Maria Gordon Buse, MD: A FamilyAffair Through Six Decadesof Diabetes DiscoveryDiabetes Care 2016;39:852–856 | DOI: 10.2337/dc16-0391

Maria Gordon Buse, MD, is a product ofwartime Europe. She completed herprofessional education in four languageson three continents and continues anearly 60-year career as an investigator,educator, and practicing endocrinologist.This brief reprisal is written collabora-tively by her biological offspring and in-tellectual progeny, an appropriate reflectionof a career where family and work werejoyfully intertwined in an irresolvable way.

THE EARLY YEARS

Maria Gordon Buse was born MariaFelice Gordon in Budapest, Hungary. Hermother, Elizabeth Szana, was the “greatbeauty” of her social circle, and her fa-ther, Geza, was an earnest accountantwho tried his hand at several failedentrepreneurial activities before buyinga cafe on the Danube near the sym-phony hall. In that venture, Elizabeth’scharms and Geza’s practical businessacumen resulted in a successful enter-prise that was a gathering place for stu-dents, artists, and the middle class inBudapest. Maria was raised speakingGerman in the home and only learnedHungarian when she went to school.She mastered French as a third lan-guage in middle school. Maria lovedpoetry, literature, theater, art, music,walking in the woods during trips tothe nearby mountains, and ice skating.

She aspired to become a poet and a jour-nalist. She was 16 in 1943 when Germantroops occupied Budapest. Through theintercession of friends, Maria and hermother took refuge in a cloister, andher father, in a monastery. Her motherwas fearless about going out into thecity through bombings and gunfire,leveraging her many social connectionsto find food and supplies. Maria nevertakes for granted how lucky she and herfamily were to survive. As the Allies ap-proached to “liberate” Hungary, she re-calls laughing at the sky, seeing theshowering bombs as symbolic of theirimpending freedom and the justice thatthe Axis powers would face. She wel-comed her Russian liberators in thatspirit, only to discover that they wereas cruel as the Nazis. She was brieflyinterred in a labor camp. Her childhoodleft her with an absolute intolerance ofany hint of fascism or prejudice and adrive to take advantage of any opportu-nity for enjoyment of the simple plea-sures that she had been exposed to as achilddlearning, good food, beauty in allits forms, and nature. Maria says, “I reallywanted to be a writer. But my motherand everyone else explained to me thatI would never make a living. And I hadalways been interested in science andmedicine. I sort of thought it might befun to be a doctor.” Fascination and fun

with science has been the hallmark of hercareer.

At the war’s end in 1945, her parentsdivorced. When her mother remarried achildhood sweetheart, BartholomewRichter, she gained a stepbrother, Paul,who would become an oncologist inAtlanta.

Maria Gordon Buse, MD, in front of a rack ofLangendorff baths used to perfuse isolated beat-ing rat hearts circa 1972. These studies resultedin important findings about cardiac fuel me-tabolism and changes induced by epinephrine,glucagon, and nutritional states with continuingrelevance to diabetes treatments today (cour-tesy of the Waring Historical Library, MUSC,Charleston, SC).

1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI2School of Music, Florida International University, Miami, FL3Department of Medicine, Medical University of South Carolina, Charleston, SC4Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC

Corresponding author: Charles F. Burant, burantc@umich.edu.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered.

Charles F. Burant,1 Caroline R. Buse,2

Katherine A. Robinson,3 and John B. Buse4

852 Diabetes Care Volume 39, June 2016

PROFILESIN

PROGRESS

Maria started medical school at thePazmany Peter University School ofMedicine in Budapest. However, as itwas essentially destroyed, she left tocontinue her studies at the Universityof Basel from 1946 to 1948. As a for-eigner in Switzerland, she knew thatshe could not be licensed to practicemedicine there and immigrated to Ar-gentina with the assistance of an uncle.She had to learn Spanish adequately topass the exams required to enter theUniversity of Buenos Aires as an ad-vanced medical student without losingthe 2 years of credit she had completedin Europe. Her mother, stepfather, andPaul joined her shortly afterward. Shereceived her MD in 1952. After house-staff training in the Hospital Rivadavia,she was able to do research in Nobel Lau-reate in Physiology Bernardo Houssay’sinstitute with Drs. Houssay, EduardoBraun-Menendez, and Carlos Rapela.Her work on the seasonal variation incatecholamine production in the toadresulted in the faculty prize for best the-sis in 1956. When asked “Why toads?”she replied, “Toads are cheap. You could

catch them in the courtyards of his in-stitute.” Frugality and opportunism in re-search would become a recurring themein her career.

The prize allowed her to travel to Phil-adelphia to continue her studies withDr. Francis D.W. Lukens at the GeorgeS. Cox Medical Research Institute at theUniversity of Pennsylvania. Dr. Lukenssent a shy endocrine fellow from SouthCarolina named John Buse to pick her upat the airport. Thus began an almost50-year partnership in research, teach-ing, clinical medicine, and child-rearing.They published their first article to-gether on the action of sulfonylureasin animal models in Diabetes in 1957.They were married in August 1957 andborrowed a car and honeymooned onthe Blue Ridge Parkway on the drive toCharleston, SC, where they both joinedthe faculty of the then-named MedicalCollege of South Carolina, now calledtheMedical University of South Carolina(MUSC).

“Dr. Maria” and “Dr. John,” as theycame to be known, were the first trainedendocrinologists in the state. Maria wasappointed in the Departments of Medi-cine and Biochemistry. The coupleshared an office suite and laboratoryfocused on metabolism research andworked in the same clinic and hospitalwards. InMaria’s first fewmonths at thenew job, the hospital recognized theneed to establish a unit to explore andharness the diagnostic and therapeuticpower of radioisotopes in medicine.Given that Maria had completed a1-week course on the subject at WoodsHole while a fellow, she was asked toestablish the Nuclear Medicine Labora-tory. She led the unit from an endocrine-oriented hospital service to a full sectionof Nuclear Medicine in the Departmentof Radiology and participated in its prac-tice for nearly 50 years.

Their first child, John, future Presi-dent, Medicine & Science of the Ameri-can Diabetes Association, was born in1958. After the Hungarian Revolution,Maria’s father Geza immigrated toCharleston, became a successful printframer and art dealer, settled into anearby apartment, and shared dinnerwith the family every day until he diedin 1976. Maria settled into a life balanc-ing family life, raising three children,medicine, and science. She read to thechildren or helped with homework every

night, returning to the dining room tableto her slide rule and piles of data andjournal reprints to write manuscriptsand grants. Having been raised in a land-locked country, she loved the ocean andspent almost every weekend and amonth in the summer with her familyat the Isle of Palms, where John boughther a small beach front cottage whilethey were still renting an apartment intown.

THE 1960S

In the early years in Charleston, Mariaand John shared equally in the clinicaland laboratory duties. Their initial re-search involved organ culture explor-ing the effects of denervation onglucose uptake and insulin action inmuscle. Together, with John as principalinvestigator, they wrote a grant applica-tion to the National Institutes of Health(NIH) entitled “Factors that modify insu-lin action.” On first review they were un-successful, with the critique includingthe stinging rebuke that they wrote “asif paid by the word instead of by thethought.” On resubmission in 1960,they received the first NIH grant awardedto the state of South Carolina, which con-tinued through 10 competitive renewalsthrough 2014. She rather humbly sug-gested that having one of the longestcontinuous grants at the NIH was dueto coming up with a grant name thatcould accommodate the evolving focusof the grant.

For Maria and John, the constant mix-ture of marriage, scientific and medicalpartnership, child-rearing, training, andresearch mentorship blurred the dis-tinctions between family and work.Maria did not drive and always thoughtthat taxicabs were an extravagance. So,they bought a house just two blocksfrom the medical school in 1962, wherefor over 50 years there was an endlessstream of trainees and colleagues thatwere an accepted part of the family evenamong the three children (John Buse,MD, PhD; Paul Buse, MD; and ElizabethBuse King, MBA).

In 1960, based in part on Maria’sHungarian accent as an impediment topatient care and John’s lesser interest inwriting manuscripts and grants, they be-gan to differentiate. Maria took moreof the lead in the laboratory aspects oftheir collaboration, while John contin-ued work as one of the most respected

Top: Maria Gordon Buse, MD, and John F. Buse Jr.,MD,circa1970,standinginfrontoftheBeckmanmodel121 amino acid analyzer that was almost like theirfourth child, only more expensive, fussy, and ill-behaved. Bottom: Maria Gordon Buse, MD, circa2003 (both courtesy of theWaringHistorical Library,MUSC, Charleston, SC).

care.diabetesjournals.org Burant and Associates 853

clinicians in the medical school. Thispartnership was a boon to the multipleclinician-scientists who worked withMaria. All of them can remember sit-ting in the laboratory when John woulddrop by and suggest that they put on awhite coat (mostly to cover the ratherinformal laboratory attire) and accom-pany John to thewards, whichwere justdown the hall from the laboratory.There, John would demonstrate someinteresting physical finding in his inim-itable manner, such as xanthomatouseruptions from “the greasy blood.” Thismanner delighted the patients, whowere quickly put at ease, and allowed

the students to learn. Indeed, in an erabefore institutional review boards, manytimes Maria would instruct that bloodbe obtained from interesting patients todo additional studies.

Maria transferred her experiencefrom using isotopes in radioimmuno-assays, clinical thyroid imaging, andtreatment to their use in translationalstudies, becoming the first person touse radioisotopes at MUSC in research.In a landmark article published in theJournal of Clinical Investigation in 1962(1), she administered 131I-insulin towomen (after first treating with potas-sium iodine) prior to birth and deter-mined that little, if any, insulin crossedthe placenta. This showed that any in-crease in size of the fetus in a motherwith diabetes was due to increased pro-duction of insulin by the fetus and notdue to transplacental insulin transfer.When talking about this study, she wouldpoint out that this was her first use ofa computer in her studies. Accessedthrough The Military College of SouthCarolina (The Citadel), she used a Donneranalog computer for curve fitting the ob-served degradation of insulin. It was likelythe first “portable” computer used atMUSC.

In addition to her work with radioiso-topes, Maria began studies that wouldoccupya significant portionofher research

career, the effect of insulin and branched-chain amino acids (BCAAs) on skeletalmuscle metabolism (2,3). Although itwas known that exercise could have aprofound effect on insulin sensitivity,the effect of immobility on insulin actionhad not been studied until 1959, whenMaria, working with John in some of theirfirst studies in South Carolina, began aseries of experiments that showed thatdenervation of diaphragms or hind limbsof rats resulted in a rapid and markeddecrease in insulin responsiveness toglucose uptake and to amino acid uptakeand protein synthesis.

The initial report (2), published in 1959,was one of the first ever to assess insulinbinding to whole-tissue mammalian tis-sue. Using 131I-insulin, Maria showedthat there was no significant differencein insulin binding between innervatedand denervated hemidiaphragms whenassessed both in vitro and in vivo, dem-onstrating the first “postreceptor” defectin insulin action, a topic that she wouldcontinue to investigate throughout hercareer. These were heroic experimentsperformed in the laboratory by injectingup to 10 mCi of 131I-insulin intravenouslyinto rats, their cages shielded by leadbricks. These rather crude studies havestood the test of time and have been con-firmed by multiple researchers usingmore sophisticated techniques. The initial

MariaGordonBuse,MD, and a portion of her extended family of colleagues, trainees, and progeny in AngkorWat, Cambodia, July 2007. Left to right: AnnePeters, Mark Harmel, Maggie Burant, Charles Burant, Maria Gordon Buse, Linda Cann, Richard Kahn, Stephanie Kahn, and John Buse (courtesy of MarkHarmel).

Maria Gordon Buse, MD, circa 2012, engaged inconversation on the porch of her beach house(courtesy of Katherine Buse).

854 Profiles in Progress Diabetes Care Volume 39, June 2016

studies investigating the effects of dener-vation were done in hemidiaphragmsfollowing phrenectomy. Over the years,hundreds of phrenectomies and dia-phragm isolations were performed inthe laboratory and nearly every proce-dure was done personally by Maria. Shewas, and continues to be, proud of hersurgical skills and insisted that she wasthe only one skilled enough to performphrenectomy and diaphragm isolationproperly, thoughmore than one graduatestudent and postdoc suspected that shesimply wanted to continue to participatein the “hands-on” portion of the studiesand, importantly, participate in the cama-raderie that was part of the enjoyment ofworking in the Buse laboratory.

THE 1970S

In studying the effect of insulin in skel-etal muscle, Maria’s studies found thatfatty acids had a unique effect to in-crease the oxidation of BCAA in muscleand heart with a pronounced effect onleucine oxidation as opposed to valineand isoleucine. The observation thatconditions that are associated with in-creased levels of fatty acids, such as un-controlled diabetes or insulin resistance,were associated with increased catabo-lism of BCAA and muscle wasting led toanother seminal article in the Journal ofClinical Investigation (4) that demon-strated that leucine, but no other aminoacid, stimulated the uptake and incorpo-ration of 14C-lysine into hemidiaphragmproteins. This effect was modulated min-imally by insulin but could be affected byfatty acids, diabetes status, and denerva-tion of muscle. In addition to stimulatingprotein translation initiation, blockingtranscription or translation also showedthat leucine had the ability to simulta-neously reduce protein breakdown. Overthe past three decades, it has becomeclear that much of the effect of leucineto alter metabolism is via the activationof the enzyme mammalian target of rapa-mycin (mTOR), an enzyme complex thatis a primary sensor of nutrient status, a pri-mary mediator in the regulation of skeletalmuscle protein dynamics (5).

THE 1980S AND 1990S

During this time, studies in the labora-tory centered on the continued explora-tion of insulin action in denervatedskeletal muscle as well as definingBCAA metabolism. Some of the first

studies ever to examine the activationof the insulin receptor kinase in intactanimals (6) showed that the rapid de-cline in insulin-stimulated glucose up-take was not due to alterations in theautophosphorylation or the kinase ac-tivity of the insulin receptor, but definedthe signaling disruption as a postrecep-tor defect, subsequently found to be dueto impaired insulin receptor substrate-1–mediated increase in phosphoinositide3-kinase activation (7). The regulation ofBCAAmetabolism continued to be stud-ied with detailed examination of therate-limiting step in BCAA metabolism,the multisubunit ketoacid dehydroge-nase complex, which shares severalsubunits with the pyruvate dehydroge-nase enzyme. Detailed studies showedregulation in the muscle, liver, andother tissues by fasting/refeeding,high-fat diets, insulinopenic diabetes,glucocorticoids, and endotoxins, amongothers. The data showed an intimaterelationship between BCAAmetabolismand the control of protein synthesis anddegradation in tissues under pathologi-cal states. These studies helped clarifythe beneficial effects of both BCAA andtheir ketoacids in disease states (8).

In the 1990s, Maria’s research inter-ests also evolved to investigationsaround the way in which glucose, aminoacids, and other nutrients modified in-sulin signaling, including posttransla-tional modification of insulin receptorsand their downstream targets and alter-ation in glucose transporter functionglucosamines (9,10). These studiesshowed that modification of serine res-idues by glucosamine could have a sig-nificant effect on the signaling in cellsand tissues.

THE 21ST CENTURY

The focus of the Buse laboratory in-creasingly focused on the regulation ofinsulin receptor signaling and the poten-tial for posttranslational changes in sig-naling molecules in insulin-resistantstates. Maria identified a novel muscle-specific variant of the glutamine:fructose-6-phosphate amidotransferase-1 (GFAT-1),the rate-limiting enzyme of the hexos-amine synthesis pathway, which altersenzymatic activity and may predisposemuscle to insulin resistance inhigh-glucoseconditions (11). She described the sitesof O-linked b-N-acetylglucosamine mod-ification in a number of proteins and

showed that these modifications al-tered their function, likely part of thebroad array of changes in the insulin-resistant, diabetic state that is part ofthe alteration in insulin signaling (12).Thus, she continued a line of researchthat stretches back to before the vastmajority of her trainees were born.

Clinically, her career came full circle.After retiring from radiology, based onher vast experience as a “dot spotter”(John’s characterization of her work innuclear medicine), she returned to theendocrine division to precept fellowsand students. When her funding fromthe NIH ran out in January 2014, herfamily encouraged her to use funds ather disposal to continue with her pas-sion for research and teaching. Sherefused, insulted at the suggestion, re-lating that if her ideas were not goodenough for the NIH, it was time to callit quits. Her last article (13), with firstauthor Katherine (Katy) Robinson (whoworked with Maria for over 28 years),described the activity of Go-6976, an in-hibitor of “conventional” protein kinaseC (PKC) isoforms PKCa and PKCb, andthe mTOR inhibitor rapamycin to allevi-ate insulin resistance induced in 3T3-L1adipocytes by incubation in high-glucosemedia. They found that Go-6976 did in-duce a partial alleviation of insulin re-sistance, but it likely was workingthrough alterations in mTOR signaling,not PKC-mediated pathways. It seemsfitting that after 50 years of studyingBCAA effects, the molecular entity thatmediates the effect of BCAAs wouldbe the focus of Maria’s latest contribu-tion to the literature. There may be stillone more future article based on thecontinuing efforts of her last fellow,Dr. Lauren Ball, who continues the workin Charleston.

SUMMARY

In a career that spanned nearly 60 years,Maria believed that being able to do sci-ence and to share in the lives of traineeswas a sacred gift. At the same time, shewas selfless in her devotion to the tasksof an academic clinician and selfish inthat she was doing what she loved. Herpioneering efforts in South Carolina asan investigator, clinician, and facultymember were recognized by numerousawards from the state and her institution.Hermost prized recognitionwas receivingthe American Diabetes Association’s

care.diabetesjournals.org Burant and Associates 855

Albert Renold Award in 2003 because itcarried the name of a respected friendand colleague and because it recognizedher for her accomplishment as a mentor,which she saw as the highest possiblecalling in academia.The freedom that Maria allowed the

trainees in the laboratory encouragedrisk-taking, provided it was based onsome reasonable hypothesisdthe “idiotexperiments.” Maria says, “Only an idiotwould try it, but sometimes idiots aregeniuses in disguise.”Maria was a fixturein the laboratory, almost never pushingfor studies to be completed, but ratherdiscussing, critiquing, and encouragingdiscovery. She instilled an infectious de-sire to find out the answer. As often hap-pened, the first results of an experimentwould be obtained and a grand theorywould be based on the initial results. Asoften as not, the theory would be de-stroyed by the subsequent findings, butthe thought experiments were consid-ered valuable by the trainees as a wayto think about the project, the techniques,and the holes in the theory. Few mindedthese sometimes rambling, but always en-tertaining, discussions as they always knewmore at the end than when they started,mostly because Maria had an amazingmastery of the literature. She got this byreading voraciously and encouraged train-ees to do the same, often arranging for acouple hours of library time (before theadvent of the Internet). She instilled asense of inquiry for not only science butalso politics, cultures, and personal rela-tionships. Likely because she had fearlesslytraveled all her life to virtually every cornerof the globe, Maria encouraged and sup-ported her trainees to travel abroad formeetings for the science and perhapsmore for the cultural exposure that it pro-vided. She traveled abroad almost everyyear, usually on the pretext of a meetingbut extending the trip for a week or more.

The Buse laboratory was always the“place to be,” with the numerous medicalstudents, graduate students, postdocs, andMD/PhD students, the latter of whichseemed in particular to gravitate toMaria’slaboratory. Maria was instrumental in thecreation of the Medical Scientist TrainingProgram at MUSC, and she had a hand intraining about half of the first groups ofstudents in the nascent program.

The people in her laboratory learnedto work hard and to play hard. They en-joyed the famous fruit daiquiris on Fri-day afternoons in the conference room,and the party often migrated to Mariaand John’s home (two blocks away) for acookout and “a touch of the red,” thelatter a wonderful wine that lubricatedlively discussions of science, politics,travel, inevitable reminiscences, andeven an occasional robust recital byMaria of the Hungarian national anthem.The care and nurturing both in and out-side of the laboratory gave rise to thefeeling that one was truly part of a fam-ily, with John and Maria at the head ofthe table. This tradition continued afterher beloved John died in 2001. She trav-els very little these days, but enjoys read-ing, movies, and visits with family orcolleagues, technicians, or trainees whocome by to take her for dinner or amovie.Even after a long, successful, and enjoy-able career, Maria continues to be asourceof friendship, comfort, andwisdomto her biological and adopted family.

Acknowledgments. C.F.B. and K.A.R. are twoof amongdozensof “SOBs” (Sonsor SistersofBuse),the designation provided byMaria for themost de-serving of her professional progeny. C.R.B. is one ofher nine grandchildren and J.B.B. is her son. They allare heavily conflicted by their love forMaria. Specialthanks to E. Brooke Fox (University Archivist, theWaring Historical Library, MUSC, Charleston, SC);Mark Harmel, MPH, CDE (University of SouthernCalifornia and Harmel Health and Communications

Consulting, Los Angeles, CA); Katherine Buse, MA,MPhil (University of California, Davis, Davis, CA); andLyn Reynolds (American Diabetes Association Edito-rial Office) for help in editing the manuscript.

References1. Buse MG, Roberts WJ, Buse J. The role of thehuman placenta in the transfer and metabolismof insulin. J Clin Invest 1962;41:29–412. BuseMG,Buse J. Glucose uptake and responseto insulin of the isolated rat diaphragm: the effectof denervation. Diabetes 1959;8:218–2253. BuseMG,Buse J. The effect of denervation andinsulin on the penetration of D-xylose into rathemidiaphragms. Diabetes 1961;10:134–1414. Buse MG, Reid SS. Leucine. A possible regu-lator of protein turnover in muscle. J Clin Invest1975;56:1250–12615. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B,Sandri M. Mechanisms regulating skeletal musclegrowth and atrophy. FEBS J 2013;280:4294–43146. Burant CF, Treutelaar MK, Landreth GE, BuseMG.Phosphorylationof insulin receptors solubilizedfromrat skeletalmuscle.Diabetes 1984;33:704–7087. Hirose M, Kaneki M, Sugita H, Yasuhara S,Ibebunjo C, Martyn JA. Long-term denervationimpairs insulin receptor substrate-1-mediatedinsulin signaling in skeletal muscle [publishedcorrection appears in Metabolism 2001;50:619]. Metabolism 2001;50:216–2228. Sharples AP, Hughes DC, Deane CS, Saini A,Selman C, Stewart CE. Longevity and skeletalmuscle mass: the role of IGF signalling, the sir-tuins, dietary restriction and protein intake. Ag-ing Cell 2015;14:511–5239. Nelson BA, Robinson KA, Buse MG. High glu-cose and glucosamine induce insulin resistancevia different mechanisms in 3T3-L1 adipocytes.Diabetes 2000;49:981–99110. Buse MG, Robinson KA, Marshall BA,Hresko RC, Mueckler MM. Enhanced O-GlcNAcprotein modification is associated with insulin re-sistance in GLUT1-overexpressing muscles. Am JPhysiol Endocrinol Metab 2002;283:E241–E25011. DeHaven JE, Robinson KA, Nelson BA, BuseMG. A novel variant of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) mRNAis selectively expressed in striated muscle. Di-abetes 2001;50:2419–242412. Buse MG. Hexosamines, insulin resistance,and the complications of diabetes: current status.Am J Physiol Endocrinol Metab 2006;290:E1–E813. Robinson KA, Hegyi K, Hannun YA, Buse MG,Sethi JK. Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKCinhibition in adipocytes. PLoS One 2014;9:e108963

856 Profiles in Progress Diabetes Care Volume 39, June 2016