trial with three drugs. Partic-ipants will receive alpha lipoic acid,nicotinamide, and allopurinol — each ofwhich affects a different segment of theoxidative stress pathway — or a

Medicine at Michigan 39

Time-dependent changes in PET images of the left ventricle of the heart from a 26-year-oldfemale with type 1 diabetes. Blood flow to the heart, shown in the top four panels by bloodvessels’ ability to take up N13-ammonia, is normal. Sympathetic innervation, shown in thebottom four panels, indicates extensive lack of neurotransmitter tracer uptake and loss ofnerve endings in the heart, a characteristic of cardiac autonomic neuropathy.

Eva Feldman and her team

front: Tracy Schwab, Ph.D.,research investigator; ArnoKumagai, M.D., clinical assistantprofessor of internal medicine;Frank C. Brosius, M.D. (Residency1983), 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

The second area Arvan’s team is study-ing involves potential gene therapies fortype 1 diabetes. “Specifically, we’reinterested in trying to generate what’sknown as a single-chain insulin analog— an artificial replacement gene. I see aday when stem cells could be used thatcould differentiate into beta cells.Surrogate cells, genetically engineeredto generate insulin, could do the job andbe implanted into an individual.”

Ultimately, adds Arvan, the problem ofdiabetes has to be attacked on multiplelevels. And at Michigan, that’s happening.

Feldman concurs that although findinga lasting cure for diabetes is an ongoinggoal, learning to prevent or control its

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

“My lab is working on two main areas:insulin secretion from cultured beta celllines,” says Arvan, “and from authenticislets, from animal models — rats andmice. We’re trying to understand howinsulin gets packaged in an intracellularcompartment known as the secretorygranule. Ninety-nine percent of all insulinis stored in this compartment. The for-mation of this compartment in beta cellsand the relationship of this insulin arecrucial to glucose-regulated secretion ofinsulin into the bloodstream.”

40 Spring/Summer 2004

In February of 2003, The New Yorkermagazine published an article byJerome Groopman, M.D., entitled“The Edmonton Protocol,” aboutadvances in pancreatic islet cell trans-plants. Subjects received donor isletcells via a tantalizingly simple proce-dure and were immediately freed frominsulin dependency. If it seemed toogood to be true, it was — for now atleast. Michigan researchers are as anx-ious as anyone to find a cure for thisdisease, but transplant is not yet thesolution. For one thing, two or morepancreases are needed to harvest enoughcells for a transplant. With a millionAmericans living with type 1 diabetesand only a few thousand acceptabledonors per year, the barriers to equi-table distribution are daunting.

“There is an incipient program for islettransplantation at U-M, but sofar none have taken placehere,” says Peter Arvan, M.D.,chief of endocrinology at theU-M Medical School. “Themainstay of diabetes treat-ment is still insulin, insulin,insulin. The single biggestadvances in diabetes man-agement are still advancesin insulin.”

Photo: Juliana Thomas – Reproduced by permission of theJuvenile Diabetes Research FoundationInternational

complications will have the most imme-diate impact. And, she says, the discov-eries made here may be easily applied toa host of other neurological diseases.

“There’s an underlying common threadin nerve damage,” she says, “whetherit’s in the brain — such as in Alzheimer’s,Parkinson’s and Huntington’s diseases —or in the peripheral nerves. In all thesedisorders, it appears that cells undergo asimilar process of programmed death.So if we understand and clearly treatone neurological disorder, such as dia-betic neuropathy, there should be appli-cability to other neurological diseases aswell.”

W hat role does insulin play in cel-lular signaling? How is insulinable to “tell” a cell to open its

membrane to accept sugar, to burn upsugar, or to store it as glycogen or fat?

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

You can’t talk about diabetes researchat the University of Michigan withoutmentioning this affable scientist. Withan international reputation as an experton insulin, and well over 200 papersand 12 patents in his wake, Saltiel, theJohn Jacob Abel Collegiate Professor ofthe Life Sciences, was the first principalinvestigator to join the U-M LifeSciences Institute in 2001 — the latestchapter in the University of Michigan’stradition of world-class biomedicalresearch. He became the institute’sdirector in 2002, and also serves as aprofessor of internal medicine and of

sue is much more complex, and that itacts as an endocrine organ that releaseshormones. The hormones regulate thebody’s response to insulin.” Furtherresearch into this area by Saltiel and oth-ers may lead to a new generation ofdrugs to fight diabetes or burn fat.“Understanding problems with how wehandle fat might provide a valuable clueto developing new therapies for dia-betes,” he says, “but we first need a bet-ter understanding of how insulin workson healthy people.

“Diabetes is a worldwide epidemic —and a terrible epidemic in our state. Hereat the Life Sciences Institute, we’re build-ing a matrix organization to focus onimportant problems like this. It’s a hubfor scientists working in different areas,but focused on common problems. That’sthe exciting part for me. The NIH sup-port is great, but still inadequate. We’relooking to the Life Sciences Corridor, pri-vate industry, foundations and othertypes of philanthropy, and hope to mounta big effort in this area.” �

molecular and integrative physiology inthe U-M Medical School.

Curious and intrepid, Saltiel is deter-mined to understand how cells respondto insulin’s signals. His team is lookingat what happens inside the cell’s intri-cate machinery to determine how somany signals can spring from one hor-mone-receptor interaction. They’vefound that each signal appears to travela different path through a cell, depend-ing on what it’s saying. Says Saltiel,“The inside of the cell isn’t just a bag ofgunk; it’s very well organized.”

Though no one knows what triggers it,the first stage of developing diabetes is areduced sensitivity to insulin’s signaling,he explains. The clues may lie in thephysiology of obesity, which is a hall-mark of type 2 diabetes. But why doesan abundance of nutrition interferewith this system?

“Fat cells were once thought of as merelya cargo space for energy storage,” saysSaltiel. “Now we know that adipose tis-

Medicine at Michigan 41

“Diabetes at Michigan has a remarkable history. It trulymakes you feel part of a scientific family. I’m very proudto be part of this long tradition of diabetes research and

treatment at Michigan.”— Eva Feldman, professor of neurology and director, U-M Juvenile Diabetes Research Foundation Center

Peter Arvan and his team

front: Young-nam Park, Ph.D.,research associate; PeterArvan; Xiang Zhao, graduatestudent

back: Jaemin Lee, graduate student; Yukihiro Yamaguchi,Ph.D., postdoctoral fellow; JoseRamos-Castaneda, Ph.D., post-doctoral fellow; Ming Liu, M.D.,Ph.D., research associate;Roberto Lara-Lemus, M.D.,Ph.D., postdoctoral fellow

Phot

o: P

aul J

aron

ski

42 Spring/Summer 2004

there yet. The prevention and cure ofdiabetes isn’t going to happen overnight,but progress is being made at anastounding rate. I’m hoping that withtime, we’ll reach the stage where dia-betes mellitus is no longer a worldwideaffliction.”

A new program at U-M isdesigned to give medical stu-dents direct experience with

people who are living with chronic dis-eases. Says Arno Kumagai, M.D., whoconceived of and initiated the program,“The Family Centered Experience is arequired course for first- and second-yearmedical students. The purpose is to givethem the opportunity to learn medicine

room learning from each other. Jasonasks Anne about her initial diagnosis,how the news of her diabetes was brokento her, and how that felt. Suhani asks herabout the different doctors she’s seen,how their styles of communication dif-fered. Then, the group completes anexercise. All of them, including the stu-dents, share a story of a personal loss,and how someone helped them copewith that loss.

The students gain valuable interviewingand listening skills, but beyond theseobvious things, they encounter patientson their home turf, seeing them as muchmore than just a collection of symptoms.

T he leading diabetes researchtaking place at Michigan everyday owes a profound debt to

every dedicated investigator who hascome before. Stefan Fajans (pronounced“fi-yuns”) (M.D. 1942, Residency 1949)has researched and treated diabetes atthe University of Michigan since 1946.Now retired, he still comes to his officeevery day to continue deciphering thefascinating puzzles of this disease. Fajanspoints to the top shelf of his bookcase,to a long line of battered, beige note-books dating back to 1950 and chroni-cling diabetes in one Michigan familysince 1958. Fajans’ careful observationof that and other families led to a star-tling discovery that has significantlyaffected medicine’s understanding oftype 2 diabetes by introducing the con-cept of MODY (mature-onset diabetesof the young).

“See all those books up there?” he asks.“These are all records of individuals —people who were completely asympto-matic and healthy. Most weren’t dia-betic at the time of their firstexamination. But they had a first-degreefamily history of diabetes: a parent, asibling, a child. The conventional wis-dom in those days was that type 2 dia-betes occurred only in middle age, butby doing these family studies, and bytesting not only adults but also kids, Ifound that type 2 diabetes developedand could be diagnosed in children aswell. This familial predisposition wasactually inherited in an autosomal dom-inant fashion in some families to form asubtype of type 2 diabetes (MODY). Bymaking the diagnosis early and treatingyoung patients, we have avoided com-plications.” In 1991, he co-published thefirst paper to describe a genetic markerfor MODY; from this discovery, the geneitself was found in 1996. In addition tothat pioneering research into MODY,Fajans led the team in the 1960s thatshowed the involvement of amino acids ininsulin release.

“I love the discovery of new knowl-edge,” he says, “and being able to helpfamilies with diabetes. But we’re not

Stefan Fajans

Photo: Paul Thacker

‘from the other side of the stethoscope’by listening to the stories of individualswith chronic or serious illnesses.”

Anne Jackson and her family are partici-pating in the program. On an icy eveningin January, medical students Jason Bachaand Suhani Bora stand in the Jackson/Held family’s front hall, stomping thesnow from their boots. Within a fewminutes the students and the entire fam-ily are sitting downstairs in the family

Says Bacha, “The program helps usunderstand how the patient experiencestheir illness outside of the doctor’s office,and the profound effects that an illnesscan have not only on a patient’s body,but also on their sense of self, their emo-tions, their family, their beliefs, theirrelationships, their work ... in otherwords, their entire life. It’s one thing toread about an illness in a textbook, butit has been an entirely different experi-

Alan Saltiel

Photo: Paul Thacker

“The prevention and cure of diabetes isn’t going to happen overnight, but progress is being made at an

astounding rate.”

— Stefan Fajans, professor emeritus of internal medicine

endocrinologist, Dr. Robert Lash. I’mliving proof of someone who has bene-fited from medical research and the newtechnologies and treatments for type 1diabetes. When I was diagnosed, I wastold I’d be on insulin for the rest of mylife. It’s been 18 years and, yes, I’m stillon insulin, but instead of four shots perday, my insulin is now delivered by aninsulin pump the size of a beeper. I’mlooking forward to the day the insulinpump will be so small that it can be implanted and deliver insulin auto-matically, acting much like a ‘normal’pancreas.”

A sk anyone with diabetes abouthope and the answer will comeswiftly: 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

ence meeting, talking with and learningfrom an individual who actually has theillness.

“Getting to know Anne and her familyhas been an extraordinary experiencefor me. Not only has she taught memore about diabetes than I’ve learnedfrom lectures, but the entire family hasalso taught me, through their own per-sonal experiences and stories, how to be amore caring and compassionate doctor.”

It’s this balance between hard-line basicscience and the immeasurable value ofpersonal interaction between patientand health professional that makesMichigan’s approach to diabetes singu-larly effective. Jackson concurs.

“I have the best of both worlds in mymedical care — the latest knowledgeand technology at my disposal, and car-ing, patient-focused clinicians, like my

Medicine at Michigan 43

Suhani Bora, Jason Bacha andAnne Jackson

Photo: D.C.Goings

with her colleague Bob Anderson helpedcoin the term “patient empowerment,”is that while her involvement with herpatients’ health yields immediate satis-faction, communicating the wide spec-trum of diabetes research at Michiganstirs ongoing excitement. “It’s a thrill tobe able to tell people about all theresearch that’s going on here. That’swhere the hope comes from — it’simportant for anyone with an illness.”

And Funnell confides she has a hope ofher own. “My fervent wish,” she sayswith a smile, “is that one day I’ll be outof a job .... ”