2015 Presidential Address:75 Years of Battling Diabetes2OurGlobal ChallengeDiabetes Care 2016;39:3–9 | DOI: 10.2337/dc15-1818

This address was delivered by Samuel Dagogo-Jack, MD, President, Medicine &Science, of the American Diabetes Association (ADA), at the Association’s 75thScientific Sessions in Boston, MA, on 7 June 2015. Dr. Dagogo-Jack is a professor ofmedicine and the director of the Division of Endocrinology, Diabetes and Metab-olism and the director of the Clinical Research Center at The University of Ten-nessee Health Science Center, Memphis, TN, where he holds the A.C. MullinsEndowed Chair in Translational Research. He has been an ADA volunteer since1991 and has served on several national committees and chaired the Association’sResearch Grant Review Committee. At the local level, he has served on commu-nity leadership boards in St. Louis, MO, and Tennessee. A physician-scientist,Dr. Dagogo-Jack’s current research focuses on the interaction of genetic andenvironmental factors in the prediction and prevention of prediabetes, diabetes,and diabetes complications. He is the principal investigator of the Pathobiology ofPrediabetes in a Biracial Cohort (POP-ABC) study and also directs The University ofTennessee site for the Diabetes Control and Complications Trial/Epidemiologyof Diabetes Interventions and Complications (DCCT/EDIC) and the DiabetesPrevention Program (DPP)/DPP Outcomes Study (DPPOS). Dr. Dagogo-Jackearned his medical and research doctorate degrees from the University ofIbadan College of Medicine in Nigeria, holds a master’s of science from theUniversity of Newcastle upon Tyne in England, and completed his postdoctoralfellowship training in metabolism at the Washington University School of Med-icine in St. Louis in Missouri. A board-certified endocrinologist, Dr. Dagogo-Jackhas been elected to the Association of American Physicians and is the 2015recipient of the Banting Medal for Leadership from the ADA. The ADA andDiabetes Care thank Dr. Dagogo-Jack for his outstanding leadership and serviceto the Association.

To begin with, I would like to congratulate all of us on our 75th birthday as anAssociation. During the Second World War, with the world facing an existentialthreat, a small band of intrepid physicians thought it fit to declare another kindof war, with these words:

Thepatient suffering from the syndromeof diabetesmellitus is the reason for the existence

of this Association. His medical, social, and economic problems are our problems. Since the

incidence of diabetes and the mortality from this disease are increasing in spite of modern

developments in medicine and surgery, a concerted attack on diabetes is essential.

Approximately 750,000 Americans had been diagnosed with diabetes whenDr. Cecil Striker, the first American Diabetes Association (ADA) president, declared war

Division of Endocrinology, Diabetes and Metab-olism, The University of Tennessee Health Sci-ence Center, Memphis, TN

Corresponding author: Samuel Dagogo-Jack,sdj@uthsc.edu.

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

Samuel Dagogo-Jack

Diabetes Care Volume 39, January 2016 3

PRESID

ENTIA

LADDRESS

on diabetes in 1941 (1). Today, withover 29 million Americans with diabe-tes and nearly 400 million similar indi-viduals worldwide, the enormity of thediabetes problem has escalated expo-nentially (Fig. 1). Therefore, the wardeclared on diabetes by the first ADApresident in 1941 must be prosecutedwith renewed vigor. Our battle cry is“to prevent and cure diabetes and toimprove the lives of all people affectedby diabetes.” Our rallying vision is “Lifefree of diabetes and its burdens.” Ourmission statement communicates threekey goals: prevent, cure, improve. I wouldlike to sharemy thoughts with you todayon each of these critical pillars.

IMPROVING THE LIVES OF PEOPLEWITH DIABETES

Each year nearly 2 million people arenewly diagnosed with diabetes in Amer-ica, and millions more around the worldreceive that diagnosis. Receiving a diag-nosis of diabetes can trigger a rangeof emotions. Let me introduce you toValerie, “America’s Supermom”! Valerieand her husband have six children, andthen she decided to adopt and raise ad-ditional children, particularly childrenwith troubled histories. In recognitionof her work in opening her alreadycrowded home to kids from all back-grounds, Valerie has been called Amer-ica’s Supermom. Then Valerie wasdiagnosed with diabetes and this ishow she expressed her feelings to herphysician:

After taking care of myself, watching

mydiet andworking out, how could I get

the diagnosis of diabetes? Had I eaten

the wrong things? No. Do I work out

or exercise enough? Yes, I did. I just

didn ’t understand why or where I

went wrong. So I just blamed myself.

When I looked in the mirror I felt

like a failure with this sudden life

change, which seemed very drastic

and it just felt like a death sentence

to me. There needs to be more help

for new patients and understanding

this new, foreign lifestyle.

Supermom Valerie, the ADA hearsyou! You give voice to the nearly 2 mil-lion Americans and millions morearound the world diagnosed with dia-betes every year. At no time is the feel-ing of vulnerability, consternation, andhelplessness greater than soon afterreceiving the diagnosis of diabetes. Atno time is the need for support and in-formation greater! The ADA “LivingWith Type 2 Diabetes” program pro-vides critical information for newly diag-nosed patients and valuable resourcesfor self-management (2). We are alsoworking on a parallel program fortype 1 diabetes. In the past 4 years, “Liv-ing With Type 2 Diabetes” materialshave been distributed to nearly 20,000health care providers and have reachednearly 1.8 million patients, but that isfar short of the 2 million new patientswe need to reach each year. This valu-able program is funded by the industry.With additional funding, we can extend

coverage to every newly diagnosedAmerican with diabetes.

To improve the lives of people withdiabetes, the ADA sets standards ofcare for diabetes, delivers educationalcontent to professionals and the laypublic, and advocates for people withdiabetes. Our Standards of MedicalCare in Diabetes provides a blueprintfor standardized management of diabe-tes. Our books and journals lead thefield in the science and clinical practiceof diabetes. With regard to textbooks,our Therapy for Diabetes Mellitus andRelated Disorders (“Green Book”) hasmaintained its greenness but is nowmassively obese in its sixth edition, re-flecting the explosion of knowledge thathas taken place since the last edition.Our lay publications, including DiabetesForecast and cookbooks, informationalbrochures, online resources, and ourCall Center and social media presenceall connect us to a vast global diabetesinterest community.

Our advocacy efforts take us to manyplaces from schools to the halls of Con-gress to sensitize elected officials to theenormity of the diabetes problem andto solicit increased public funding fordiabetes research. We fight workplacediscrimination, advocate for safety atschools for children with diabetes, andtrain police officers regarding the manyfacets of diabetes that can be misinter-preted during encounters with law en-forcement. Sometimes, the opportunityto advocate for patients with diabetesmay take nontraditional forms. In 2012,I received an e-mail from a womancalled Shery, who lives in Tennessee,about her daughter. Shery wanted meto know that her daughter had been di-agnosed with type 1 diabetes, whichhad “drastically changed” their lives.The daughter desires to become a doc-tor, but juggling diabetes with school-work was becoming quite a challenge.Sensing a family in need of encourage-ment, I wrote back to Shery the sameday and reassured her that her daugh-ter could indeed become a doctor ifshe so desired. I placed my services atthe family’s disposal to help to guideand mentor them through the medicalschool preparation and application pro-cess. The daughter recently wrote tomethat she is doing well in medical schooland continues to volunteer for ADA’sTour de Cure and Diabetes Camp for

Figure 1—Number and percentage of U.S. population with diagnosed diabetes, 1958–2013.Source: Centers for Disease Control and Prevention. Available from www.cdc.gov/diabetes/data/center/slides.html. Accessed 20 May 2015.

4 Presidential Address Diabetes Care Volume 39, January 2016

Children. She has enjoyed helping kidswith diabetes in camp, an experiencethat has reinforced her commitmentto pursuing a career in endocrinology!Health surveys and reports consistently

show marked ethnic disparities in therates of diagnosed diabetes, as well asin diabetes complications. In the wordsof Dr. Martin Luther King Jr.: “Of all theforms of inequality, injustice in healthcare is themost shocking and inhumane.”Extensive genome-wide association stud-ies have not provided a compelling expla-nation for the ethnic differences in type 2diabetes prevalence (3). For example, theallelic frequencies of diabetes-relatedgene variants such as TCF7L2 are quitesimilar across major ethnic/racial groups(4). In the multiethnic Diabetes Preven-tion Program (DPP), individuals from dif-ferent ethnic backgrounds progressedfrom impaired glucose tolerance totype 2 diabetes at similar rates (5). Todetermine whether ethnic disparities oc-cur more proximally, in the Pathobiologyof Prediabetes in a Biracial Cohort (POP-ABC) study, we evaluated the transitionfrom normoglycemia to prediabetes inAfrican American and Caucasian adults,all of whom have parents with type 2 di-abetes. As was observed in the DPP, ourresults showed similar incidence of pre-diabetes in this biracial cohort (6). Thus,the factors that account for the markedethnic disparities in the prevalence of di-abetes remain to be fully elucidated.

In contrast, marked ethnic disparitiesin the quality of diabetes control and theprevalence of diabetes complicationshave been noted, and have persisted,for more than 30 years (7,8). Yet, thereis abundant evidence that optimized gly-cemic control prevents complications,regardless of race/ethnicity (9,10). Forexample, the national disparity in therates of amputation (and other compli-cations) by race/ethnicity is consider-ably attenuated among patients withdiabetes enrolled in a health care systemof uniform access and equal treatment(9). Health disparities are predicatedupon a triangular interaction (Fig. 2)among the patient, the provider, andthe health care system. Each one con-tributes significantly to the health andwell-being of the patient. The ADA rec-ognizes the need to reduce and elimi-nate disparities in diabetes. We havehad in place for many years a high-riskhealth disparities initiative that reachesout to African Americans, Latinos, Na-tive Americans, Asian Americans, NativeHawaiians, and Pacific Islanders. I amdelighted to note that in 2014 ourhigh-risk health disparity programsreached 4.5 million individuals in thesecommunities!

PREVENTING DIABETES

Preventing diabetes has become a globalchallenge. It has been projected that thenumber of people around the world

diagnosed with diabetes will increasefrom 387 million (in 2014) to 592 millionby the year 2035. Diabetes continues tobe among the top 10 causes of death inmost countries. Interestingly, that pat-tern is strongly linked to economic de-velopment: mortality from diabetesincreases as countries transition fromlow-income through lower-middle andmiddle-income status (Fig. 3). This ne-farious link between economic progressand death from diabetes is not inevita-ble. Leaders of countries in economictransition would be well advised topay heed and institute timely preven-tive measures. Low- and middle-incomecountries are projected to experiencethe steepest increase in diabetes prev-alence (Fig. 4). Yet, many of thesecountries lack the resources to dealeffectively with the challenges ofdiabetes. Even among economicallyadvantaged countries, it is concerningthat nearly one-half of the patientswith diabetes are not at an optimallevel of control. This lack of adequatecontrol drives the development of ex-pensive complications. As we confrontthe global challenges of diabetes, wemust also embrace the opportunityfor primary prevention. Today, morethan 300 million people around theworld have prediabetes, and the num-ber is projected to nearly double bythe year 2035 (Fig. 5). The unequivocaldemonstration that type 2 diabetes canbe prevented presents a tremendousopportunity for stemming the globaltide of diabetes (5,11).

Although local in its initial focus, itmust be recognized that our Associationhas always had a global outlook from itsearliest beginnings. For example, at the1946 ADA Scientific Sessions held inToronto, Canada, five Banting medalswere awarded to recipients from fivedifferent countries (Dr. Bernardo Hous-say of Argentina; Dr. Hans Hagedorn ofDenmark; Dr. R.D. Lawrence of England;Dr. Eugene Opie, American patholo-gist; and Sidney Smith, president ofthe University of Toronto, Canada). Inhis 1946 Presidential Address, ADAPresident Dr. Joseph Barach notedthat attendees had come “from manycountries, bound together with a soleaim and common cause, to see thatdiabetes the world over is treated atthe highest level of efficiency. . . .” Iam proud to observe that the ADA hasFigure 2—The health disparities triangle.

care.diabetesjournals.org Dagogo-Jack 5

maintained that early tradition of rec-ognizing talent without national or geo-graphical restrictions. At the 2015Scientific Sessions held in Boston, at-tendees came from every inhabitedcontinent of the globe, and our pro-gramming covered topics of global sig-nificance. Recognizing that healthprofessionals in many countries are un-able to attend our valuable scien-tific sessions, the ADA has developeda supplemental program. The “Best ofADA” program distills the material ofthe highest caliber from our ScientificSessions for delivery to professionalsaround the world. The ADA will con-tinue to embrace what has nowbecome a global imperative. We willcontinue to partner with kindred orga-nizations nationally and internation-ally that advocate for the rights,privileges, and well-being of individu-als with diabetes wherever they maycall home.

FINALLY, CURING DIABETES

We share the disappointment and impa-tience of those who take us to task for

not yet having found the cure for diabe-tes. Understandably, parents of childrenwith type 1 diabetes are particularly vo-cal in expressing that frustration. Thewar against diabetes has been a seriesof escalating battles. Viewed in thatlight, we can take comfort in the undis-puted victories that have been recordedin many critical battles of the war. Be-fore the 1920s and well into thecentury, there was tremendous igno-rance surrounding diabetes. The battleagainst ignorance and misconceptionsabout diabetes is largely settled. Avery critical battledstop people fromdying from diabetic ketoacidosisdwasdelivered by the discovery of insulin.Since then we have gone on to scorevictory after victory, discovering aplethora of oral agents and designer in-sulins and delivery systems, creatingthe modern diabetes team, and transfer-ring self-management skills to pa-tients with diabetes. Along the way, wehave also deciphered a good deal regard-ing the pathophysiology of diabetes,mechanisms of glucose counterregulationand iatrogenic hypoglycemia, the role of

autoimmunity in type 1 diabetes, andthe complex genetic landscape oftype 2 diabetes. We are also makingsignificant progress in reducing diabe-tes complications. Indeed, Gregg andcolleagues (12) reported that many ofthe complications of diabetes havedeclined significantly across U.S. de-mographic groups over the past 2decades.

But we have several battles that arestill in progress (Table 1). We need tounravel the biological and social deter-minants of human adherence, eliminatedisparities, decrease excess cardiovas-cular burden, translate type 2 diabetesprevention globally, and accelerateknowledge to enable the predictionand prevention of type 1 diabetes. Wemust decode and interrupt the role ofintrauterine factors in programmingadult disorders. We need to developtechnologies for the optimization of gly-cemic control and come upwith commonplatforms to enable interoperability ofblood glucose meters and test stripsin order to minimize waste and frustra-tion. There is an epic battle that is now

Figure 3—Top 10 causes of death in countries of the world grouped by income status. COPD, chronic obstructive pulmonary disease. Source: WorldHealth Organization. Available from http://www.who.int/mediacentre/factsheets/fs310/en/index1.html. Accessed 20 May 2015.

6 Presidential Address Diabetes Care Volume 39, January 2016

raging in the field of diabetesdthat ofunlocking the mysteries of the b-cell.Insulin secretion by theb-cells in amountscommensurate with the body’s demandguarantees freedom from diabetes. Itis known that the b-cells expand toincrease their insulin output to meetdemands in obese individuals as well

as in pregnant women. What has goneawry with the natural processes forb-cell expansion in our patients withdiabetes?

The epic battle of the b-cell is beingfought on two frontsdin vivo and exvivo. The in vivo tasks are to protect theb-cells from damage or to repair or

regenerate damaged cells. The ex vivo ap-proach has been based on transplantationof donor cells, an approach fraught withproblems of supply and immunologicalrejection. The donor-independent ap-proach involves the creation and prolif-eration of new b-cells, either throughtransdifferentiation of endoderm-derived cells (such as pancreaticexocrine cells and hepatocytes) orthrough induced pluripotent stem(iPS) cells (Fig. 6). In 1962, Dr. JohnGurdon replaced the nucleus of afrog egg with the nucleus from anadult frog. The result was a tadpolegenerated from the frog egg bearingdonor DNA from the adult frog. Thatwas the first example of a cloned ani-mal. Several decades later, in 2006,Dr. Shinya Yamanaka inserted fourtranscription factors into adult mouseskin cells, which then became reprog-rammed to a more primitive form,akin to embryonic stem cells. The useof such iPS cells derived from adultcells obviates the moral and ethicalarguments that plague the use of em-bryonic stem cells. Already, thesetechnologies are being applied in nu-merous laboratories, including thoseof Dr. Douglas Melton and others, toaddress the b-cell problem in diabe-tes. Skin cells from patients withtype 1 diabetes have been success-fully reprogrammed to become iPScells, which have then been differen-tiated to become pancreatic islet cellsthat produce insulin and glucagon(13). Recently, Dr. Raikwar and col-leagues (14) transplanted human-derived iPS cells into diabetic miceand showed that the iPS cells secretedsufficient insulin to regulate bloodglucose. We are still a long way fromusing these cells for human therapy,but, as the saying goes, a journeyof a thousand miles begins with thefirst step, and we have taken thoseinitial steps.

Research is the only credible path towinning the ongoing battles and find-ing a cure for diabetes. The ADA’s re-search program was initiated in 1952,and since then we have disbursedmorethan $700million. Our funded researchprojects cover a broad range of topicsin the basic, clinical, translational, andbehavioral sciences (Fig. 7). We havefollowed the traditional approach inselecting applications to fund, but

Figure 4—Projected increases in diabetes prevalence in different regions of the world. Source:International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium, InternationalDiabetes Federation, 2013, p. 12.

Figure 5—Global burden of prediabetes, or the number of people with impaired glucose toler-ance (IGT). Source: International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels,Belgium, International Diabetes Federation, 2013, p. 40.

care.diabetesjournals.org Dagogo-Jack 7

have recalled the words of the Nobel

laureate, Max Born:

. . . there is no philosophical high road in

science, with epistemological signposts.

No, we are in a jungle and find our way

by trial and error, building our road be-

hind us as we proceed. (15)

That iswhy, in 2013, theADA launchedanew funding mechanism to acceleratediscovery: The Pathway to Stop Diabetesprogram guarantees significant supportand invests in the success of the investi-gator rather than of a specific project.Pathway is funded by donations from in-dividual and corporate donors. Researchneeds money, and we all can be fund-raisers for the ADA. Experience hasshown that scientists can be effective

fund-raisers. After all, we are the bridgebetween science and society. If we com-municate clearly and passionately, wewill strike a common chord with the in-ner philanthropist that resides in mostpeople.

In conclusion, today, as in 1940, pa-tients with diabetes remain the sole rea-son for the existence of this Association.Their medical, social, economic, andpsychological problems are our prob-lems. At no time in history have forcesbeen better aligned for victory over di-abetes as now. The global brainpowerdeployed in diabetes research, theamazing opportunity for global collabo-ration, and the speed with which re-search results can be shared (almostinstantaneously), all bode well for vic-tory. Indeed, we are nearing the crestof the Shakespearean wave of opportu-nity and discovery:

There is a tide in the affairs of men,Which, taken at the flood, leads on to

fortune;Omitted, all the voyage of their lifeIs bound in shallows and in miseries.On such a full sea are we now afloat;And we must take the current when it

serves,Or lose our ventures. (16)

With the enormous assets of ourera, sooner than later, diabetes willsuccumb to the overwhelming forceof science! This I believe with all myheart.

Acknowledgments. The author acknowl-edges the early mentorship and support ofhis parents (Karibi and Biribota Dagogo-Jack),the abiding support of his wife (Dr. Agbani

Dagogo-Jack) and children (Karibi, Ibiayi, Alali, andSokiente), and the research and clinical mentor-ship of Professor Pat Kendall Taylor of the Uni-versity of Newcastle andDrs. Philip E. Cryer andWilliam H. Daughaday of Washington Univer-sity School of Medicine in St. Louis. The authoralso gratefully acknowledges the support ofDr. Abbas E. Kitabchi, Dr. Solomon S. Solomon,and other colleagues at The University of Ten-nessee. Theauthor thanks his current and formerresearch volunteers, research fellows and asso-ciates, administrative staff, and the staff of theADA Scientific and Medical Division, particularlyMatt Petersen.Duality of Interest. S.D.-J. has served as aconsultant for Merck, Novo Nordisk, AstraZeneca,Boehringer Ingelheim, and Janssenandhas servedas an investigator on clinical trial contracts to TheUniversity of Tennessee from AstraZeneca, NovoNordisk, and Boehringer Ingelheim. No otherpotentialconflictsof interestrelevanttothisarticlewere reported.

References1. American Diabetes Association. The Journey& the Dream. A History of the American Diabe-tes Association. Alexandria, VA, American Dia-betes Association, 1988, p. 102. American Diabetes Association. LivingWithDi-abetes, [Internet]. Available from http://www.diabetes.org/living-with-diabetes/. Accessed15 May 20153. Dagogo-Jack S. Predicting diabetes: our re-lentless quest for genomic nuggets. DiabetesCare 2012;35:193–1954. Hivert MF, Jablonski KA, Perreault L, et al.;DIAGRAM Consortium; Diabetes PreventionProgram Research Group. Updated geneticscore based on 34 confirmed type 2 diabetesloci is associated with diabetes incidence andregression to normoglycemia in the DiabetesPrevention Program. Diabetes 2011;60:1340–13485. Knowler WC, Barrett-Connor E, Fowler SE,et al.; Diabetes Prevention Program ResearchGroup. Reduction in the incidence of type 2 di-abetes with lifestyle intervention or metformin.N Engl J Med 2002;346:393–4036. Dagogo-Jack S, Edeoga C, Ebenibo S, NyenweE, Wan J; Pathobiology of Prediabetes in a Bi-racial Cohort (POP-ABC) Research Group. Lackof racial disparity in incident prediabetes andglycemic progression among black and whiteoffspring of parents with type 2 diabetes: thePathobiology of Prediabetes in a Biracial Cohort(POP-ABC) study. J Clin Endocrinol Metab 2014;99:E1078–E10877. Schneider EC, Zaslavsky AM, Epstein AM. Ra-cial disparities in the quality of care for enrolleesin Medicare managed care. JAMA 2002;287:1288–12948. Selvin E, Parrinello CM, Sacks DB, Coresh J.Trends in prevalence and control of diabetes inthe United States, 1988-1994 and 1999-2010.Ann Intern Med 2014;160:517–5259. Karter AJ, Ferrara A, Liu JY, Moffet HH,Ackerson LM, Selby JV. Ethnic disparities in di-abetic complications in an insured population.JAMA 2002;287:2519–252710. Bower JK, Brancati FL, Selvin E. Noethnic differences in the association of gly-cated hemoglobin with retinopathy: the

Table 1—Areas of critical need forprogress in diabetes research andpracticec Unravel the biological and socialdeterminants of human adherence

c Understand behavior and motivationfor wellness

c Eliminate disparities in access, quality,and outcomes of diabetes care

c Reduce excess cardiovascular morbidityand mortality in diabetes

c Translate type 2 diabetes globally anddiscover novel approaches to predictionand prevention of type 1 diabetes

c Decode and interrupt the role ofintrauterine factors in programming ofadult cardiometabolic disorders

c Develop diabetes technologies foroptimization of glycemic control andguidelines for their proper use

c Develop common platforms to enableinteroperability of blood glucose metersand test strips

c Unlock the mystery of b-cell demise/dysfunction in diabetes and developrescue/replacement strategies

Figure 6—Schema of in vivo and in vitro ap-proaches to b-cell preservation or replace-ment. Transdiff., transdifferentiation; tx,transplantation.

Figure 7—Approximate distribution of focusareas of research projects funded by grantsfrom the ADA.

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National Health and Nutrition ExaminationSurvey 2005-2008. Diabetes Care 2013;36:569–57311. Echouffo-Tcheugui JB, Dagogo-Jack S.Preventing diabetes mellitus in developingcountries. Nat Rev Endocrinol 2012;8:557–56212. Gregg EW, Li Y, Wang J, et al. Changes indiabetes-related complications in the United

States, 1990-2010. N Engl J Med 2014;370:1514–152313. Maehr R, Chen S, Snitow M, et al. Genera-tion of pluripotent stem cells from patients withtype 1 diabetes. Proc Natl Acad Sci U S A 2009;106:15768–1577314. Raikwar SP, Kim E-M, Sivitz WI, Allamargot C,Thedens DR, Zavazava N. Human iPS cell-derived

insulin producing cells form vascularized organo-ids under the kidney capsules of diabetic mice.PLoS One 2015;10:e011658215. Born M. Experiment and Theory in Physics.Cambridge University Press, 1943, p. 4416. Shakespeare W. Julius Caesar. In: The Com-plete Works of William Shakespeare, WordsworthEditions, 1996, p. 604

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