Guenther Boden, MD (1935–2015):A Pioneer in Human Studies ofNutrition and ObesitydAnd theMystery of Insulin Resistance forHandling GlucoseDiabetes Care 2020;43:2910–2915 | https://doi.org/10.2337/dci20-0041

Professor Guenther Boden, MD, wasdrawn to the field of diabetes researchthrough an unconventional route, but inthat journey he brought a perpetuallyfresh set of eyes to help unravel therelationships between nutrition, obesity,and defects in insulin action.

Early Life

Guenther Boden was born on 8 January1935 toDr.AlwinBoden, an internistwhopracticed from a home office, and IrmaBoden (nee Godelmann), a homemakerwho had trained as a medical technol-ogist. During his early years, the familylived in Ludwigshafen am Rhein, an in-dustrial city in southwestern Germany.The place and time would leave Guentherwith vividmemories of a childhood spentduring, and immediately after, WorldWar II.Guenther oncewrote that when Allied

bombing of key industrial sites in Lud-wigshafen began, the bombs were, froman 8-year-old child’s perspective, “morea matter of excitement than threat forme[,] and together with my friends,we would rush out of the cellar afterthe air raids to look for bomb shards,which we boys considered a valuablecollection item. This lost much of itsattraction as the air raids became morefrequent. . . .”When his father was draftedas a medical officer in the Luftwaffe

(Air Force), Guenther’s mother tookhim and his two sisters to the rela-tive safety of her parents’ home inHeidelberg.

Early life promoted an independentspirit, a healthy skepticism of authority,and remarkable resourcefulness. Roughlessons came at a personal level, fromthe “sadist” who taught his 3rd and 4thgrade classesdusing frequent corporalpunishmentdand fromGuenther’s child-hood experiences of hungerdtoday calledfood insecurity. Hard lessons also camefrom learning of the genocidal war crim-inals in the Nazi government who hadruled his birth country.

Guenther often told the story of anepisode during World War II when hispaternal grandfather, Dr. Alois Boden,also a physician, took his young grandsonon a house call to see a patient on anearby farm. At that time, food wasrationed, and if you got caughtwith extrafood, you were in serious trouble. Thefarmers often paid the doctor with foodrather than money. That particular time,his grandfather was paid with half of anold sheepormutton.On thewayhome, itwas already dark. Opa (Grandpa) Alois,was trying to keep a low profile with hisillegal treasure in the trunk. He drove hisold car with the lights turned off along thewinding country road toward home. Buttherewas amechanical problemwith the

carhorn.Every timetheymadearight turn,

the horn honked. Both were sweating

A delighted Guenther Boden in ski gear, ElkMountain, PA, 1980

1Department of Physiology and Department of Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA2Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden3Harvard Medical School and Joslin Diabetes Center, Boston, MA4Division of Endocrine and Metabolic Disorders and Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA

Corresponding authors: Kevin Jon Williams, kjwilliams@temple.edu, and Elias S. Siraj, sirajes@evms.edu

© 2020 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. More information is available at https://www.diabetesjournals.org/content/license.

Kevin Jon Williams,1,2 Edward S. Horton,3

and Elias S. Siraj4

2910 Diabetes Care Volume 43, December 2020

PROFILESIN

PROGRESS

blood and tears during that journey.

They eventually made it home safely

without being caught, and, for over a

year, this mutton was served for meals.

This is why Guenther never ate lamb

afterward, even though lamb never tasted

like mutton. Perhaps he just did not want

to be reminded of those sad and horrible

times.Looking back, Guenther felt fortunate

under the circumstances that Heidelbergwas occupied by the Americans, not bythe Soviets, and so Guenther began totake English lessons. Years later, hewrote,“Myfirstwordswere: ‘Giveme chocolate,please!’ I practiced my English with GIs[Americansoldiers] . . . . Ioccasionally stolecigarettes and oranges from them.Cigarettes in particular were the onlycurrency. . . . I was 10 years [old] atthat time.”In Kaiserslautern, near Ludwigsha-

fen, Guenther attended high schooldGymnasium in Germandwhich broughtformal instruction and an emphasis onscience,meaning biology, chemistry, andphysics. Guenther was also on the trackand field team and remained athletic hisentire life, skiing into his late 70s. In theGerman system, medical school beginswith preclinical studies right after highschool. Guenther attended the Heidel-bergUniversity School ofMedicine forhismaster’s degree and then the MunichUniversity School of Medicine for hisMD. Years later, Guenther remembered,

“Because Germany had eliminated thedeath penalty, there was a shortage ofcadavers and we had to autopsy a deerto learn anatomy,” (K.J.W., personalcommunication).

Early Career in Medicine andResearch

After final exams in medical school,Guenther trained in a series of differentspecialties: 4 months as a surgical assis-tant (passing out once from an ether leakduring anesthesia of a patient), 6monthsin internal medicine, 4 months of obstet-rics and gynecology, and then, in 1961,6 months of inpatient psychiatry in Ber-lin. Guenther wrote that he had “wit-nessed the building of the [Berlin] Wall,right in front of my room . . . . As a westGerman, I could pass through the Walland did visit . . . . After dinner one night[in the eastern sector], I crashed my 2CV[‘deux chevaux,’ a popular small, inex-pensive Citroen automobile] into theWall from the east. The police let mego. [It was noted] in the west newspaperas another unsuccessful effort to flee.”

At that time, Guenther’s wish wasa career in psychiatry/neurology, andhe landed a position in Munich. Un-expectedly, “this became so boring thatI quit after 2 months. To finish my 24months of mandatory [medical intern-ship time], I found a job at theHautklinik(Dermatology and Venereology) inStuttgart.”

In 1963, an opportunity opened up bychance at the Biochemistry Institute ofTubingen, Germany, owing to the de-parture of one of their young research-ers. Guenther obtained his first positionto study metabolism, specifically, theeffects of insulin. He would remain withthe topic for the rest of his life.

Before Yalow and Berson’s radioim-munoassay (1,2), the only way to assayinsulin concentrations was by bioassay,using the responses of rat diaphragmsand epididymal fat ex vivo. A prominentprofessor at the Biochemistry Institutehad developed a tripeptide that seemedto be equally as effective as insulin. Thistripeptide looked like a possible answerto concerns that clinical demands for in-jectable insulinwould outstrip the supplyfrom pigs and cattle. Diligent from thestart, Guenther Boden could not repro-duce the resultsdand later discoveredthat a technician had added bicarbonateto the buffer to help dissolve the tripeptide.

“The entire insulin-like effect of [thetripeptide] was due to the bicarbonate.(H. Krebs had described this bicarbonateeffect in the 1920s),” Guenther laterwrote.

Early Career in the U.S.

In 1965, Guenther was recruited fromTubingen to the Joslin Research Labora-tory in Boston, Massachusetts. His wifeIrene (nee Dingeldein) recalls Guenthertelling her later that he had applied toseveral research institutions in the U.S.Guenther sent a letter directly to Dr.George Cahill, a pioneer in diabetesresearch and then the research directorof Joslin, even offering to work for free.His letter to Cahill and the favorableresponse he received are still in thepossession of the Boden family.

Among Guenther’s early work there,he and his coauthors published the firstreport of the glucose suppression test forthe diagnosis of acromegaly, using whatwas then state-of-the-art technology ofa new radioimmunoassay for humangrowth hormone (3).

Guenther then had to move to Ro-chester, New York, to complete his clin-ical training, from 1967 to 1970, as amedical resident at Rochester GeneralHospital. While in Rochester, Guenthermet his wife, Irene. Irene recalls, “I, atthat time, lived with relatives in Roches-ter andworked in the biochemistry lab atthe hospital.WhenGertrud [his long-timelab technician] left, she [Gertrud] suggested

Guenther Boden in 1965, the year he came to theU.S.

Young Guenther Boden with mother Irma andtwo sisters, Marianne and Ilse, in Durkheim,Germany, 1950

care.diabetesjournals.org Williams, Horton, and Siraj 2911

to Guenther to ask that ‘German girl’ inthe biochemistry lab, if she wanted towork for him. So he did, I worked forhim and eventually after three years wemarried.”In 1970, after completing his clinical

training in the U.S., he accepted a posi-tion at Temple University in Philadelphia,Pennsylvania, where he remained for therest of his career. At Temple, Boden com-bined his three professional passionsdnamely, the clinical care of patients withdiabetes, research into the causes ofdiabetes, and teaching generationsof physicians and scientists. The majorfocus of his research was why overeatingand obesity cause insulin to lose itsability to control the level of glucosein the bloodstream. It is a huge medicalproblem, and Guenthermademajor con-tributions to our understanding of thisproblem.

He became Director of the DiabetesOutpatient Clinic at Temple (1975), thenChief of the Section of Diabetes (1978–1987), Chief of the newlymerged Sectionof Endocrinology, Diabetes and Metab-olism(1987–2009), andProgramDirectorof the General Clinical Research Center(1989–2003). He also became a proudAmerican citizen.

During his long tenure at Temple,Guenther worked with a team of en-docrinologists and diabetologists con-sisting of Drs. Charles Schumann, BertramChanick, Alan Marks, and Victor Adlin, apartnership that lasted for more than35years,whichwasanunusually success-ful and durable collaboration for such alarge group. Itwas also during this era, in1973, when Guenther met one of au-thors of this article (E.S.H.) at a diabetesconference in Snowmass, Colorado.They shared common interest not only

in diabetes research but also skiing.This started a long-standing friendship,both professionally and between theirfamilies.

Guenther had come to Temple Uni-versity in large part out of respect for twogreats: Dr. Oliver Owen, a distinguisheddiabetes researcherwhoat that timewasthe Director of the General Clinical Re-search Center at Temple, and Dr. SolSherry, the great thrombosis researcherwho at that time was Chairman of theDepartment of Medicine at Temple andwhose work led to the developmentof thrombolytics. Guenther collaboratedwith Dr. Owen in his research, includingtheir description of the effect of glucagonin healthy human volunteers to alteramino acid metabolism through “in-creasing their inward transport, theirdegradation, and their conversion intoglucose” (4). From a collaboration with

The TempleUniversity Section of Endocrinology, Diabetes andMetabolism, 2013. Left to right, front row: Dr. Elias S. Siraj, Dr. Kevin JonWilliams (succeededDr.Bodenas SectionChief), Dr. VictorAdlin, andDr.GuentherBoden; second row:Dr. AjayRao,Dr. CherieVaz,Dr.VijayBalakrishnan (clinical fellow),Dr.DanRubin; third row: Dr. David Ni, Dr. Tatiana Gandrabura (clinical fellow), Dr. Pankaj Sharda (clinical fellow), nurse practitioner Victoria (Tori) Maffey (notpictured: Dr. Carol Homko)

2912 Profiles in Progress Diabetes Care Volume 43, December 2020

Dr. Alan J. Garber, who was training atTemple University at that time, cameanother seminal article from that era,in which they directly measured the in-crease in hepatic ketogenesis and gluco-neogenesis in humans undergoing a3-day fast (5).

Key Studies in Human Volunteers:Coagulation in T2DM, Fatty Acids,and Satiating Power Per Calorie

Guenther also successfully collaboratedacrossdisciplinesat Temple.Ofparticular

note are his more than 10 years ofNational Institutes of Health–supportedwork with Dr. A. Koneti Rao, a prominentresearcher in thrombosis. Together, theirlaboratories focused on the effects ofhyperglycemia and hyperinsulinemia, inhealthy subjects and in subjects withdiabetes, on prothrombotic and immu-nostimulatory mechanisms, particularlythe tissue factor pathway of coagula-tion. One of their important findingsis their description of activation ofblood coagulation mechanisms and pla-telets by combined hyperglycemia-hyperinsulinemia even in healthy humansubjects without diabetes (6). The workprovides a mechanistic basis for the well-known hypercoagulable state in type 2diabetes.

During this time, Guenther’s labora-tory made several additional seminalobservations. Perhaps the most influen-tial finding from the Boden laboratorywas when they became the first todemonstrate that elevated plasma lev-els of nonesterified fatty acids (NEFAs,also known as free fatty acids) produceperipheral resistance to the glucose-lowering actions of insulin (7–9). More-over, the Boden laboratory found thatlowering of chronically elevated plasmaNEFAs in obese patients with eitherimpaired glucose tolerance or frank di-abetes was able to substantially, thoughonly partially, improve sensitivity to theglucose-lowering actions of insulin (10).These results have since been widely

confirmed and suggested that elevatedcirculating NEFAs may account for up to50% of insulin resistance for handlingglucose in obese patients with impairedglucose tolerance or type 2 diabetes. Anadditional contributor to impaired insu-lin action that they found in humans isthe ability of hyperinsulinemia to in-duce endoplasmic reticulum stress, alsoknown as the unfolded protein response(11).

Drawing on his early training in ob-stetrics, Guenther performed seminalstudies of carbohydrate metabolismduring and after pregnancy and the re-lationship between NEFAs and insulinresistance for handling glucose in obesewomen during pregnancy (12,13). Thesestudies in the 1990s began a long-termpartnership with Dr. Carol Homko, anurse-PhD who was an expert in patient-oriented research and became a prom-inent leader in the American Associationof Diabetes Educators (now known as theAssociation of Diabetes Care&EducationSpecialists). In 2000, Guenther formallyrecruited Carol to become the NurseManager of Temple’s General ClinicalResearch Center, and the two of themcoauthored over 30 articles together, allon research in humans. Their partner-ship lasted two decades, throughout therest of Guenther’s life.

Another research area of Guenther’swas the relationship between nutrition,insulin action, and body weight. In amajor publication in 2005, his team

Effects of three steady-state levels of plasmaNEFAs (;50, 550, and 750 mmol/L) on ratesof glucose uptake in healthy volunteers duringeuglycemic-hyperinsulinemic clamping. PlasmaNEFA levels were increased by intravenous in-fusion of a 20% triglyceride emulsion,without orwith heparin to release lipoprotein lipase intothe circulation to rapidly hydrolyze the trigly-cerides. Indicated are low (filled circles, n5 6),medium (open circles, n 5 4), and high NEFAconcentrations (open triangles, n 5 4). Shownare mean 6 SE. Comparison of individual timepoints: *P , 0.05, §P , 0.01, comparing filledcircles vs. opentriangles.Reproducedfromthetoppanelof Fig. 3 in Boden et al. (8), with permission.

TheBoden family inAmerica. (Left panel) Proud parents, their four children, spouses, and thefirstfive grandchildren, on thebeach, August 2012; top row:Guenther, Irene, Liz, Eric, Dirk, Amie, David, and Kevin; bottom row: Stephanie, Elisabeth, William, Andrew, Abbie, and Karin. (Right panel) The happycouple dancing:Mrs. Irene and Dr. Guenther Boden at thewedding of son Eric and daughter-in-law Liz at the Hotel Du Pont,Wilmington, DE, September2009

care.diabetesjournals.org Williams, Horton, and Siraj 2913

addressed a mystery that was poorlyunderstood at the time: how does alow-carbohydrate diet, such as the pop-ular Atkins diet, cause people to loseweight? There were at least four differ-ent mechanistic explanations, includingthe leading idea of “different utilizationof calories [meaning] that people on low-carbohydrate diets can eat more caloriesthan people on high-carbohydrate dietsand still lose more weight” (14). But theleading idea was wrong. By placing hu-man volunteers with obesity and type 2diabetes on different diets that wereavailable ad libitum in his inpatient met-abolic unit, Guenther and his researchgroup demonstrated that people on thelow-carbohydrate diet freely “chose” toeat about 1,000 kcal less per day, andthis effect on intake “completely ac-counted for” the weight loss (14). Thelow-carbohydrate diet had no effect onenergy expenditure. Despite the largedrop in daily caloric intake, the low-carbohydrate diet also had no significanteffects on “feelings of hunger, satisfactionprovided by the diets, feelings of comfortor discomfort, [or] energy levels” (14).During just 2 weeks on the low-

carbohydrate dietdand reduced caloricintakedthe volunteers’ 24-h glucoseprofiles, insulin resistance for handlingglucose, plasma triglyceride concentra-tions, and even hemoglobin A1c levels allimproved. That work proved Guenther’sfavorite phrase, “calories in, caloriesout,” indicating that what mattered inweight management was the caloricamounts consumed and burned, notnecessarily the source of the calories.Most importantly, the Boden group hadshown that some calories are moresatiating than others (14), a crucialfinding that has withstood the test oftime (15) and continues to have broadimplications for individual and popula-tion health.A fewweeks before his death, Guenther

published new research indicating hownormal, healthy volunteers who overeatfor just a few days already show signs ofimpaired insulin action (16).A major strength of Guenther’s work

was that he conducted most of his inves-tigations in human volunteers, meaningthat his findings were directly relevantto patient care. He specifically dislikedthe use of imperfectdand therefore of-ten misleadingdanimal models. “Are wemouse doctors?” he asked.

Colleagues, Friends, Trainees, andFamily

Since 1982, Guenther was an electedmember of the prestigious InterurbanClinical Club, founded by Sir WilliamOsler in 1905 to encourage dialogue andexchange among academic physician-scientists in Baltimore, NewYork, Boston,New Haven, and Philadelphia. The Clubmeets twice a year, and its mission is tosupport collegial interactions that pro-mote sharedgoals including state-of-the-art, high-impact biomedical research andthe training of physician-scientists.

In 2006, Guenther recruited one of theauthors of this article (E.S.S.) to come toTemple and serve as a clinical diabetes re-searcher and Endocrine Fellowship direc-tor. Having trained in Germany, Elias hadan immediate connection with Guenther,and Guenther greatly influenced Elias’ssubsequent approach to diabetes researchand teaching of fellows.

In 2009, another author of this article(K.J.W.)dalso formerly a student inGermanydwas recruited to Temple tosucceed Guenther as a Chief of the Sectionof Endocrinology. As he took over theSection, some higher-ups pulled Kevin Jonaside to warn him about Guenther’s“strong personality”! But the two menhit it off immediately and became greatscientific partners and coauthors. Theirprofessional and personal associationscontinued throughout the rest of Guenther’slife, includingriding ski chairlifts together,often with Ed Horton, while discussinginsulin.

Another highlight ofGuenther’s careeris his impact on students and trainees atTemple, many of whose names can befound on his scientific publications.With his enthusiasm for teaching andhis knack at describing complex con-cepts in a straightforward way, his impactwas profound. He always promoted sci-entific discourse at all levels. Guentherdid not care much about long admin-istrative meetings, but the moment ascientific concept was raised he imme-diately becameanimated. Science, in andoutside of medicine, continued to besource of fascination for Guenther untilhis death.

We will sorely miss Guentherdhisdeep insights, sharp wit, decency, andgenerosity. Guenther did indeed have astrong personalitydand no tolerancefor nonsense. And “nonsense” was the

mildest word we ever heard him use forfoolish things that he did not like.

He was a risk-taker in his professionallife, but personally and politically con-servative. “A capitalist without capital,”he described himself. Guenther had theold-fashioned passion for medicine as acallingda profession, not just a tradedand he inspired the rest of us.

Our thoughts are with his wife, Irene,their four children and 10 grandchildren,and the rest of the Boden family.

Acknowledgments. The authors would like toacknowledge and thank Mrs. Irene Boden, thewife of the late Dr. Guenther Boden, for givingthem a more complete picture of his early lifeand for sharing his photographs and otheroriginal documents. The quotations from Dr.Boden come from notes he wrote during thelast 3months of his life that were provided to K.J.W.courtesy of the Boden family. The authors arealso indebted to Dr. A. Koneti Rao, a friend andcollaborator of Guenther’s at Temple University,for insights he gave regarding Guenther’s longprofessional career at Temple. They also thankDr. Victor Adlin of Temple University for sharinginformation regarding the early days ofGuentherat Temple University.Dualityof Interest. K.J.W. reports an ownershipinterest in Hygieia, Inc., and in Gemphire Ther-apeutics, Inc., and has served on theMedical andScientific Advisory Board of Gemphire Therapeu-tics, Inc. Over the last 12 months, E.S.S. hasserved as a consultant and speaker for NovoNordisk, Boehringer Ingelheim, and Eli Lilly, all inthe area of diabetes management. No otherpotential conflicts of interest relevant to thisarticle were reported.Author Contributions. K.J.W. and E.S.S. wrotethe original draft of the manuscript. E.S.H. re-viewed and edited the manuscript.

References1. Yalow RS, Berson SA. Assay of plasma insulinin human subjects by immunological methods.Nature 1959;184(Suppl. 21):1648–16492. Yalow RS, Berson SA. Immunoassay of endog-enous plasma insulin in man. J Clin Invest 1960;39:1157–11753. Boden G, Soeldner JS, Steinke J, Thorn GW.Serum human growth hormone (HGH) responseto IV glucose: diagnosis of acromegaly in femalesand males. Metabolism 1968;17:1–94. BodenG,TappyL, Jadali F,HoeldtkeRD,RezvaniI, Owen OE. Role of glucagon in disposal of anamino acid load. Am J Physiol 1990;259:E225–E2325. Garber AJ, Menzel PH, Boden G, Owen OE.Hepatic ketogenesis and gluconeogenesis inhumans. J Clin Invest 1974;54:981–9896. Vaidyula VR, Rao AK, Mozzoli M, Homko C,Cheung P, BodenG. Effects of hyperglycemia andhyperinsulinemia on circulating tissue factorprocoagulant activity and platelet CD40 ligand.Diabetes 2006;55:202–2087. Boden G, Jadali F, White J, et al. Effects of faton insulin-stimulated carbohydrate metabolismin normal men. J Clin Invest 1991;88:960–966

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8. Boden G, Chen X, Ruiz J, White JV, Rossetti L.Mechanisms of fatty acid-induced inhibition ofglucose uptake. J Clin Invest 1994;93:2438–24469. Boden G, Chen X. Effects of fat on glucoseuptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 1995;96:1261–126810. Santomauro ATMG, Boden G, Silva MER,et al. Overnight lowering of free fatty acidswith Acipimox improves insulin resistance andglucose tolerance in obese diabetic and non-diabetic subjects. Diabetes 1999;48:1836–1841

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appetite, blood glucose levels, and insulin re-sistance in obese patients with type 2 diabetes.Ann Intern Med 2005;142:403–41115. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake andweight gain: an inpatient randomized controlledtrial of ad libitum food intake. Cell Metab 2019;30:67–77.e316. Boden G, Homko C, Barrero CA, et al. Ex-cessive caloric intake acutely causes oxidativestress, GLUT4 carbonylation, and insulin resis-tance in healthy men. Sci Transl Med 2015;7:304re7

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