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A PUBLICATION OF VANDERBILT UNIVERSITY MEDICAL CENTER
p . 3 0 G r a b b i n g t h e g o l d e n r i n gp . 1 0 A d i s p a r a t e b u r d e np . 4 P a t h w a y t o a c u r e p . 1 6 O n t h e h o r n s o f a r e v o l u t i o n03S U M M E R
Unraveling the mysteries of an ancient disease.
Diabetes
A N e w W a y o f L o o k i n ga t S c i e n c e
Lens
Lens – A N e w Wa y o f L o o k i n g a t S c i e n c e
SUMMER 2003
VOLUME 1, NUMBER 2Lens is published by Vanderbilt University MedicalCenter in cooperation with the VUMC Office of Newsand Public Affairs and the Office of Research.© Vanderbilt University
EDITORBill Snyder
DIRECTOR OF PUBLICATIONSMEDICAL CENTER NEWS AND PUBLIC AFFAIRSWayne Wood
CONTRIBUTING WRITERSMary Beth GardinerLeigh MacMillanBill SnyderBeth Barker
PHOTOGRAPHY/ILLUSTRATIONDean DixonMary DonaldsonDominic DoyleDana JohnsonAnne Rayner PolloJudy G. RolfeLarry Willson
DESIGNDiana Duren/Corporate Design, Nashville
COVER ILLUSTRATIONDiana Duren
EDITORIAL OFFICEOffice of News and Public AffairsCCC-3312 Medical Center NorthVanderbilt University Nashville, Tennessee 37232-2390615-322-4747E-mail address: [email protected]
Discovery consists ofseeing what everybodyhas seen, and thinkingwhat nobody hasthought.
– A L B E R T V O N S Z E N T - G Y O R G Y I
About the cover: A 3-D image of an intact rat pancreatic islet, in which is coiled an insulin pump
infusion set, courtesy of SpectRx, is shown against a background of images that suggest the
past and future of diabetes research.
In the background: Dr. Frederick Banting (top right) and Charles H. Best (bottom left), co-discoverers
of insulin, and early insulin bottles, courtesy of Eli Lilly and Company Archives. Squiggly lines are
images of blood vessels in the islet and surrounding tissue, courtesy of Marcela Brissova,
Vanderbilt University.
The islet image, visualized with multi-color, laser scanning confocal immunofluorescence
microscopy, is courtesy of T.C. Brelje and R.L. Sorenson of the University of Minnesota Medical
School. It shows insulin-secreting beta cells in green, glucagon-secreting alpha cells in blue and
somatostatin-secreting delta cells in red.
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contentsLens
T A B L E O F
2 EDITOR’S LETTER
3 FACES OF DIABETES
4 PATHWAY TO A CURETransplanting human islets into patients with type 1 diabetes can cure the disease, but there aren’t enough islets to go around. Scientists hope one day toflip “genetic switches” to convert human stem cells into transplantable insulin-producing cells, a potential solution to the islet supply problem. Still, there arehurdles that loom in the pathway to a cure.
10 A DISPARATE BURDENMinority groups in the United States are disproportionately affected by diabetesand complications of the disease. Nashville’s two medical schools, Vanderbilt andMeharry, have forged partnerships with community health centers and publichealth programs to improve treatment, prevention and patient education. Areport from the front lines of diabetes care.
16 ON THE HORNS OF A REVOLUTIONOscar Crofford set out to bring scientific rigor to the care of patients with diabetes. Along the way, the persistent, determined Vanderbilt professor helpedput diabetes on the federal government’s agenda, and directed a landmark clinicaltrial that established the value of aggressive blood glucose control to reduce therisk of complications from the disease.
22 A DISORDERED THERMOSTATThe incidence of type 2 diabetes is skyrocketing throughout the world, and isclosely associated with its companion epidemic – obesity. Recent advances inimaging and genetics – from two-photon microscopy to “knock-out” mice – are helping scientists understand the complexity of metabolism, and what can happen when the body’s energy system is thrown out of balance.
28 FORGING NEW PARTNERSHIPSDr. Allen Spiegel, director of the National Institute of Diabetes and Digestiveand Kidney Diseases, on the importance of investing in basic medical research,the need for more “cross-cultural” exchanges between medicine, mathematics, thephysical sciences and computational biology, and the challenge of translatingresearch findings into benefits for patients.
30 GRABBING THE GOLDEN RING: A HISTORY
32 JUNK FOOD IN SCHOOLS
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One of the pivotal events of the 20thCentury was the discovery of insulin in1921 by researchers at the University ofToronto. Within a year, diabetes had beentransformed from a hopeless, wastingdisease into one that could be controlledthrough the injections of a miraculouspancreatic extract.
Daily injections of the hormone savedhundreds of thousands of lives, but it wasnot the cure for diabetes that many peoplehad hoped it would be. Because glucosecontrol was fairly crude, many patientsdeveloped long-term complications ofchronic hyperglycemia – blindness, kidneyfailure, heart disease, neuropathy, andpoor circulation requiring amputation ofthe lower extremities.
When I diagnosed myself to havetype 1 diabetes as a medical student in1968, there were two schools of thought.One of my professors discouraged tightglucose control because of the risk ofhypoglycemia, too little glucose in theblood that could lead to coma and death.Others, including my personal physician,urged me to try to keep my glucose levelas close to normal as possible.
I chose the latter course because I didn’twant to find out at some future time that Ihad missed an opportunity to prevent thecomplications of the disease. This was beforethe Diabetes Control and ComplicationsTrial confirmed the value of tight glucosecontrol. And it was before glucose meters,so I had to guess what my glucose levelwas by testing my urine.
Thanks to the technological andpharmacological innovations of the past15 years, I now use an insulin pump thatinjects a rapid-acting form of the hormonebelow the skin, and a glucose meter thatgives me a reading of my blood glucoselevel in five seconds.
But we still don’t understand why andhow diabetes and its complications developas clearly as we’d like. Obesity and type 2diabetes have reached epidemic proportionsthroughout the world, and the incidence oftype 1 diabetes also is increasing.
This is where medical research playsa critical role. Following in the footstepsof Dr. Frederick Banting, Charles Bestand their colleagues at Toronto, scientistsaround the world are pursuing avenues ofinquiry that are improving understandingof this complex disease and which maylead to better methods of treating, pre-venting and – perhaps one day – curing it.
Vanderbilt University Medical Center has an especially rich heritage indiabetes-related research. Charles “Rollo”Park, John Exton, Earl Sutherland, JoelHardman, Oscar Crofford, Daryl Grannerand Alan Cherrington, to name only a few,helped pioneer current understanding ofhow glucose and lipid metabolism is regulated. That tradition and that dedica-tion to deciphering the riddle of diabetescontinue today. I consider it to be a privilege to be here, both as a patient andas a faculty member.
This issue of Lens provides a glimpseof exciting advances in understandingdiabetes: new ways of visualizing thepancreas; decoding the complex interplayof tissues and chemical signals that regulateglucose and body weight; and the prospectsfor “cell-based therapy” – transplants ofinsulin-secreting cells that have been created in the laboratory.
I hope our readers will come awaywith an appreciation for how discoveriesin what appear to be unrelated researchfields provide important clues to improvingdiabetes treatment. Interpreting and integrating diverse sources of informationis crucial for understanding. That’s thescientist’s job. That’s the nature of science.
Steven G. Gabbe, M.D.DeanVanderbilt University School of Medicine
Dr. Gabbe is professor of Obstetrics andGynecology and Medical Administration, and anexpert on treating diabetes during pregnancy.
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A NEW CLINIC AT VANDERBILT PROMISES“ONE-STOP SHOPPING”
Vanderbilt University Medical Center,
site of the nation’s first federally
funded diabetes research center, is devel-
oping plans for a comprehensive program
that will more fully integrate diabetes care,
training and clinical research.
The Vanderbilt-Eskind Diabetes Clinic
will bear the name of Dr. Irwin B. Eskind, a
Nashville physician and philanthropist who
chairs the board of the existing Vanderbilt
Diabetes Center. Patients will be able to
see specialists and have all their tests
done at one location, starting at childhood
and continuing through adult life.
"We want this to be as close to one-
stop care as possible," says Dr. Stephen N.
Davis, chief of the Division of Diabetes,
Endocrinology and Metabolism and Rudolph H.
Kampmeier Professor of Medicine.
“Our objective is to have Vanderbilt be
a place that affords the best care available
and to discover new care that we don’t
have yet, so that patients consider this as
the place to go for their care, and health
care professionals consider it as the place
to go for their training,” adds Dr. Daryl K.
Granner, director of the Vanderbilt Diabetes
Center and Joe C. Davis Professor of
Biomedical Science.
Faces of diabetes
Meet Emily Alexander and Ellis Hollerman. They share a workplace anda disease – diabetes.
Mr. Hollerman is principal of Shafer Middle School in Gallatin, Tennessee,about 30 miles northeast of Nashville, where Mrs. Alexander teaches TeenLiving – health and wellness – to students in the sixth through eighth grades.
They represent the breadth and complexity of a disease that touchesevery community in this country and – to an ever-growing extent – throughoutthe world.
Mrs. Alexander has type 1 diabetes, characterized by an attack by herbody’s immune system on the insulin-producing beta cells in her pancreas.She wears an insulin pump, which feeds a programmed amount of the vitalhormone into her body to keep the amount of glucose in her blood within anormal range, and to reduce the risk of the complications of diabetes,including blindness, kidney failure and heart disease.
Mr. Hollerman also requires insulin. But he has type 2 diabetes, themost common form of the disease, in which his tissues have become“resistant” to insulin and do not absorb glucose like they should. At thesame time, his beta cells have lost their ability to produce sufficient levelsof the hormone.
In the past 15 years, a plethora of new drugs and devices have beenbrought to market to aid patients in controlling their disease. Progress continues to be made, thanks to the nation’s substantial investment inmedical research. The challenge is to bring these advances from the laboratory into the clinic, for the benefit of people like Mrs. Alexander andMr. Hollerman, and the millions of others who share their disease.
– B ILL SNYDER
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One step into Chris Wright’s Vanderbilt office, and it’s clear
that this guy is fond of frogs. Perched on a long low bookcase are
all manner of them – wooden, ceramic, stuffed. The figures join a
striking series of models that show, in hand-painted detail,
stages of the developing frog embryo.
The décor pays homage to the animal that gave Wright his
scientific start. It was in studies of the frog embryo – a system
long-favored for developmental biology research – that Wright
discovered a gene critical to the development of the pancreas.
The findings launched a path of inquiry that has landed Wright in
the thick of the push to cure diabetes.
BY LEIGH MACMILLAN
It’s not a place he set out to be. Thepressure of finding something thatwill benefit the millions of patients
suffering from diabetes can be daunting,says Wright, professor of Cell &Developmental Biology, but “it’s alsoinvigorating.
“Our research really has a chance tohelp people; it’s not just an academicquestion whose answer might be in thetextbooks, if you’re lucky.”
Wright’s team and a handful of otherlaboratories are seeking the set of genesthat control the development of the specialized cells of the pancreas. “If wecan identify the factors that make a pancreas,” Wright says, “we might beable to coerce embryonic stem cells orother cells to turn into pancreas.”
Success could mean unlimited supplies of insulin-producing cells fortransplantation therapy. And transplantationappears to be as close to a cure for diabetesas we’ve come.
Only one kind of cell in the body –the pancreatic beta cell – can sense bloodglucose and respond by secreting insulin.Destruction of these precious cells by aperson’s own immune system gives riseto type 1 diabetes.
Although glucose testing andinsulin injections can stand in for thelost beta cells, they cannot begin tomatch the minute-to-minute control ofblood glucose normally exerted by thesecells. While intensive insulin therapyreduces the long-term complications ofdiabetes, it does not eliminate thesecomplications and often results in dangerous episodes of hypoglycemia.
So why not simply replace the lostbeta cells with new ones? That is thepremise of transplantation therapy as acure for diabetes.
One option is to transplant an entirepancreas, and indeed, pancreas transplan-tation has proven successful in restoringnormal blood glucose levels.
pathwayto a cureTransplantable cells offerhope, but face obstacles
Pictured left: An intact rat pancreatic islet is shown against a background of images: a3-year-old child held by his mother (upper left),one of the first patients to receive insulin; gels used to identify genes involved in thedevelopment of the pancreas (lower right); and the different kinds of cells that make upthe newborn mouse pancreas. For more onthe islet, see inside front cover. Other imagescourtesy of Eli Lilly and Company Archives and Chris Wright, Ph.D.
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More encouraging results began tosurface in the late 1990s, with groups inMiami, Minneapolis, and Milan achievinglonger periods of islet cell survival, higherpercentages of insulin independence, and,for those transplant patients who stillrequired insulin, avoidance of dangerousblood glucose extremes.
The breakthrough report came inJuly 2000 from a group at the Universityof Alberta in Edmonton, Canada. Dr. JamesShapiro and colleagues announced thateach of seven islet transplant recipients –patients with type 1 diabetes and a historyof severe hypoglycemia – were insulinindependent, the longest for 15 monthsand counting. Their strategy used a novelcombination of non-steroid immunosup-pressant drugs – ones that were kinder tothe fragile islets and that were less likelyto induce insulin resistance in the transplantrecipients. And it used islets from two,and in one case three, donor pancreases.
The Edmonton group “made a leap forward in terms of immunosuppression andstandardization of islet isolation techniques,culminating in a very high success rate,”says Dr. Christopher Marsh, chief of theorgan transplantation service at the ScrippsClinic in La Jolla, Calif., and co-director ofthe Organ and Cell Transplantation Centerat Scripps Green Hospital.
The approach, now known as the“Edmonton protocol,” triggered a surge ininterest in islet cell transplantation andprompted the National Institutes ofHealth and the Juvenile Diabetes ResearchFoundation (JDRF) to fund larger clinicaltrials of the protocol and variations of it.
Unfortunately, the procedure carries highmorbidity and mortality rates, restrictingit as a therapy to those patients with diabetes and significant end-stage organdisease like renal failure.
Most patients with type 1 diabetesneed a safer alternative. Perhaps, investi-gators reasoned, the surgical complicationsof full pancreas transplants could be avoidedby transplanting only the “islets ofLangerhans,” named for the Germanpathologist who first described the characteristic cell islands in the pancreas.Islets are home to the insulin-producing betacells, along with several other hormone-releasing cell types.
The idea showed early promise. In1972, Paul Lacy at WashingtonUniversity in St. Louis reported that islettransplantation could cure diabetes in rats.Investigators raced to apply the procedureto human beings. But of the hundreds ofattempts made over the next 20-plusyears, less than 10 percent resulted ininsulin independence.
Since the Edmonton group’s originalpublication, more than 150 patients world-wide have received islet transplants as partof these trials, according to the JDRF.
Preliminary results from at least oneJDRF-sponsored transplant center supportthe idea that islets from a single donorpancreas might cure diabetes. Using onecadaveric pancreas per diabetes patientwould stretch the islet supply, but notenough to provide islet transplantation toall the patients who could benefit from it.
Last year in the United States, fewerthan 2000 pancreases were recovered fromdonors. More than a million patients havetype 1 diabetes.
“What you need is more tissue,” saysVanderbilt’s Wright. “Where do you getmore tissue?”
Islet tissue could potentially comefrom another species, like pig, an area ofresearch called xenotransplantation. Orinsulin-producing cells could be grown inthe laboratory, as genetically engineeredcells or as the products of stem cells –embryonic or adult.
None of these options is clear-cut.Xenotransplantation must overcome concerns that pig-specific pathogens willinfect the human recipients and potentiallyendanger public health. Genetic engineeringof cells requires an appropriate cell startingpoint and knowledge of all the genes thatare necessary for glucose-regulated insulinsecretion. Likewise, turning stem cellsinto pancreatic cells requires identificationof the complete set of factors that willelicit that conversion.
Securing a plentiful supply of islets oran alternative source of insulin-producingcells is just one of the hurdles looming forislet transplantation. Equally vexing is thelong-term immunosuppression required toprevent attack of the transplanted cells.
Immunosuppressive drugs can bluntthe immune system’s attack on transplantedtissues, as well as its attack on beta cells,the hallmark of type 1 diabetes. But eventhe Edmonton protocol’s newer, less toxicdrug cocktail has “side effects that are notjustified lifelong in juveniles,” says Dr.Allen Spiegel, director of the NationalInstitute of Diabetes & Digestive &Kidney Diseases. Immunosuppression putspatients at increased risk for infections ofall types, for lymphomas and relatedmalignancies, and for renal toxicity.
One appealing way to leap over thisobstacle, Spiegel says, would be to induce“tolerance” of the transplanted cells, with-out requiring chronic drugs and withoutsuppressing immunity overall. The
Pictured below: Chris Wright (left) and YoshioFujitani, senior post-doctoral fellow, discusstheir mouse embryo research. They have usedgenetic manipulations to introduce an inheritedmarker – a blue color that can be followed incells that turn on the p48 gene and form thepancreas (shown on computer screen).
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Immune Tolerance Network, a $144 millionproject co-funded by the National Instituteof Allergy and Infectious Diseases, theNIDDK and the JDRF, is working towardthis goal. “There are some encouragingresults, but a lot of work remains to bedone,” Spiegel says.
It might also be possible to sheatheislets, or cell clusters, in materials thatprotect them from immune system attackbut that allow passage of nutrients, glucoseand insulin. Encapsulation strategiesinclude ultrathin polymer membranes –microencapsulation – and porous matrixeswith cells or islets dispersed inside –macroencapsulation.
“What we like about encapsulation isthat it will eliminate the need for long-termimmunosuppressive drug therapy,” saysTaylor Wang, Centennial Professor ofMechanical Engineering and AppliedPhysics at Vanderbilt, and a former astronautwhose 1985 space shuttle experimentsinvolving water and oil droplets turned outto have implications for encapsulating islets.
Wang and colleagues developed anencapsulation method – materials andbioreactor system – and successfullyreversed diabetes in a mouse model bytransplanting encapsulated rat or pigislets. But their capsules failed in dogs.The investigators have since workedthrough nearly 20 different engineeringparameters, adjusting each in order tooptimize performance.
Now, bolstered by a new grant fromNASA, they are preparing to test theimproved capsules in larger animals and,assuming success, in human beings. “Weare starting to see the light at the end ofthe tunnel,” says Wang, who directs theVanderbilt Center for MicrogravityResearch and Applications. “You can get alittle bit edgy though. Is it really thelight, or a train coming at me?”
As investigators make progress inshielding transplanted cells from host
immune attack, islet transplantation willbecome all the more desirable as a treatmentand cure for diabetes. Translating it into awidespread option, however, will dependon securing a suitable and plentiful sourceof insulin-producing tissue.
Even if xenotransplantation provesworkable, the number of donor animalsrequired to meet patient demand for isletswould likely be excessive. Insulin-releasingcells that could be produced in unlimitedquantities in the laboratory – or pharmaceu-tical factory – are a more desirable option.
Toward that end, an internationalgroup of scientists, assembled together asthe NIH-supported Beta Cell BiologyConsortium, are working toward the ultimate goal of converting human stemcells into functional beta-like cells or complete pancreatic islets.
Stem cells, the basic building blocksof the body’s many different tissues, offerpromise for a variety of ills. They come intwo types: embryonic, which normallypopulate the early embryo and give rise toall the tissues of the body, and adult,which are found in and serve to replenish“mature” tissues – the best known are thebone marrow-residing cells that renew theblood supply. Embryonic stem cells areconsidered more versatile than their adultstem cell relatives, in terms of the cell
types they can become, but they are more controversial.
That controversy might be avoidedby identifying human adult pancreaticstem cells – cells that spin off renewedpancreatic cells, including beta cells.Evidence from several laboratories suggeststhat these adult stem cells exist, but noone has yet isolated the actual cells.
“In the next couple of years, one mayunequivocally identify the adult pancreaticstem cell,” says Douglas Melton, a Harvardinvestigator studying the development ofthe pancreas. “The problem is whether itcan be replicated to any appreciable extent,to be useful in a clinical context. Can youcoax it to grow outside the body, to makea pile of cells?”
More promising, Melton says, is theembryonic stem cell. “Here, two of theproblems have already been solved. Thiscell is available, and it grows like a weed.You can make virtually an infinite amount.
“That leaves one big problem: how doyou direct differentiation into pancreaticcells?”
This is where studies of pancreasdevelopment come in – finding the geneswitches that turn an undefined bit ofembryonic tissue into the specialized cells
Images of a developing mouse embryoshow the ventral (v) and dorsal (d) pancreatic buds as two blue spots (leftpanel). A section through one of thebuds (middle and right panels) showsblue color only in cells that will go on toform the pancreas. Brown color markscells that not only will form the futurepancreas, by also the stomach (s) andgut (g). See story, page 8.
Courtesy of Chris Wright, Ph.D. and colleagues, and Nature Genetics.
INTERNATIONAL GROUP CHANGES THE WAY SCIENCE IS DONEBased at Vanderbilt University Medical Center, the Beta Cell Biology Consortium
includes researchers from more than a dozen universities around the world and from theNational Institute of Diabetes and Digestive and Kidney Diseases, which funds the effort.
When the consortium was created two years ago, Vanderbilt was chosen to be thecoordinating center because, at the time, “we had the only program project (funded bythe institute) that was focused entirely on the pancreatic beta cell,” says Dr. Mark A.Magnuson, assistant vice chancellor for research at Vanderbilt who chairs the consortium’ssteering committee.
Other Vanderbilt faculty who participate in the consortium include Chris Wright,Roland Stein, Jason Moore, David Piston and Maureen Gannon.
Magnuson is optimistic that this coordinated effort will lead to the identification offactors necessary to convert stem cells into pancreatic islet cells. “These mega-organizations are really changing the way that we approach doing science,” he says.
For more information, visit the consortium’s Web site at www.betacell.org.
(continued on next page)
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of the pancreas. Wright’s observations inthe frog embryo identified one of the first.
In the mid-1980s, Wright was plug-ging away as a postdoctoral fellow atUCLA, looking for new members of the“homeobox” gene family – genes that hadjust been identified as being critical forproper pattern formation in the fruit fly.Of the several he identified, one had aninteresting pattern of expression in thedeveloping frog embryo; it was turned onin the area that would give rise to thepancreas and part of the intestines.
Wright launched his Vanderbilt laboratory with the intention of studyingthe function of the gene, now called pdx1,in mammals, specifically mice. “I was sureit would be exciting,” he recalls. He wasright. Mice without the pdx1 gene failedto develop a pancreas.
The pdx1 gene is a transcription factor –it turns on other genes, a cascade of whicheventually turns undifferentiated embryon-ic tissue into the pancreas.
In recent studies, Wright and colleagueshave characterized the action of anothertranscription factor, a gene called PTF1p48(p48 for short).
The group reported last summer inNature Genetics a novel and powerful cellmarking method that they used to trackcells in the mouse that express the p48 gene,starting very early in embryonic pancreasformation. The method relied on geneticmanipulations to introduce an inheritedmarker – a blue color that could be followedin cells that turned on the p48 gene, and inall the cells that came from those cells.
A simple way to think about the technique, Wright says, is to picture thecrowd at a football stadium and to imaginethat somewhere in the stadium, for a limited time, a man gave away unique bluehats and asked people to wear them. “Nowwe can follow the people who got hats, nomatter where they go,” Wright says.“Whether they go to get a hot dog or leavethe stadium entirely, we can find them.”
Wright and colleagues found that cellsexpressing the p48 gene, blue hat-wearingcells, formed the pancreas. When theinvestigators knocked out the p48 gene,they found that cells, which would havenormally formed the pancreas, becameintestinal cells instead.
“The really important point is thatthese cells without p48 don’t just die; theygo on to behave as a different tissue,”Wright says. “That is very powerful infor-mation when you are thinking aboutmanipulating stem cells in the laboratory.Because you know now – at least for somegenes – that you can put them in or takethem away and you don’t kill the cells;you manipulate what they’re going tobecome. And that’s exactly what we wantto do therapeutically.”
The next step, he says, is to see whetherintroducing the p48 gene into cells thatwould normally become intestinal cellschanges their fate and causes them tobecome pancreas cells instead.
“If we can do that,” Wright says,“we’re a big step further towards knowingthat p48 is one of the gene triggers thatyou might want to put into an embryonicor other stem cell to make pancreas.”
But one of how many? Wright wonders.“We’re just sort of clutching and still trying to get some basic understanding. It’slike climbing an ice wall with ice picks:you’d better have a good hold before youstart going up too high.”
Even knowing the complete set offactors that will convert stem cells intopancreas doesn’t address the logisticalproblems of applying that information ona large scale to generate products for humantransplantation. Simple manipulation oflaboratory growth conditions, for example,may not be sufficiently rigorous to passFDA muster.
“We have to understand very deeplythe physiological behavior of those cells,”Wright says. “How long do we spendcharacterizing those cell types before wesay it’s appropriate to put them into people? I don’t know the answer to that.”
At the end of the day, it is the funda-mental academic question that drivesWright’s quest for answers. Relaxing inhis office of frog companions, he pondersthe intricacies of pancreas development. “I’mstill fascinated by how a piece of tissuebuds out, goes through a branching process,makes the right numbers of cells of differenttypes, and generates an organ that worksso beautifully,” he says. “It’s an amazingthing.” LENS
Political “chill” slows scientific progress
Their very name raises hackles –embryonic stem cells. These are thecells that populate the early embryo andgive rise to all of the body’s tissues. Theseare the cells that can be grown in virtuallylimitless quantities in the laboratory.And these are the cells that scientistshope will someday provide replacementsfor cells damaged in diabetes and otherdisease states.
Embryonic stem cells come fromhuman embryos – those created by invitro fertilization and donated to researchin lieu of being discarded – landing thecells squarely at the center of politicaldebate. Should the federal governmentsupport embryonic stem cell research?
Congress has repeatedly passed legislation barring federal funding for anyresearch that involves the creation ordestruction of human embryos. Privatefunding supported isolation of the firsthuman embryonic stem cells in 1998 byinvestigators at the University of Wisconsinand Johns Hopkins University. In 2001,President Bush decided that federal fundscould support embryonic stem cellresearch, but only using stem cell linesthat existed as of August 9 that year.
The controversy and “political chill”have hindered stem cell research in theUnited States, says Douglas Melton, aHoward Hughes Medical Institute investi-gator at Harvard University. “One canimagine in another circumstance, thebest and brightest young people wouldbe very much attracted to the area ofstem cell research. We don’t see thathappening,” he says.
“Scientifically, it doesn’t make senseto only have access to these particular celllines when people are just now discoveringhow best to grow human embryonic stemcells,” adds Christopher Wright, a devel-opmental biologist at Vanderbilt University.
The research is proceeding in theUnited States, but not as rapidly as incountries with fewer restrictions. Someuniversities, including Harvard andStanford, have established private foun-dations to support human embryonicstem cell research. Relieving the “chill”and boosting stem cell research in theUnited States requires a public betterinformed about the issues, Melton says.
“These are complex issues about whenlife begins, and there may not be universalanswers,” he says. “But we shouldn’tshy away from this discussion.”
– LE IGH MACMILLAN
As investigators make progress in shielding transplanted cellsfrom host immune attack, islet transplantation will become all themore desirable as a treatment and cure for diabetes.
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Two years ago, Katie Rush was havingfrequent and unsettling episodes of hypoglycemia – low blood glucose.
“I’d just feel really sleepy and hungry,”says the active Nashville seventh grader,now 12, who’s had type 1 diabetes sinceshe was 3. “I wouldn’t remember anythingthat happened before I got low. I just feltreally bad.”
Fortunately, at that time, insulin pumpswere beginning to be used more frequentlyin children, and Katie was fitted with onein the summer of 2001. Since then,“we’ve only had five or six of the kind ofspells we’d been having twice a week,”says her mother, Dr. Meg Rush, assistantprofessor of Pediatrics at Vanderbilt.
Insulin pumps are among the recenttechnological and pharmaceutical marvelsthat are improving the lives of people withtype 1 diabetes.
The battery-powered device, which is a little larger than a pager, contains a cartridge of rapid-acting insulin that ispumped through a plastic catheter insertedunder the skin. With the help of a minia-ture computer, the pump can deliver precise amounts of insulin throughout theday, even when the patient is asleep.
Rapid-acting forms of insulin helpimprove blood glucose control becausethey more closely mimic the body’s normal
insulin response after eating a meal.There are also long-acting forms of thehormone, designed for people who cancontrol their blood glucose with once-a-dayinjections.
Patients still must test their blood glucosefrequently, but they can program theirpumps to deliver an additional dose ofinsulin before snacks and mealtimes tohelp avoid the “highs” and “lows” of bloodglucose that can occur with traditionalinsulin therapy.
“You have to be aware of how you feel,”Katie Rush says. “You have to monitor itclosely.”
Of all the complications of diabetestreatment, hypoglycemia is perhaps themost frightening. “Often (patients) willprefer to have their blood glucose valuesrunning a little bit high in order to preventhypoglycemia,” says Dr. Stephen N.Davis, chief of the Division of Diabetes,Endocrinology and Metabolism andRudolph H. Kampmeier Professor ofMedicine at Vanderbilt.
Davis is trying to figure out why thebody doesn’t compensate for insulin-induced drops in blood glucose, for example, by boosting secretion of glucagon,another pancreatic hormone that canstimulate glucose release by the liver.
A clue is cortisol, a stress hormonethat appears to blunt the body’s ability tocompensate for low blood glucose. Drugsthat may block the cortisol effect are nowbeing tested in humans.
In the meantime, new forms of insulinare being tested, including a form thatcould be inhaled, and efforts are underwayto develop an insulin “pill.” Also in thepipeline: devices that can “read” bloodglucose levels by shining infrared light onthe skin.
The “holy grail,” of course, is therestoration of normal beta cell function.Whether or not that day ever comes, “wehave spent the last eight years reallyencouraging her to know she can live anormal life,” Meg Rush says of Katie.
“This does make her different, but itdoesn’t have to change her dreams.” LENS
A normallifeNew technologies helppatients avoid the “highs” and “lows” of diabetes
by Bill Snyder
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Katie Rush (right) participates in sportsyear round, thanks to her insulin pump.She’s pictured at home with her parents,Drs. Charlie and Meg Rush, and heryounger sister, Libby.
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hen 19-year-old Ron Reid went tothe doctor’s office he knew something was seriously wrong. It took his falling into a hyperglycemia-induced coma, however, beforethe problem was nailed as diabetes.
WThe week or two before that day,
Reid had been feeling pretty bad.Normally active and athletic, he
was dragging, his glands swollen and hisvision blurred. He battled cottonmouth,awaking each morning with a thicklycoated tongue. An unusual craving forButterfinger candy bars had him baffled.“I had never had a taste for sweets, even asa kid,” he says.
Scared and fearing the worst – it wasthe early ‘90s and AIDS was escalating –he finally headed to a clinic. As the staffplied him with juice, chocolate milk, andsoda pop to quench his bottomless thirst,he made trip after trip to the restroom,what seemed to Reid “every three seconds.”When he began vomiting, the fruity alcoholic odor raised suspicious eyebrows.“They thought I was drunk,” Reid laughs.As they continued trying to make himcomfortable, Reid lapsed into a coma.Finally, they checked his blood glucoselevel. It measured a whopping 1244 milligrams per deciliter of blood, over 10times the normal value.
Now 28 years old, Reid works as a diabetes educator in Nashville, Tenn., determined, he says, to ensure that othersnot reach the point he did before learningthey have the disease. Reid heads out each
day into his own community where he andother African Americans like him are disproportionately at risk, not only for developing diabetes but also for the long-term complications that come withadvanced disease.
This disparity isn’t limited to AfricanAmericans. That population is joined byother racial and ethnic minority groups,including Hispanics, Native Americans,Asians and Pacific Islanders, in experiencingsome of the highest incidences of diabetesand its complications, particularly type 2diabetes. Though there is little doubt thatgenetics plays a part in this inequity, there is mounting evidence that lifestyle,cultural factors, and access to healthcarealso strongly contribute to what is now agrowing tsunami of new cases.
Reid has type 1 diabetes, which hasan abrupt onset of characteristic symptoms,frequent urination and terrific thirst beingtwo of them. Type 2 diabetes, on the otherhand, comes on more quietly. Often, by thetime it’s diagnosed, the disease is advanced.
Reid’s disease, which is much lesscommon, typically develops at a youngerage and results from destruction of theinsulin-secreting cells of the pancreas.Insulin, a hormone key to converting food
A disparate burdenBy Mary Beth Gardiner
Genes, culture and thechallenge of prevention
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Ron Reid (foreground), a diabetes educator who also has type 1 diabetes, poses infront of the Matthew WalkerComprehensive Health Center inNashville, Tenn., with co-workersin Project REACH, a federallyfunded effort to reduce the disproportionate impact of diseases including diabetes on minority groups.
From left behind stair rail areTarese Gardner, Atha Jackson,Linda McClellan (project director)and Dayo Bailey. Seated onstairs are Tunu Kinebrew,Stephanie Hill, Bola Teyinka,Consuela Greene and WilliamOwens (a patient in the program).Standing on stairs are DorlisaSmikes and Deborah Carpenter.
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into energy, must be injected to restorenormal function.
Making the caseType 2 diabetes differs in that it
usually develops later in life and resultsfrom, essentially, an overworked pancreas.Insulin resistance in predisposed individualscauses the pancreas to pump out largerand larger amounts of the hormone eachtime food is eaten. Eventually, the insulin-secreting cells die a premature death, forcingthe need for insulin injections.
Diabetes currently affects 17 millionAmericans, with about 90 percent of casesbeing type 2. An estimated one-third areunaware they have the disease. Since WorldWar II, type 2 diabetes has mushroomedin this country, becoming one of thecostliest and most devastating diseases inrecent history. While Caucasians sufferfrom the disease in high numbers, the disease is most ruthless in its attack onthose whose ancestors came from placesother than Europe.
African Americans are at especiallyhigh risk for diabetes. The rate of type 2diabetes in that population is 60 to 70 percent higher than that seen in CaucasianAmericans, a tripling of the rate seen in1963. Complications from diabetes aregreater, too. African Americans suffer a
two-fold higher rate of blindness and lowerlimb amputation, and a three- to five-foldhigher rate of end stage kidney disease.
Hispanic Americans, the secondlargest and fastest growing minority groupin the United States, are twice as likely asnon-Hispanic whites to develop type 2diabetes and, like African Americans,Hispanics also see higher rates of long-term complications.
Native Americans are the populationin this country most disproportionatelyaffected by diabetes, especially type 2 diabetes. The Pima Indians of the desertSouthwest have one of the highest incidencesknown worldwide. The disease is so common – more than 50 percent of adultsdevelop type 2 diabetes – that public restrooms on reservations are equippedwith hazardous waste bins for safe disposalof insulin needles and lancets. Most Pimasgrow up assuming it is their destiny.
The prevalence of type 2 diabetes isestimated to be about two to four timesgreater in Asians living in the U.S. thanin those living in their native country,though that may be changing. Recentreports suggest a wave of obesity is sweep-ing through Asia as populations thronginto burgeoning cities emulating theWestern bent for fatty fast foods andurban conveniences.
It is this modern Western lifestyle oftoo much food and too little exercise thatmany are concluding is behind the explosion of type 2 diabetes in this country.While genes may set us up for diabetes, itappears to be behavior that tips the scale.
And tipping the scales is literallywhat we’re doing, from all evidence.Obesity among adults has doubled since1980, while overweight among adolescentshas tripled, according to former U.S.Surgeon General Dr. David Satcher’s 2001report “Call to Action.” Especially at perilare children, where obesity and type 2 diabetes – formerly known as “adult-onset” – are increasing hand-in-hand at analarming pace, leaving them vulnerablefor years to come.
So is it genetics or is it environmentat the heart of the epidemic? And why arecertain people at particular risk for whatDr. James R. Gavin III, president ofMorehouse School of Medicine in Atlanta,Ga., and chair of the National DiabetesEducation Program, calls “diabesity”?
One of the most durable theories asto why so many humans are poorly suitedfor our modern lifestyle, is a notion firstposed three decades ago by genetics pioneer Dr. James V. Neel, that of the so-called “thrifty genes.” Neel proposedthat certain genes allowed ancestral
Having become a diabetes expert out of necessity, Reidknows that the tighter he controls his blood sugar – throughwatching what he eats and keeping active, as well asthrough judicious insulin supplementation – the more likelyit is he will avoid health complications down the road.
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hunter-gatherers to store fat duringtimes of feast to survive times of famine.Today, with our easy access to caloricabundance, those genes that weredesigned to protect us from starvationare now a major handicap.
The anatomy of changeSome experts say it is this heritable
penchant for high-energy foods that makesdiabetes so hard to beat. The current wisdom for diabetes prevention and control – weight loss through sensible dietand moderate exercise – is good advice foranyone. Making those changes, however,can be difficult for many people.
Fast food is everywhere, it’s cheap,and it tastes good. When money is tight,it’s hard to argue when a hungry familycan be satisfied for just a few dollars.
But food can be more than mere sustenance. Holidays, reunions, weddings,funerals. Saturday picnics and Sunday dinners. Gatherings of family and friendsoften revolve around special meals, rich withtradition and steeped in cultural meaning.
“A meal is often a cultural event,”says Marilyn Skaff, Ph.D., associate adjunctprofessor of Family and CommunityMedicine at the University of California,San Francisco. “Within the ChineseAmerican population, for instance, thefamily gathers and eats from one big pot,making it very difficult to measureamounts eaten and calories consumed.”
African Americans in her communityalso talk of how tough it is to stick to adiet when they go to family gatherings,she says. “Convincing people to changethis part of their life is very difficult.”
Physician Patricia Weaver agrees.Weaver is medical director of the MatthewWalker Comprehensive Health Center inNashville, where 90 percent of those
treated for diabetes are African American.Adding physical activity to her patients’lives is just as challenging, she says. “We have a lot of patients who I think, to the best of their ability, are makingsome changes in terms of diet, but theydon’t have the exercise component. That,without a doubt is the most difficult partto change.”
Reid, whose job is based out of thefederally funded health center, knowsfirst-hand how much difference physicalactivity can make in regulating blood glucose. Reid walks, rather than drives, asmuch as he can during his daily neighbor-hood rounds, and at his second job at a carlot. In the evening, the insulin pumpplugged into his torso comes off for hisnightly game of basketball.
All this activity makes it so that Reidprograms his pump to deliver additional
insulin usually only once a day, before hisevening meal. He’s become so attuned tohis body, he’s learned that the mile-longwalk to Burger King and back is enoughto reduce by half or more the insulinneeded to take care of the burger and frieshe will consume there.
Having become a diabetes expert outof necessity, Reid knows that the tighterhe controls his blood glucose – throughwatching what he eats and keeping active,as well as through judicious insulin supplementation – the more likely it is hewill avoid health complications down theroad. The same complications that tookthe legs and eventually the life of his diabetic grandfather.
Breaking barriersOn the frontline of diabetes care, the
barriers to success are daunting. In for herquarterly check-up at Nashville’s VineHill Community Clinic, Susana Solanoepitomizes the challenges faced by thosewith advanced diabetes. Solano contendswith heart disease, which commonlyaccompanies diabetes, as well as searingleg pain caused by neuropathy. She movesslowly these days, with the aid of a cane.
“She gets very tired and also light-headed,” explains daughter MariaRamirez. “She just wants to stay in herchair a lot, because if she’s up after a fewminutes her head spins. My husband and Igo to work during the day…so it’s very,very hard.”
Solano moved to this country fromMexico a decade ago to live with herdaughter. Insulin-dependent for twenty
years, she administers her own injections,before each meal and at bedtime, butdoesn’t monitor her blood glucose. Fingerpricks are just too painful – and tooexpensive.
Although glucometers, instrumentsfor measuring blood glucose, are commonlydonated by manufacturers and made avail-able at no cost to the largely impoverishedclientele seen at Vine Hill, the test stripsare expensive. At 75 cents apiece, the costsadd up quickly.
“It’s not blue ribbon care, but we dothe best we can under the circumstances,”says nurse practitioner Jason Jean. Solanowill have blood drawn by Jean today fortesting her hemoglobin A1c level.Hemoglobin A1c is a form of the oxygen-
African Americans are at especially high risk for diabetes. The rate of type2 diabetes in that population is 60 to 70 percent higher than that seen inCaucasian Americans, a tripling of the rate seen in 1963.
Pictured at right:Susana Solano has blood drawn byVanderbilt nurse practitioner JasonJean at the Vine Hill Community Clinicin Nashville. Her blood will be tested tosee how well she has controlled herglucose over the past several months.
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carrying blood protein that also binds toglucose, and thus can give a measure ofhow well Solano has been controlling herblood glucose over the past few months.
About half of his client visits at VineHill, a clinic founded and staffed byVanderbilt’s School of Nursing, involvediabetes in some form or fashion, Jean says.“Every diabetic patient I see gets poundedon three things: diet, exercise, and stoppingsmoking. Whether or not they follow thatregimen is another matter.”
“It is a tough, tough disease to livewith,” says nurse practitioner Anne Brown.“I can’t think of any other disease wherewe ask people to do so much to take careof themselves.”
Brown sees referral patients in herendocrinology practice as part of theDiabetes Improvement Program, one element of Vanderbilt’s NIH-fundedDiabetes Research and Training Center.The nurse practitioner-run program aims to help patients fine-tune their glucose control.
With the help of dietitians, theadvanced care nurses intensively counselpatients over a three-month period, meetingweekly to adjust medication regimens andfacilitate lifestyle changes. Once glycemic
targets are achieved, patients return to thecare of their primary physicians.
A similar program, conceivedthrough an alliance between Nashville’shistorically black Meharry MedicalCollege and Vanderbilt University, existsat local “safety net” clinics to ensure thatevery diabetic patient receives a recommended standard of care, whichincludes annual measurement of hemoglobinA1c, cholesterol, weight, and blood pressure,in addition to a kidney function test andeye and foot exams.
“There is no aspect of these patients’lives that diabetes does not touch and thatthey don’t have to make adjustments for,”says Brown.
The demands of the disease can causefrustration and anxiety in patient and family, leading to marital strife and otherstresses. Feelings of helplessness can overwhelm, and depression is common,especially at diagnosis and later, at theonset of long-term complications.
Addressing patients’ expectations ofbeing disabled by diabetes and how thosefeelings affect self-care is the researchfocus of Dr. Kathleen Figaro, assistantprofessor of Medicine at Vanderbilt.
“In my practice I had noticed that
my black patients felt overwhelmed andisolated by coping with the disease,” saysFigaro, “that diabetes was a curse andthere was nothing they could do about it.”
The patients not only didn’t trust theirmedical system, she says, but they also didn’tbelieve that their own behavior could affectoutcome. “I thought that might havesomething to do with the disparities andoutcomes between whites and blacks, becauseself-care is so important in diabetes.”
With funding from a Robert WoodJohnson Career Development Award,Figaro plans to create a scale for measuringpatients’ expectations. She hopes the toolwill help tailor interventions aimed atempowering patients.
Raising awarenessPutting the brakes on escalating
diabetes incidence in disadvantaged andminority populations will not be easy, butmost agree that the greatest impact willcome from education, both at a local community level and on a broader national scale.
“Certainly, community outreach andintervention is critical to the control ofthis problem,” says Satcher, who is nowdirector of the National Center for
A: Kidney diseaseDiabetes can damage the glomeruli, the blood-filtering units ofthe kidneys (shown here). As a result, protein (green) is lost inthe urine, and the kidneys gradually lose their ability to removewaste products (blue) from the bloodstream. Ultimately, the kid-neys may fail and patients will require artificial kidney dialysis.
B: Heart diseaseMost adults with diabetes have high blood pressure and highblood levels of triglycerides and low-density lipoprotein (LDL) cho-lesterol. Elevated cholesterol can lead to atherosclerosis, thebuild-up of fatty deposits in artery walls (shown here). Both highblood pressure and atherosclerosis, if untreated, can lead toheart attack or stroke.
C: RetinopathyDiabetes can damage tiny blood vessels in the retina at the backof the eyeball. The damaged vessels can leak fluid into the reti-na, blurring vision. Fragile new blood vessels also may grow intothe retina and leak blood (shown here) ultimately destroying theretina and causing blindness.
D: Nerve damageDiabetes can damage nerves throughout the body, causing numb-ness. Sores may appear on numb areas of the foot becausepressure or injury goes unnoticed. Poor circulation (shown here)may inhibit healing. If the injury is not treated and infectionspreads to the bone, the foot may have to be amputated.
A. B.
C. D.
Complications of diabetesILLUSTRATIONS BY DOMINIC DOYLE
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Primary Care at Morehouse School ofMedicine. “There isn’t any substitute forit, really. It’s going to get more peopleinto care early. It’s going to, in some cases,prevent onset in people who are at highrisk. And when people get into care…itwill help them stay in care.”
Community outreach is precisely the goal of the Nashville REACHCoalition, a group of the city’s academicinstitutions – including Meharry, FiskUniversity, Tennessee State University, andVanderbilt University – working withlocal, county, and state healthcare agenciesand providers to address area racial andethnic health disparities.
A primary focus of the coalition isProject REACH 2010, a multi-center,Centers for Disease Control andPrevention funded effort to end disparitiesin a number of diseases. Nashville’s armtargets a pocket north of the city whereAfrican Americans are particularly hard-hitby diabetes and heart disease when com-pared to Caucasians in the same area, andwhen compared to African Americans inother parts of the country. The goal of theseven-year project is this: to better under-stand why the disparity exists and to workwithin the community to stem the tide.
As an educator with Project REACH,Ron Reid spends his days spreading thegospel of diabetes prevention to at-riskneighbors, often working through com-munity centers and churches. Reid is onone of four teams who fan out into thecommunity of 43,000, 85 percent ofwhom are African American, with thegoals of screening for undiagnosed cases,increasing access to quality healthcare,decreasing tobacco use, and teaching thebenefits of nutrition and physical activity.
A lot of what he sees, Reid says, is fear and mistrust. Fearing the worst, manydiabetes patients either don’t go to the doctor or when they go, they try to slip bywith as limited an exam as possible.
“People are afraid to talk to physicians,”says Reid. “Usually, they won’t take theirshoes off, because they want to keep theirfeet as long as they can. A blind patient Iknow put off telling her doctor for sixmonths (about her feet), because they areso important to her independence.”
Trust in a healthcare provider makes abig difference in how effective treatmentis, according to Jason Jean. “I thinkpatients are interested in a community-based practice where they can sit downwith a provider and talk about the diseaseprocess or their family life or whatever elseis impacting their care.”
No medical “home”Far too many Hispanics and African
Americans don’t have a medical home, saysSatcher. “A lot of them go to emergencyrooms for their care,” he says, where culturalissues, such as language barriers or racialstereotyping, often make for a less thansatisfactory experience.
Satcher points to a 2002 Institute ofMedicine report on racial and ethnic biasin health care – Unequal Treatment – as“pivotal in increasing sensitivity” amongproviders, especially in its potential toaffect training of future physicians andnurses. “There is, for example, a programhere at Morehouse School of Medicine thatattracts people from around the country toa course on cultural competence.”
Increased cultural sensitivity inproviders is a major feature of the NationalDiabetes Education Program, according toits chairman. The NDEP has a specialpopulations work group, says Gavin, thatis “heavily invested in looking at approachesto help bridge the cultural chasms thatmake it difficult for some of these cross-cultural encounters to be successful.”
As to raising consciousness about thedisease within minority populations, Gavinbelieves that the success of diabetes educa-tion efforts will hinge on repetition ofmessage, not just isolated, one-hit attempts.
“There has been this tendency tothink that…as long as content is accurateand the message is compelling, it shouldn’ttake much exposure to drive the pointhome,” he says. “I think consistency ofmessage will be required, and that meansoften and it means early.”
Gavin advocates setting up educationalprograms in schools and in worksites,through public service announcements,and through working with healthcare-oriented cultural organizations – such asIndian Health Services, the NationalCouncil of La Raza, and the Association ofAsian Pacific Community HealthOrganizations – to accomplish his goals.
“I hope that the national conversationon diabetes is one that will rise to the samelevel as the one we saw in the nationalconversation on cholesterol. Everyone knewit was important; everyone knew theirnumber,” he says. “When we see penetrationof that level of awareness among our at-risk and affected populations, then we’llknow that we’re really beginning to movethe needle and gain some traction.” LENS
Meharry, Vanderbilt hostnational meeting on diabetes disparities
“Overcoming Diabetes Health
Disparities” is the subject of a conference
sponsored by the Meharry-Vanderbilt
Alliance Nov. 13-15, 2003, at the Loews
Vanderbilt Hotel in Nashville, Tenn.
Dr. James Gavin III, president of
Morehouse School of Medicine in
Atlanta, Ga. and chair of the National
Diabetes Education Program, will be the
keynote speaker.
Other speakers include:
Dr. Ralph DeFronzo, chief of the
division of diabetes at the University of
Texas Health Science Center at San
Antonio;
Dr. William Dietz, director of the
division of nutrition and physical activity
at the U.S. Centers for Disease Control
and Prevention in Atlanta; and
Dr. Griffin Rodgers, deputy director
of the National Institute of Diabetes,
Digestive and Kidney Diseases.
The Meharry-Vanderbilt Alliance is a
four-year-old collaboration between histor-
ically black Meharry Medical College and
Vanderbilt University Medical Center to
advance patient care, medical education
and research in Nashville.
For more information about the
conference or the Alliance, contact Diana
Marver, Ph.D., director of Biomedical
Research and Research Training for
the Alliance, at 615-936-0854 or
Dr. James Gavin III, longtime diabetesresearcher and chair of the NationalDiabetes Education Program.
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BY BILL SNYDER
o some of his former colleagues in the world of diabetesresearch, Dr. Oscar B. Crofford is now living the life of Riley, toolingaround the bucolic hills of his Arkansas farm on his four-wheeler,checking on his herd of Black Angus cattle.
What they may not realize is that the retired Vanderbilt Universityprofessor approaches his new passion with the same intensity andhumor with which he led a landmark study that established the valueof rigorous blood glucose control a decade ago.
“I’ve learned more about labor and delivery and care of the new-born from these cows than I ever did in medical school,” he says witha chuckle, his sky-blue eyes twinkling under a shock of white hair.
The tale of the study, called the Diabetes Control andComplications Trial (DCCT), is worth repeating, for it revolutionized thetreatment of the disease. Crofford’s life story is equally compelling, forit illustrates how an adventurous spirit can achieve a breakthrough inunderstanding that dramatically improves the lives of patients.
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On the horns of a revolutionOscar Crofford and the landmark trial thatchanged diabetes forever
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Born in Chickasha, Okla., in 1930,Crofford attended high school inMemphis, and after graduation,
decided to go to Vanderbilt. Because of thepost-war shortage of physicians, he wasable to enroll in an accelerated program,and earned both his bachelor’s and medicaldegrees in seven years. He and the formerJane Long, a recent Vanderbilt nursingschool graduate, married during his resi-dency in 1957.
After a two-year stint as a medicalofficer in the Navy to fulfill his militaryobligation, Crofford returned to Vanderbiltfor a fellowship in clinical physiologyunder the late Dr. Elliott V. Newman, apioneering physician-scientist who estab-lished Vanderbilt’s federally fundedClinical Research Center – one of the firstin the nation.
Newman “was really one of the firstof a new breed of physicians who bridgedthe gap between clinical medicine andbasic science,” Crofford recalls. “He toldme, ‘Here’s your lab. Go in there and discover something.’ It was sort of thesink-or-swim philosophy of science.”
Newman also became a trusted advisorand counselor. “He was a wonderful scientistand a wonderful human being,” Croffordsaid. “I’d say my character and sense ofhow to work with people I’ve learnedmostly from Elliott Newman … I probablymodeled my life to a large extent after(him) and the way he treated me.”
Vanderbilt in the early 1960s wasbrimming with scientific excitement, inlarge part because of the “brain trust” inmetabolism research attracted by the trail-blazing physiology professor Charles“Rollo” Park. “Those were the grandestyears ever of medical science,” Croffordmaintains. “We were just in the forefrontof the technological revolution in medicine, the scientific revolution, thingsthat were never possible in the past …That’s where the excitement was. That’swhere the fun was.”
In 1963, Crofford went to theUniversity of Geneva to continue his studies under the late Albert Renold, arenowned diabetes expert who discoveredthe role of insulin in fat metabolism.
After returning to Nashville in 1965,Crofford became Vanderbilt’s first full-time diabetes specialist. He knew moreabout insulin action than diabetes care,but fortunately he was able to learn on thejob under the direction of the late Dr.Addison B. Scoville Jr., a member ofVanderbilt’s clinical faculty who ran theVanderbilt diabetes clinic.
“Virtually everything I learned aboutcaring for people with diabetes I learnedfrom ‘Ad’ Scoville,” he says.
Crofford also expanded his adminis-trative skills. He established the Divisionof Diabetes, and helped bring the nation’sfirst federally funded diabetes researchcenter to Vanderbilt in 1973.
“The person who sent in the application(to the National Institutes of Health) hadto be a physician … so I served as theprincipal investigator (for the center),”Crofford says. “But it was really capitalizingon work done by … a whole slew of out-standing basic scientists.”
At the time, Scoville was president ofthe American Diabetes Association, andintroduced his protégé to the potential
Pictured below: At left, Dr. Oscar
Crofford (at microphone) testifies in
1973 for increased federal funding for
diabetes research. At right, he and Dr.
Addison B. Scoville Jr. (left) hold a
chart showing unanimous support for
a national diabetes plan by
Tennessee’s congressional delegation.
Photos courtesy of Dr. Oscar B. Crofford
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and power of the non-profit organization.Soon Crofford was serving as vice chairmanof its research committee, and he wascalled to Washington, D.C., to testify onbehalf of a bill to increase federal fundingfor diabetes research.
“I had no earthly idea what to do,” herecalls. “I didn’t even know what youcalled your congressman or senator – YourHonor, or what?” So Crofford went to theVanderbilt library, and taught himself theart of testifying by poring over transcriptsof previous hearings.
The hearing before Sen. Ted Kennedy’shealth subcommittee, and subsequent lob-bying by the diabetes community ultimatelywere successful, and in 1974, PresidentRichard Nixon signed what the ADAdescribes as the first diabetes law in U.S.history. Among other things, it mandatedestablishment of a National Commission onDiabetes to formulate a “long-range plan tocombat diabetes.”
Crofford was appointed to the com-mission and elected chairman. “Weinvolved virtually every scientist and diabetes specialist in the nation, and overthe course of nine months … laid out thestrategy for what should be done in thefuture to deal with diabetes at the clinicallevel, at the research level, at the publicinformation level,” he says.
The report was delivered to Congressin December 1975. “I spent a lot of timeas a health lobbyist at that point,”Crofford recalls, trying to get the recom-mendations implemented.
Crofford and Scoville approached theTennessee congressional delegation, andconvinced every member to support additional diabetes legislation. They tooka group photo of the now-unanimous delegation, displayed it at the ADAnational meeting, and urged other statechapters to do the same thing.
“It worked,” Crofford says. Thanks totheir efforts, those of the JuvenileDiabetes Foundation (now the JuvenileDiabetes Research Foundation) and medical institutions like the JoslinDiabetes Center in Boston, “virtually allof the legislative things that had to bedone in order for the diabetes plan to becompleted (were) passed,” he says.
In 1977, Congress appropriated $5million to open five more diabetes centers,and to expand their mission to include thetraining of diabetes specialists. They arenow called Diabetes Research andTraining Centers.
The commission also recommendedthat a study be conducted to determinewhether strict control of blood glucosecould prevent the disabling and life-threatening complications of diabetes,including blindness, kidney failure, amputation and heart disease.
The NIH asked Crofford to help getit started. “This was a new endeavor forme,” he recalls. “I had never run what wenow call clinical trials.” So back to thelibrary he went.
A clinical trial attempts to determinethe effectiveness of a drug or other treatment,by comparing one group of patients whoreceive the treatment to a closely matchedgroup that is not given the treatment andwhich serves as the “control.”
What made the diabetes study so difficult was that it would require the participation of more than 1,000 patientsat multiple research centers over thecourse of several years.
Despite his relative inexperience,Crofford was a natural to lead the study,his colleagues say. He had continued toadvise the NIH on the direction of diabetesresearch and, in 1981-1982, he served asADA president. “He was on the groundfloor, both from the scientific and public
policy aspects,” says Dr. Phillip Gorden,who directed the National Institute ofDiabetes and Digestive and KidneyDiseases from 1986 to 1999.
In addition to scientific curiosity,Crofford was motivated by empathy forthe plight of his patients. “He saw peoplehaving terribly devastating complicationsfrom diabetes,” says Vanderbilt researchnurse Janie Lipps, who worked with himon the trial and who continues to followsome of the participants. “He wanted toknow the truth. Does (controlling bloodglucose) really matter?”
This was not the first time that scien-tists had tried to answer the question.
In 1970 another U.S. study, theUniversity Group Diabetes Program, foundno benefit in controlling blood glucose intype 2 diabetics. But it was hampered bythe lack of a reliable method for measuringchronic high blood glucose. The hemoglobinA1c test would not become available forseveral years.
Hemoglobin is the protein in redblood cells that transports oxygen to bodytissues. A form of the protein also canbind to glucose, and carry it around forseveral weeks. Measuring hemoglobin A1c,then, is a way of determining a person’saverage blood glucose level over a two- tothree-month period.
“That was a very important tool forthe clinical trial,” says Dr. David M. Nathan,who, as a young investigator at HarvardMedical School, had helped develop thehemoglobin A1c test. “It gave you this wonderful … timed window on averageblood sugar control in a single measurement.”
Two other developments in the 1970smade the study possible: portable glucosemonitors, which enabled patients to checktheir blood glucose conveniently and accu-rately; and new forms of insulin and insulinpumps, which made it easier for patients
Ellis Hollerman, principal of Shafer MiddleSchool in Gallatin, Tenn., demonstrates tostudents in a Teen Living class how he usesa portable glucose monitor to check hisblood glucose. Frequent “finger pricks” tocheck blood glucose are essential for controlling diabetes. Portable monitors, introduced in the 1970s, enable people withdiabetes to check their glucose levels moreconveniently and accurately.
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overgrowth of blood vessels in the retinaof the eye that can cause blindness.
Between 1983 and 1989, more than1,400 participants were enrolled, makingthe Diabetes Control and ComplicationsTrial (DCCT) one of the largest studies ofdiabetes ever undertaken.
It was also one of the most difficult.Participants were randomly assigned to a“treatment group” or a “control group,” asis the case in most clinical trials, but thosein the treatment group required anunprecedented amount of monitoring byhealth professionals.
These participants used an insulinpump or gave themselves three or moreinsulin injections every day, monitoredtheir blood glucose at least four times aday, and adjusted their insulin doseaccordingly. They also visited their studycenter once a month and were in frequentphone contact with the researchers toreview and adjust their regimens.
In comparison, participants in thecontrol group gave themselves one or twoinsulin injections a day, at the time thestandard treatment for type 1 diabetes.They did not adjust their insulin dose asfrequently, and they were examined onceevery three months.
While the study was being designedand throughout the entire trial, Crofford
to keep their blood glucose within thenormal range.
By the early 1980s, the pieces “wereall falling into place,” says Nathan, now aprofessor of Medicine at Harvard anddirector of the Diabetes Center atMassachusetts General Hospital.
Nathan’s center was one of 29 acrossthe United States and Canada that partici-pated in the study, which focused onpatients with type 1 diabetes who had notyet developed complications of the disease,or who had only mild retinopathy, the
took great pains to listen to the ideasexpressed by the physician investigators, andby the dietitians and research nurses. “It’sthe well trained, highly motivated nurse whoreally does most of the work … in terms ofcaring for people with diabetes,” he explains.“Their role in this is critically important.”
Smooth as a United Nations diplomat,Crofford worked to reach consensus and toresolve disputes that could have stoppedthe study in its tracks.
“I’d say Oscar masterfully allowed,fostered, stimulated, directed and finallyconcluded those discussions in a way thatwe had a sound protocol,” says Dr. SaulGenuth, professor of Medicine at CaseWestern Reserve University in Cleveland,Ohio, who was vice chair of the DCCTand chaired its planning committee.“Oscar pushed us when we needed to bepushed, and he pulled us when we neededto be pulled.”
Just as important to the study’s successwere the participants themselves. “Theyweren’t human guinea pigs,” Croffordsays. “They were partners in doing themost important study in diabetes that hadever been done since the discovery ofinsulin. If they dropped out, they were notonly hurting themselves but they mightblow the whole study ... So they had to bepart of the team.”
Pictured below:Starting with 12 cattle seven years ago, Oscarand Jane Crofford now have about 40 head ontheir Arkansas farm. Mornings and evenings willfind them feeding and checking on the livestockwith their five dogs in tow.
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Drawing on his experiences in theADA and Congress, Crofford visited eachof the 29 research centers, attending banquets, speaking to participants andencouraging them “to hang in there.”
The team approach seemed to work.Better than 99 percent of participantscompleted the study, which lasted for mostof them an average of six-and-a-half years.Because of the high “adherence” rate, thestudy was able to end a year early.
The results, reported in 1993, showed that strict control of blood glucosedramatically delayed the onset and slowedthe progression of three common compli-cations of diabetes – retinopathy, kidneyproblems and nerve damage.
There was a downside: Participants in the treatment group were more likelyto experience severe hypoglycemia,episodes of low blood glucose that can belife threatening. They also gained moreweight on average than those in the controlgroup, a side effect of the more aggressiveinsulin therapy.
But for Emily Alexander, a Gallatin,Tenn., schoolteacher who has been fol-lowed for nearly 20 years by the DCCTand a follow-up study, participation hasmeant a life essentially free of diabetescomplications. “Research certainly makeslife easier,” she says.
The DCCT was not the only study todemonstrate the benefits of blood glucosecontrol, nor was it the largest. But it setthe standard for how a comprehensive andcomplicated clinical trial should be run,Genuth says.
At Crofford’s insistence, “we madeextraordinary attempts to collect good, verifiable, high-quality data, to analyze itby the best bio-statistical means we could,and then to publish our conclusions in a non-speculative, straightforward manner,” he says.
At the same time, Crofford workedwith the NIDDK to ensure the study waswithin its budget, and met federal datamanagement and safety requirements.
“He was astride four horses, if youwill,” Genuth says, like Charlton Hestonin the movie Ben-Hur. “Oscar was the key
person in this whole trial in getting allthese horses to pull in the same direction.”
The challenge now is to continue toeducate health care providers and theirpatients about the importance of aggressiveblood glucose control, and, throughadvances in technology, make it easier forpatients to keep their disease in check.
Many patients don’t have the opportunity to be monitored by nursesand dietitians in the way that study participants were. “The issue is notwhether it works or not, but how hard it isto do,” Crofford says. “And believe me, …it’s very difficult for patients to follow aregimen of strict glucose control. It willtake technological advances that we do nothave today in order for the average personto be able to do that.
“The good news is that even if you’renot perfect, if you make a little bit ofimprovement, you get a little bit of benefit,”he adds.
Two years after the DCCT ended,Crofford began a new chapter in his life.He and Jane “retired” to his family’s 700-
acre spread in the Ozark Mountains toraise Black Angus bulls.
Starting with 12 cattle seven yearsago, the Croffords now have about 40head on their Rocky Bayou Angus Farm,named for the creeks running through it.Mornings and evenings will find themnavigating their pastures aboard the four-wheeler and a golf cart, feeding andchecking on the livestock with their fivedogs in tow.
Crofford hasn’t retired completelyfrom diabetes research. He attends scientific meetings, keeps up with hisjournals and e-mail, and recently chaired acommittee that monitored the progress ofanother clinical trial.
But he doesn’t spend much timedwelling on the achievements of the past,or brooding over tasks left undone. He’stoo busy for that. There are too many newthings to learn. LENS
Oscar Crofford may look like a man of leisure, but breeding and sellingBlack Angus bulls on his family’s farm in north central Arkansas hasbecome nearly a full-time occupation for him and his wife Jane.
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Understanding the delicate balanceof glucose metabolism
by Bill Snyder
A disordered thermostat
our years ago this month, Gary Webb’s body was in trouble.“I was doing a lot of sitting and eating,” says the 56-year-old Nashville
man, who was carrying 256 pounds on his 6-foot, 2-inch frame. His triglyc-erides were high, a major risk factor for heart disease, and he had developedtype 2 diabetes.
Dr. MacRae Linton, who directs the Vanderbilt Lipid Clinic, prescribeddrugs to lower Webb’s triglyceride and blood glucose levels, referred him to adietitian to help him change his eating habits, and recommended that he begina program of regular aerobic exercise
Scared and depressed by his diagnosis, Webb responded immediately. “Istarted eating veggie burgers on high fiber/low carbohydrate bread, and a lot ofsalad,” he says.
He also started exercising for the first time in a very long time. “That firstday, I walked a mile. I thought I was going to pass out,” he recalls. “My feethurt, my knees hurt. But I kept it up.”
A month later, Webb was walking three to four miles a day. In September,he started running, two to three miles a day, then up to eight miles a day.
By March 2000, Webb was down to 194 pounds, a better-than 60 poundweight loss in eight months. His triglyceride, cholesterol and glucose levelswere all normal, and he no longer needed medication to control them. He nolonger had diabetes.
Pictured above: An image taken with aconfocal microscope shows the inside of ainsulin-producing beta cell in remarkabledetail. The nucleus is the dark spot,upper left. Stained with green fluorescentprotein, the mitochondria, which areinvolved in generating energy for the cell,are yellow, while the Golgi vesicles, whichhelp direct secretory proteins to theirproper locations in the cell, are blue.
Courtesy of David Piston, Ph.D.Vanderbilt University
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Today, more than three years later,Webb has kept most of the weight off,and his blood chemistry is in check. Hisdiet has relaxed a bit, but he still runsabout 15 miles a week.
“He responded amazingly well,” says Linton, professor of Medicine andPharmacology. “It makes the point, whichI think is so powerful, that you can changeyour metabolism through lifestyle changes.”
That was the lesson of the DiabetesPrevention Program, a landmark studythat showed that moderate exercise andweight loss reduced by 58 percent theincidence of type 2 diabetes in people athigh risk for developing the disease.
The problem is that few people haveaccess to the intensive diabetes manage-ment provided to the study participants.
There also is growing evidence thatsome people are genetically susceptible tobecoming obese and developing type 2diabetes, and no matter how hard they tryto lose weight, their bodies are workingagainst them. “It’s extraordinarily difficult,”says Dr. Rudolph Leibel, who co-discov-ered the fat hormone leptin.
A variety of medications, includingthose used to treat heart disease and lowercholesterol, can help prevent diabetes. Butmany of these drugs have side effects, andthey don’t work in all patients.
Thanks in large part to the geneticand computer revolutions of the past 30years, there has been a flood of new infor-mation about diabetes and obesity. Muchof it at this point is incomplete. Butprogress is definitely being made.
First, a few definitions:Glucose, a form of sugar primarily
supplied by the diet, is a major fuel forthe body and virtually the only source ofenergy for the brain. Because it’s so vital,extra glucose is stored in the liver andmuscle in the form of glycogen. The liveralso can make glucose from raw materialsif an emergency supply is needed.
Insulin is secreted by “beta” cells, oneof four types of cells that are clumpedtogether in “islets” in the pancreas. One ofits main jobs is to activate a pathway ofbiochemical signals that ultimately movesglucose from the bloodstream into muscle.
In the late 1970s, Dr. Daryl K.Granner and his colleagues at theUniversity of Iowa showed that insulinalso turns down glucose production in theliver – another way of lowering blood glucose levels – by inhibiting the gene foran enzyme called PEPCK.
“This was the first example of insulinaffecting a specific gene,” says Granner, nowdirector of the Vanderbilt Diabetes Centerand Joe C. Davis Professor of BiomedicalScience. “There are probably now 200 ofthose examples.” For instance, there is evidence that insulin acts on the brain toinhibit appetite and help regulate weight.
Other hormones are involved in thecontrol of blood glucose. Glucagon, whichis secreted by “alpha” cells in the islet,opposes the action of insulin and stimulatesglucose production by the liver. So doescortisol, a stress hormone secreted by theadrenal glands on top of the kidneys.
This push-pull system is designed tokeep blood glucose levels in balance, evenafter a feast, a fast or a flight from a predator.
Not enough blood glucose, a conditioncalled hypoglycemia, can cause uncomfort-able symptoms, including dizziness, confusion, heart palpitations and fatigue.It can lead to coma and death unless theglucose supply is replenished.
Too much blood glucose, the hallmarkof diabetes, can damage the delicate innerlining of blood vessels, eventually leadingto some of the major complications of diabetes – heart disease, kidney failure andblindness, caused by an overgrowth andleakage of tiny blood vessels in the retinaof the eye.
“In type 2 diabetes there is an overproduction of glucose because thesesignals don’t work right,” says Alan D.Cherrington, Ph.D., chairman of theDepartment of Molecular Physiology andBiophysics and Charles H. Best Professorof Diabetes Research at Vanderbilt whohelped discover what glucagon does.
How do the beta cells know when tosecrete insulin? Here’s part of the answer:They contain an enzyme called glucokinase,which puts a phosphate group on the glucose molecule. In the process, theenzyme stimulates the beta cell to secrete insulin.
Dr. Mark A. Magnuson, professor ofMolecular Physiology and Biophysics atVanderbilt, helped identify the role of
Gary Webb runs about 15 miles a week, a regimenthat has helped him reverse high blood triglyceridesand glucose levels – and type 2 diabetes. “I feellike I’m a recovering diabetic,” Webb says. “If Iwere to gain 50 pounds and stop exercising, I don’tknow what would happen.”
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glucokinase in insulin secretion. He compares it to a “thermostat.” Dependingupon whether it is blocked or activated,blood glucose rises or falls.
Maturity-onset Diabetes of the Youngor MODY, a rare form of diabetes, canresult from mutations in any one of atleast six different genes that play a role inthe ability of the beta cell to sense thepresence of high levels of glucose, includingthe gene for glucokinase.
“Type 2 diabetes … may actually be adisease of a disordered thermostat,”Magnuson says.
The challenge is to develop drugs orother treatments that can adjust the thermostat without causing serious sideeffects. “That’s why (diabetes), despite allthe investment of money, intellect andresources, is still getting worse,” says
Cherrington, president-elect of theAmerican Diabetes Association. “As yetwe don’t understand the complexity of the disease.”
As an example of that complexity, anestimated 17 million Americans have diabetes, but nearly four times that numbermay have metabolic syndrome, also calledinsulin resistance, a constellation of symp-toms that places them at high risk for developing type 2 diabetes and heart disease.
Symptoms include abdominal obesity,high blood pressure, high blood glucose,high levels of trigylcerides and low levelsof high-density lipoproteins (HDL).Trigylcerides are a form of fat that contribute to atherosclerosis, the build-upof fatty deposits in blood vessels, whereasHDL is a type of cholesterol that seems toprotect against it.
“With mouse models, we’ve beenable to understand the action ofinsulin and the role of each of theseparticular tissues a little bit morethan we have any time in the past.”
Dr. Mark A. Magnuson, professor ofMolecular Physiology and Biophysicsat Vanderbilt.
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Naomi Berrie Diabetes Center atColumbia University. “We’re after theinteraction of multiple genes … We’retrying to study the whole biology.”
Thanks to a recent initiative supportedby the National Institute of Diabetes andDigestive and Kidney Diseases, researchersat Vanderbilt and elsewhere are creatingpancreas-specific microarrays – chips thesize of a saltine cracker that contain all ofthe genes expressed over the life span ofthe beta cell in mice and humans. Thismethod allows scientists to determinewhich genes are turned “on” or “off” inpancreatic cells, and it has aided the discovery of previously unidentified genesthat play a role in the development ofpancreatic islets, Magnuson says.
In vivo imagingThe secret life of the beta cell is
being revealed. Recent advances in lasermicroscopy have enabled scientists tostudy the “behavior” of beta cells in pan-creatic islets grown in the laboratory, andeven in animals.
At Vanderbilt, for example, David W.Piston, Ph.D., has helped pioneer the useof fluorescence imaging methods to tracethe sequence of events, beginning withthe entry of glucose into beta cells, thatultimately leads to insulin secretion.
A goal is to figure out why, in type 2diabetes, beta cells are unable to respondnormally to blood glucose, and whatmight be done to “fix” that problem. “It’s
hard to learn these things without lookingin the intact animal,” says Piston, professorof Molecular Physiology & Biophysics and Physics.
The techniques, which include two-photon excitation microscopy, also enablePiston to watch mouse islets grow a newblood supply when they are transplantedinto another part of the body. This infor-mation could lead to improvements inislet transplantation as a treatment fortype 1 diabetes.
“Islets are really a cellular transplantas opposed to an organ transplant. Theyhave to develop new blood vessels,”explains Dr. Alvin C. Powers, associateprofessor of Medicine and MolecularPhysiology & Biophysics at Vanderbilt,who is studying how new blood vesselsform in transplanted islets. “How do cellsthat are transplanted survive, and how canyou improve that process?”
Whole animal studiesMany studies of how glucose is
produced or used have been conducted indogs because their blood vessels are largeenough to allow detailed studies of glucose,insulin and all of the other factors thatplay a role in the disease.
At Vanderbilt, Masakazu Shiota,Ph.D., assistant professor of MolecularPhysiology & Biophysics, has miniaturizeda method for measuring insulin sensitivityin muscle so it can be applied to rats andmice. The technique enables researchers to
Fat cells, also called adipocytes, alsocan build up in the liver and pancreas,affecting their ability to function properly.In addition, recently discovered hormonesreleased by adipose tissue, including leptin,resistin and adiponectin, can influenceglucose metabolism in one way or another,some by opposing or complementing theeffects of insulin, others by signaling thebrain to suppress appetite. So can hormonesreleased the digestive tract, such as ghrelin,PYY and GLP-1.
“You cannot study the beta cell inisolation,” explains Christopher B.Newgard, Ph.D., director of the Sarah W.Stedman Nutrition and MetabolismCenter at Duke University. “There is aremarkable interplay and dovetailing ofthese regulatory circuits.”
How are scientists able to tease outthe elements of this complex network ofinteractions? Here are some of the ways:
Gene microarrays The recent sequencing of the human
genome and the genomes of other animalsis just the latest in a series of criticaladvances during the past quarter centurythat have enabled scientists to identifyspecific genes, map their location anddetermine what they do.
In just the past three or four years,researchers have figured out how to monitorthe expression of thousands of genes simul-taneously by spreading complementary bitsof genetic material across a glass slide, calleda microarray. Active genes will bind to thearray in a way that can be detected by fluo-rescence or other tagging techniques.
“We’re not after single genes anymore,”explains Leibel, head of the Division ofMolecular Genetics and co-director of the
This sequence of images, showing beta cellsin an isolated mouse islet becoming moremetabolically active in response to glucose,was created using two-photon excitationmicroscopy. The technique monitors the rise inthe autofluorescence of NADH, one of themolecular byproducts of metabolic reactions.The final image in the sequence shows anislet stained with antibodies that attach tothe beta cells (green) and the alpha cells (red).
Courtesy of David Piston, Ph.D.
The recent sequencing of the human genome and the genomes of other animalsis just the latest in a series of critical advances during the past quarter centurythat have enabled scientists to identify specific genes, map their location anddetermine what they do.
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measure how much radiolabeled glucose isabsorbed by muscle in response to a con-tinuous infusion of insulin.
These studies are helping researchersdetermine how glucose gets into the muscle cell, and what may be going onwhen tissues become resistant to insulin,says David H. Wasserman, Ph.D., directorof the federally funded Mouse MetabolicPhenotyping Center at Vanderbilt. Thecenter, one of four in the country, helpsdevelop new mouse models of diabetes tofurther research in the disease.
Animal studies also are sheddinglight on the complications of the metabolic syndrome. Two years ago, forexample, Drs. MacRae Linton and SergioFazio at Vanderbilt and their colleague,Dr. Gokan Hotamisligil at Harvard, foundthat they could protect mice from athero-sclerosis by eliminating a protein linkedto insulin resistance.
The adipocyte fatty-acid-binding protein(aP2) is produced by adipocytes (fat cells),which contribute to insulin resistance, and
also by macrophages, inflammatory cells thatplay a crucial role in atherosclerosis.
The researchers studied apoE-deficientmice, a widely used mouse model of highcholesterol and atherosclerosis. Mice thatlacked aP2 were dramatically protectedfrom atherosclerosis, even though theyremained insulin resistant, suggesting thatthe expression of aP2 by macrophages promotes atherosclerosis.
This finding was confirmed in the following way: apoE-deficient mice lackingexpression of aP2 only in macrophages weresimilarly protected from developing atherosclerosis. Earlier studies found thatobese mice lacking aP2 expression in adipose tissue showed increased insulin sensitivity.Thus, aP2, which links two major featuresof the metabolic syndrome, is a potentialdrug target for preventing both atheroscle-rosis and insulin resistance.
Viral vectors as Trojan HorsesOne of the new tools in the researchers’
armamentarium is the recombinant
adenovirus, a common respiratory virusthat has been genetically engineered sothat it is relatively harmless.
Earlier this year, researchers at Baylor College of Medicine in Houstonand Shiga University in Otsu, Japan,reported they had used this tool to completely reverse diabetes in mice thathad high blood glucose because of non-functioning beta cells.
The researchers inserted genes forbeta cell growth and transcription factorsinto the genetic material of the adenovirus.After injection into the bloodstream, theviral “vector” traveled to the liver. There,the imported genes, also called “transgenes,”expressed factors that seemed to stimulateformation of new, insulin-secreting betacells and reversed the hyperglycemia.
While more study of these “transgenic”mice is needed before the technique can beattempted in humans, this finding, reportedin the journal Nature Medicine, raises hopesfor a gene therapy that could reverse type1 diabetes in humans.
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Adenovirus vectors also have provenuseful in exploring the relationshipbetween obesity and insulin resistance.
For example, Newgard and his colleagues recently tested an adenovirus vector that contained the gene for malonyl-CoA decarboxylase, an enzyme that essentially can “melt fat” out of tissue.The vector was used to carry extra copiesof the gene into the livers of rats that hadbecome insulin resistant after being fed ahigh-fat diet.
The researchers found that when theenzyme was over-expressed and specificallymelted fat out of the liver, insulin sensitivityin the muscles improved.
“Somehow melting the fat out ofthe liver is a signal to restore insulinaction in the muscle,” Newgard says.“So there’s tissue networking going on(messages sent between organs and tissues)that we are only at the threshold ofunderstanding.”
Knock-out miceAnother important research tool
pioneered by Magnuson and his col-leagues at Vanderbilt involves the use of“tissue-specific knock-out” mice – animals in which a gene has been inactivated in a specific tissue like theliver or pancreas by an enzyme calledCre recombinase.
In 1999, for example, Magnuson, Dr. C. Ronald Kahn, president and director of the Joslin Diabetes Center inBoston, and their colleagues discoveredthat beta cells have their own functionalinsulin receptors. When these receptorsare “knocked out,” the beta cells don’tsecrete insulin normally in response to arise in blood glucose.
This finding suggests that insulin canregulate its own secretion and thatimpaired regulation may contribute toinadequate insulin secretion that is a hallmark of type 2 diabetes.
“There is nothing that is so precise,so accurate and so useful as that (Cre)enzyme,” Magnuson says. “It is like acruise missile for manipulating the mousegenome.”
“We are in a truly golden era of biomedical research,” adds Kahn. “The technologies and the insights we have intobasic biology and genetics and biochem-istry are so great and so powerful that wecan do almost any experiment that wethink about.
“What is limiting in many cases are both the monetary and the humanresources to do that … The number ofpeople training in pediatric diabetes and
endocrinology is very small consideringthe number of young people now who are developing not only type 1 diabetesbut also type 2 diabetes and obesity.”
Another pressing need is public education and other measures to stem therising tide of obesity and diabetes.
“The Human Genome Project willnot solve the obesity and diabetes epidemic,”asserts Dr. Frank Vinicor, director of dia-betes translation for the U.S. Centers forDisease Control and Prevention. “We’renot going to find a magic pill … We haveto start addressing primary prevention orwe’re going to be overwhelmed.”
“Ultimately to prevent obesity, diabetesand high blood pressure, we’re going tohave to get to the children,” adds DavidG. Schlundt, Ph.D., associate professor ofPsychology at Vanderbilt who is involvedin diabetes prevention efforts. “Onceyou’re 45 years old and weigh 300 poundsand have high blood pressure and diabetes,there’s only so much that can be done.” LENS
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David Piston, Ph.D., demonstrates two-photon excitation
microscopy, a technique he has pioneered to study the
sequence of intracellular events leading to insulin secretion,
and what may go wrong in diabetes. “We know so little,” he
says. “It’s going to take a long time and a lot of very insight-
ful experiments to really dissect this out.”
Beta cells are blue in this image of mousepancreatic islets that have been transplantedbeneath the capsule, or outer layer of thekidney. Endothelial cells that line blood vessels are shown in green. Some of themgrow into the islets from the underlying kidney. Other endothelial cells, found withinthe islets and transplanted with them, continue to grow and are shown in red.
Courtesy of Marcela Brissova and Alvin C.Powers, Vanderbilt Division of Endocrinology.
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Lens: What are some of the major priorities of the Institute?
Spiegel: Because of its enormous publichealth significance, diabetes is clearly oneof our major priorities. For example, we’reinvesting substantial resources in the BetaCell Biology Consortium (BCBC), becauseinsulin-secreting beta cells are at the heartof both types 1 and 2 diabetes. The BCBCis a recently formed group that typifies anewer approach to biology and medicalresearch. We still rely on the creativity ofindividual investigators, but to tacklesome of the large issues, it’s really vital tobring together a number of investigators.That’s exactly what we’re trying to do.The goal of the consortium, coupled withother efforts, is nothing less than to under-stand everything there is to know about
Dr. Allen M. Spiegel directs the National Institute of Diabetes andDigestive and Kidney Diseases, which supports and directs much ofthe nation’s research on diabetes.
Spiegel is an internationally recognized endocrinologist whose researchhas helped define the genetic basis of several endocrine diseases.
Recently he shared his thoughts about the importance of investingin basic research and the need for greater collaboration – among universities, the government, private industry and the general public –to address the challenges of diabetes.
Forging new partnerships
An interview with NIDDK director Allen Spiegel
by Bill Snyder
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the beta cell, every gene that is expressed.It is possible to do this now, at every stageof development; to identify stem cells inthe pancreas; to work with embryonicstem cells, according to the President’sguidelines; to determine what is necessaryto create a sufficient quantity of beta cellsand islets needed to replace beta cell function in animal models of diabetes andeventually in patients.
Within the funding levels provided,the NIDDK will continue to support a scientifically robust research portfolio thataddresses all the diseases within its mission.This portfolio includes fundamental labo-ratory research; “discovery” research thatbrings new insights from the laboratory intoclinical testing; clinical research of promisingtreatment and prevention strategies; andthe translation of important results fromclinical trials, not only in the scientific literature, but also through public outreach,information and education efforts.
Lens: What will be needed to achieve success? What are the barriers?
Spiegel: There is cultural change neededat the level of the university and academicmedical center in order to foster multi-disciplinary investigations. It is increasinglyimportant to bring in the mathematical andphysical sciences, computational biology.The sheer volume of data we are inundatedwith from advances in genomics and proteomics, for example, mandates thatbiology take on more of a ‘math’ kind of tone.
Equally important is the need to breakdown some barriers between universities,and allow investigators to come together sothey can apply their talents. The currentsystem of promotion tends to discouragethis. If you are part of a collaborativeeffort, it’s hard to identify the individualcontributions upon which, historically,decisions of tenure have been made.
Lens: How important is NIH funding indiabetes research?
Spiegel: Extremely important; relativestability in funding is particularly important.In the early 1990s, the funding of the NIHhit a real low. Under those circumstances,sadly, the success rate of applicants forresearch grants began to plummet. It had aripple effect, discouraging individuals fromgoing into science.
In the past three years, NIH-widefunding of diabetes research has increasedsubstantially, from $688 million in the2000-2001 fiscal year, to an estimated
$946 million in the coming fiscal year(2003-2004).
One of the powerful messages thatneeds to be disseminated is: You can’t gofrom feast to famine. Investment in medicalresearch is something that pays off, notonly in terms of improving quality of lifeand preventing mortality, but economically.The entire biotechnology industry wasbuilt on the fundamental investment ofNIH resources.
Lens: How important is it for universitiesand the government to collaborate withindustry? What are the barriers to successfulcollaboration?
Spiegel: This is a vital partnership. Aprime example is recombinant DNA technology, which largely came out ofcuriosity-driven research about restrictionenzymes. Through the private sector, itwas converted into an enormously successfulenterprise that is delivering new, innovativetreatments.
But this partnership with industry hasto be assiduously framed and monitored,not only to guarantee appropriateness andsafety in clinical trials, but also to ensurethe sharing of resources, data and researchfindings. In recent years, universities havepromulgated some very clear guidelinesregarding the need to publish and how toaddress real or perceived conflicts of interest,both as individuals and institutions.
Lens: What are some other challenges totranslating research findings into benefitsfor patients?
Spiegel: One translational block is in thedissemination of information. It’s wellestablished, for example, that certain drugscalled ACE inhibitors are unequivocallyeffective in halting the progression of diabetic kidney disease. Why aren’t weapplying this knowledge far and wide? We just launched the National KidneyDisease Education Program, which in itspilot phase is targeting four cities –Atlanta, Ga., Baltimore, Md., Cleveland,Ohio, and Jackson, Miss. – which have adisproportionately high level of end-stagekidney disease, mostly among AfricanAmericans. If we can get the informationout about the importance of measuringprotein in the urine and using ACEinhibitors where indicated, for example,we can really make an impact.
The use of information technologyalso can be very important. One reallyneeds to look at chronic diseases through a
different management model, one thatfocuses on flagging reminders, makingsure people are monitored. This increasescost in the short run, but it can make ahuge difference in the long run in terms ofreduced hospitalization.
Lens: What about prevention?
Spiegel: Preventing disease is a high priority, and much of our research isaimed at understanding how better to prevent chronic and costly diseases such asdiabetes. If we don’t do this, we’re reallyin for trouble simply because the healthcare system is not going to be able to sustain itself, faced with a diabetes epidemicand its attendant complications – amputa-tions, blindness, kidney failure and cardiovascular mortality.
Our Diabetes Prevention Program(DPP) showed clearly that type 2 diabetescan be prevented or at least delayed in themajority population as well as all ethnicand minority groups, including AfricanAmericans, Hispanic Americans, AmericanIndians and Asian American/PacificIslanders who are at highly disproportionaterisk. We are now building on the DPPresults to develop cost-effective ways toprevent type 2 diabetes in adults and inadolescents, who increasingly are developingthe disease.
With regard to obesity, we needresearch that will address ways to interferewith inappropriate cues and signals thatlead to overeating. Behavioral efforts havebeen successful. That is the powerful message of the DPP. We’re not talkingabout running a marathon here. We’re saying that, for a group of individuals wecan identify who are at particularly highrisk, a targeted effort aimed at earlylifestyle changes would be effective.
It becomes a matter of public policy,informed by serious research, that tells uswhether having soft drinks in vendingmachines and the absence of physical education in schools predisposes childrento obesity. We are launching a type 2 diabetes school-based prevention effortwith appropriate rigorous controls thatwill inform the public policy debate.
But the public needs to participate.The public must ask its leaders to act oninformed data. That’s the only way we canadvance. LENS
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Grabbing the golden ring
by Mary Beth Gardiner
Insulin, glucose meters and the control of an ancient disease
A century ago a diagnosis of diabetes was adeath knell. There was little a physiciancould offer in the way of help, other than
home remedies and desperation diets that only slowed theinexorable wasting of flesh to skin and bone. Opiumdulled the anguish.
The discovery of insulin in 1921 was as close to amedical miracle as humanity has seen. The Lazarus-likerecovery following injection of the pancreatic extract intoa child lying literally on its deathbed seemed surreal.Within weeks, hollow cheeks turned plump and pink,frail limbs supple and sturdy.
Initial exuberance was tempered, however, as itbecame clear that though insulin might pull a personfrom the brink of death, it was not a cure. And the treatment wasn’t perfect – the injections caused bruising and painful abscesses. Maintenance of the syringeswas elaborate and time-consuming. Monitoring of urineglucose levels was crude and cumbersome. And becausenutritional thinking of the day said that carbohydratescould not be tolerated, physicians exhorted patients todrink quarts of cream and eat thrice-boiled vegetables,saccharin-flavored agar, and up to 60 grams of meat aday to restore vitality.
Managing the disease left little time for enjoying life.Today, there is still no cure, but living with diabetes
isn’t nearly the struggle it once was. Thanks to the effortsof countless basic and clinical researchers over the pasthundred years, what we know about the disease – whatgoes awry in the body and how to prevent or control it –has expanded remarkably.
THE LONG LINE OF INCREMENTAL DISCOVERIES thatbrought us to our current understanding of diabetesextends back more than 3,000 years. The Ebers’ Papyrus,which dates from 1552 B.C. Egypt and is our oldest preserved medical document, noted the most prominentsymptom of the disease, frequent and voluminous urinationaccompanied by excessive thirst and emaciation. In thefirst century A.D., Aretaeus coined the name diabetes fromthe Greek word for “pipe-like,” and described the afflic-tion as a “melting down of flesh and limbs into urine.”
The association between sugar and diabetes was initially recognized in the sixth century by an Indianphysician, Susruta, who wrote of diabetes as the honeyurine disease. Gradually, the Latin word for sweet – “mellitus” – was added to distinguish the disease from
Pictured above: Dr. Frederick Banting (top) and Charles H. Best, co-discoverers of insulin.
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Diabetes insipidus, a pituitary disorder inwhich large volumes of sugar-free urine are passed.
In the seventeenth century, Englishphysician Thomas Willis added a urinetaste test to the criteria for diagnosing diabetes. It wasn’t unusual for physiciansto first suspect diabetes in men by notingthe presence of crystals on their shoes.With the beginnings of modern chemistryin 1775, the source of the sweetness wasidentified as sugar, and by 1815 it wasknown to be glucose.
During these years, the only therapeuticadvice was dietary. The nineteenth-centuryFrench physician Apollinaire Bouchardat,who required daily urine analysis of hispatients, recognized that fasting reducedglucose levels and prescribed a spare diet.Observing that exercise increased carbohy-drate tolerance, he admonished his patients,“You shall earn your bread by the sweat ofyour brow.”
Yet the real breakthrough in treatmentwas to come not from dietary prudence butfrom basic physiological studies of glucosemetabolism that began in the latter half ofthe nineteenth century.
In 1869 a German pathologist, PaulLangerhans, discovered the existence oftwo systems of cells in the pancreas: theacinar cells, secreting the pancreatic juiceinto the digestive system, and islets floatingbetween the acini, with some as yet unknownfunction. In 1889 Oscar Minkowski andJoseph Von Mering removed the pancreasfrom a dog and witnessed symptomsindistinguishable from diabetes.
The two German physiologists wenton to eliminate acinar cell secretion as theculprit when, after tying off the ducts thatfeed digestive juices from the pancreas tothe gut, diabetes did not develop. By theearly twentieth century, a direct link hadbeen made between diabetes and damageto the islet cells.
Failure piled upon failure as scientistsfrom around the world went in search ofthe “internal secretion” responsible for diabetes. The gold ring was finally grabbedby a Canadian surgeon and a medical studentin the summer of 1921. Dr. FrederickBanting and Charles H. Best, in collabora-tion with J.J.R. Macleod and J.B. Collip,successfully reversed diabetes in a depan-creatised dog by injecting a concoction ofpancreatic extracts, which the researcherslater named “insulin.”
The discovery was front-page newsaround the world. Appeals from families ofdiabetic patients poured in, and afterBanting and Best tested the extract on
themselves and found it safe, the firstinsulin injection in a diabetic patient wasgiven to 14-year-old Leonard Thompson inJanuary 1922. Thompson, who had beensurviving on the “starvation” diet, weighedless than 65 pounds and was near death.Insulin saved his life.
SINCE 1922, MUCH HAS BEEN DONE tobetter insulin therapy, both in terms ofimproved insulin preparations and ease ofuse. Purification of insulin reduced adversereaction at the injection site, and modificationof the insulin molecule has led to greatercontrol over the duration of its effects,which translates to fewer injections.
Initially, all insulin was isolated fromeither beef or pork pancreas tissue. Beforelong, demand for insulin was outgrowingthe supply of slaughterhouse pancreases. It was a great relief when, in 1979, recombinant DNA techniques made high-volume production of human insulin possible.The U.S. Food and Drug Administrationapproved the use of the new insulin –called Humulin – in 1982.
Meanwhile, the years between 1950and 1970 saw leaps in our understandingof glucose metabolism and insulin’s role init. Vanderbilt was one of the foremost placesin the world for metabolism research, duein large part to the efforts of Charles“Rollo” Park, a physician scientist whohelped define how insulin “carries” glucoseinto cells. Assuming the helm of a physiol-ogy department of only two scientists, heset out to build a program centered onmetabolism of sugars.
Park’s work and reputation attractedan impressive array of talent to Vanderbilt,including Nobel laureate Earl Sutherland,Jr. and diabetes clinician Oscar B. Crofford.
In the 1970s and 1980s, research discoveries and therapeutic innovationscame fast and furious. For diabetic patients,the horizon glimmered with hints of animproved ability to monitor and controlglucose levels. The means for measuringhemoglobin A1c, a way of monitoringlonger term glucose control, was developedin 1977, and the first insulin pump wasintroduced in 1979. In that same year, trialsfor the use of laser photocoagulation in thetreatment of diabetic retinopathy began. Inthe early ‘80s, other methods of insulindelivery were being explored – includingmicroencapsulated islet cells and nasalinsulin – and new, more powerful bloodglucose-lowering drugs entered the market.
By this time, a series of publicationsfrom a number of laboratories had suggestedthat tight control of blood glucose levels
could prevent or retard the onset of diabeticcomplications. As a result of these reports,in 1983 the government launched theDiabetes Control and Complications Trial.Widely considered the best-run clinicaltrial ever carried out, the DCCT showedunequivocally that rigorous control ofblood glucose reduces the risk and severityof long-term complications.
Improvements in insulin delivery andglucose monitoring were essential to conducting the DCCT, and by the timethe lessons from the study became publicin the early 1990s, diabetic patients hadgained the ability to measure blood glucoselevels at home, rather than having to go toa doctor. This newfound self-sufficiencyallowed the tighter control that the DCCTtouted, but patients soon found that free-dom came at a price: a greater risk ofhypoglycemic episodes. Innovations suchas non-invasive glucose meters andimplantable insulin pumps are helping toovercome the risk, however, making insulin-dependence an easier condition to bear.
And so the efforts continue. Yet withall that’s been discovered about diabetes,much remains to be learned. To achieve aworld without diabetes, whether throughprevention or by cure, is the ultimate goalof these many efforts. At this rate, perhapsa second miracle is not too much to hopefor. LENS
Pictured here: A 3-year-old boy before,and several weeks after becoming oneof the first patients to receive insulin in 1922.
Photos courtesy of Eli Lilly andCompany Archives
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Schools nationwide are packed withvending machines that provide schoolswith extra funding. These machines areoften stocked full of sugary sweets at theexpense of students’ health.
Michael Jacobson, executive directorof the Center for Science in the PublicInterest, a consumer advocacy group inWashington, D.C., recently told ABCNews “Our society should be doing everything possible to encourage kids toeat healthy diets, and what are we doing?We are bombarding them with junk foodadvertising. We are putting junk food wherever they go.”
Two years ago, researchers at Children’sHospital Boston and the Harvard School ofPublic Health reported that children who
drink a lot of sugar-sweetened beverages areat higher risk of becoming obese. Obesity,in turn, can lead to heart disease, highblood pressure and diabetes.
Soft drinks are not the only problem.Gary Tanksley, a health science educationteacher at Franklin High School in Franklin,Tenn., believes that vending machines –and the junk food they contain – should betaken out of schools. “They are detrimentalto students’ health and are contrary to the health lessons kids should be learning,”he says.
School officials respond that theydepend on vending machine revenue to supplement the budget they get from thecounty. “These vending machines bring afixed sum of about $50,000 to (Franklin
High) yearly,” says assistant principal ToddCampbell. “Without the vending machines,the school would lack needed funds.”
Other schools are reevaluating theirviews on vending machines.
Last year in nearby Nashville, thepublic school board voted to limit avail-ability of foods of “minimal nutritionalvalue” in vending machines. Los Angelespublic schools are phasing out the sale ofcarbonated drinks loaded with sugar, andpublic schools along the upper Mississippiin Iowa and Illinois recently installeddairy-only vending machines stocked withmilk, yogurt and cheese to encouragehealthier snacking habits.
Financial pressures can make it difficultfor schools – and states– to break the vending machine habit, however. Californiarecently passed a law that mandateshealthier snack foods in school vendingmachines, but it won’t take effect unlessadditional funds for free and reduced-price meals are appropriated by the end ofthis year.
At Franklin High, there are morethan 45 vending machines serving about1,650 students. The only low-sugaryoptions they offer are water and PowerAde.
The machines are supposed to beturned off during the lunch hours, but thatpolicy is often ignored. As a result, manystudents are diverted from healthier foodchoices in the cafeteria. “Our cafeteria hasa good variety of healthy items for students,”cafeteria manager Linda Jones says. “Vendingmachines hurt our business desperately.”
Franklin High’s athletic directorKathy Caudill, has a different view.“Athletes need to eat to maintain energy atthe end of the day,” she says. “With a bitof searching, (they) can find an appropriatesnack food in the vending machines.”
Athletes are often active enough to burnoff the calories from snack foods, but manynon-athletic students also indulge themselveswith the plethora of snack choices. Candy isbeing purchased from the machines everyperiod of the day, Tanksley says.
If vending machines are a necessaryevil to supplement funds not providedthrough “free public education,” theyshould at least be stocked with healthieroptions like power bars, bananas, orangejuice and milk. LENS
Vending machine sales – at the expense of student health?
BY BETH BARKER
Beth Barker is a senior at Franklin HighSchool in Franklin, Tenn.
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Lee E. Limbird, Ph.D., Pharmacology Associate Vice Chancellor for Research
Steven G. Gabbe, M.D., Obstetrics and GynecologyDean, School of Medicine
Joel G. Lee, B.A.,Associate Vice ChancellorMedical Center Communications
Randy D. Blakely, Ph.D., PharmacologyDirector, Center for Molecular Neuroscience
Peter Buerhaus, Ph.D., R.N.,Associate Dean for Research, School of Nursing
Richard Caprioli, Ph.D., Biochemistry, Chemistry, PharmacologyDirector, Mass Spectrometry Research Center
Ellen Wright Clayton, M.D., J.D.,Pediatrics, LawDirector, Center for Genetics and Health Policy
Ray N. DuBois Jr., M.D., Ph.D.,Gastroenterology, Cancer PreventionDirector, Digestive Disease Research Center
John H. Exton, M.D., Ph.D., Molecular Physiology and Biophysics,PharmacologyInvestigator, Howard Hughes Medical Institute
William N. Hance, B.A., J.D.,Director, Office of News and Public Affairs
Michael C. Kessen, B.A.,Director, Corporate and Foundation RelationsMedical Center Development
Mark A. Magnuson, M.D., Molecular Physiology and BiophysicsAssistant Vice Chancellor for Research
Lawrence J. Marnett, Ph.D., Biochemistry, Cancer ResearchDirector, Vanderbilt Institute of ChemicalBiology
John A. Oates, M.D., Medicine, Pharmacology
Alastair J.J. Wood, M.B., Ch.B.,PharmacologyAssistant Vice Chancellor for Research
diabetes 101
Of these risk factors, being overweighttops the list.
To find out if you are overweight, calculate your body mass index (BMI).
A healthy BMI for adults -- regardlessof age or sex -- is between 18.5 and24.9. Adults with a BMI of 25.0 to 29.9are considered overweight; those with aBMI of 30.0 or more are considered obese.
You can calculate your BMI using the following formula:
BMI = [(weight in pounds) ÷ (height ininches) ÷ (height in inches)] x 703.
Or you can use a Web-based calculatoror table to find your BMI (see www.cdc.gov/nccdphp/dnpa/bmi/bmi-adult.htm).
Waist size also provides a quickweight index -- a waist circumference ofmore than 40 inches for men and morethan 35 inches for women is consideredoverweight.
Do I have diabetes?The symptoms of both type 1 and
type 2 diabetes include increased thirstand urination, increased hunger, weightloss, extreme fatigue and blurred vision.A sudden onset of these symptoms isusual in type 1 diabetes. In type 2 diabetes, the symptoms may developgradually, or not at all. People with type 2 diabetes may notice that they sufferfrom frequent infections, or that woundsheal slowly.
Should I be tested for diabetes?Even if you do not have any of the
symptoms listed above, if you are age 45or older and have other risk factors, youshould be tested. You should considerbeing tested even if you have no risk factors other than age.
If you are younger than 45, are significantly overweight, and have another risk factor, you also should consider being tested.
Sources for more information:National Institute of Diabetes &Digestive & Kidney Diseaseswww.niddk.nih.gov/health/diabetes/diabetes.htmNational Diabetes Information Clearinghouse1 Information WayBethesda, MD 20892-3560Phone: 1-800-860-8747 Email: [email protected]
American Diabetes Associationwww.diabetes.org1701 North Beauregard StreetAlexandria, VA 22311Phone: 1-800-342-2383
Juvenile Diabetes Research Foundation Internationalwww.jdrf.org120 Wall Street, 19th FloorNew York, NY 10005Phone: 1-800-533-2873
Lens Editorial Board
❑ I am over 45 years of age.❑ I am overweight (see below).❑ I have a parent, brother, or sister with diabetes.❑ My family background is African American, American Indian, Asian American, Pacific Islander, Hispanic American/Latino.❑ I have had gestational diabetes, or I gave birth to at least one baby weighing more than 9 pounds.❑ My blood pressure is 140/90 or higher, or I have been told that I have high blood pressure.❑ My cholesterol levels are not normal. My HDL cholesterol (“good” cholesterol) is 35 or lower, or my triglyceride level is 250 or higher.❑ I am fairly inactive. I exercise fewer than three times a week.
Am I at risk for type 2 diabetes?To assess your risk for type 2 diabetes, check each items that apply to you. The more items checked, the higher your risk.
Lens Vanderbilt University Medical Center CCC-3312 Medical Center Nor thNashville, TN 37232
An array of electroencephalography (EEG) electrodes monitors brain activity in a study ofcommunication and language development inyoung children at Vanderbilt's Peabody College.
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Animal models"Transgenic" and "knock-out" mice are yieldingimportant insights into attention deficit/hyper-activity disorder (ADHD).
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