Diabetes Care Volume 43, September 2020 1997

Dr. Mladen VranicdA Legend in Alan Cherrington1 and Shirya Rashid1,2 Research: 1930–2019 Diabetes Care 2020;43:1997–2000 | https://doi.org/10.2337/dci20-0010 RFLSI PROGRESS IN PROFILES

Mladen Vranic, MD, DSc, FRSC, FRCP(C), possibilities in research” and “stimu- FCAHS, was an early pioneer in the field of lated my curiosity.” diabetes, greatly advancing our under- His next move was to change the standing of diabetes physiology. Over the course of his life and career. After com- course of his scientific career, Dr. Vranic pleting his PhD thesis in 1962, he con- changed the landscape of diabetes re- tacted Charles H. Best, codiscoverer of search in North America and internation- along with ally through his groundbreaking work in 40 years prior, to explore the possibility metabolism, exercise, stress, and of continuing his work in Toronto. Charles . It is noteworthy that he Best was head of the ’s trained as the last postdoctoral fellow of Banting and Best Department of Medi- Dr. Charles Best, a codiscoverer of insulin, cal Research at the time. Mladen had at the University of Toronto. just published an article in Diabetes that Dr. Vranic’s interest in diabetes re- examined the hypothesis that pancre- search started during his early life, as did atic b-cells can arise from the ducts of his determination to thrive despite deep the exocrine pancreas (1). Charles Best’s struggles. He was born 30 April 1930 to interest in Mladen’s article led to an Vladamir and Ana Vranic in , Cro- invitation to give a seminar at the Uni- atia. His father was a professor at the versity of Toronto. He was then recruited Faculty of Economics, Engineering, and to Toronto and became the last post- Sciences and dean at the School of Eco- doctoral fellow of Dr. Best, who Mladen Mladen Vranic nomics and Engineering at the University said “always had time for people” and of Zagreb. His teaching specialty was “was extremely enthusiastic and sup- mathematics. Mladen was an only child, Upon completing medical school at portive.” Interacting with local and of Jewish heritage, and a Holocaust sur- the University of Zagreb, Mladen pur- visiting research experts while working vivor. He and his family narrowly escaped sued graduate studies in physiology, at the Best Institute increased Mladen’s captureby the Nazis multiple times during with a focus on diabetes, the only exposure to work on the pathogenesis of World War II. As a young boy he, his specialty available in the department diabetes, its complications, and possibil- parents, and his grandmother sought at the time. Concomitantly, his father ities for treatment. This was the start of a refuge in Italy, managing to flee just developed . Mladen 60-year distinguished career in diabetes ahead of their would-be captors. Despite said about the field that was to be- research and education at the University their efforts, they were eventually caught come his life’s work and passion, “I of Toronto, including as Professor and sent to a concentration camp when have never regretted for one instant (1972–2019) and Chair of Physiology Mladen was 11. He attributed his survival my commitment to a life in medical (1991–1995) and Professor of Medicine there to his and his family’s undeterred research and education” and “diabe- (1978–2019). It is noteworthy that dur- tenacity to endure and escape. tes offers an incredible number of ing a sabbatical leave he was a visiting

1Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 2Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada Corresponding author: Shirya Rashid, [email protected] © 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. 1998 Profiles in Progress Diabetes Care Volume 43, September 2020

introduced a novel approach to ameliorate hypoglycemia in diabetes by blocking the effect of pancreatic somatostatin on the pancreatic a-cell and thereby increasing secretion (22–23). Mladen sum- marized his key research accomplish- ments in a career retrospective published in the American Journal of Physiology– Endocrinology and Metabolism (24). Dr. Vranic’s exceptional scientific body of work was recognized in 1991 by the foremost international diabetes research award, the American Diabetes Associa- tion’s Banting Medal for Scientific Achievement. As an acknowledgment of his research excellence in diabetes translational medicine, he is also the recipient of a multitude of other lead- ing awards and honors; a selected list Left panel: young Mladen; right panel: 8-year-old Mladen includes the American Diabetes As- sociation’s Albert Renold Award for a research fellow at Merton College within important support for Roger Unger’s distinguished career in the training of Oxford University (1976–1977). idea that glucagon played a key phys- diabetes research scientists and facilita- Mladen’s seminal work in diabetes at iological role and that its dysregulation tion of research (2005), the Solomon A. the University of Toronto resulted in the contributed to the diabetic phenotype. Berson Distinguished Lectureship of the publication of 214 peer-reviewed journal Mladen further established new con- American Physiological Society Endocri- articles and 70 book chapters. His re- cepts regarding the role of exercise in nology and Metabolism Section (1995), search reflects both the work of his own diabetes, identifying physiological and the Canadian Diabetes Association In- graduate students and postdoctoral fel- molecular mechanisms whereby exer- augural Lifetime Achievement Award lows (over 50 in total) and a wide array of cise ameliorates or prevents the onset (2007), Laureate of the Canadian Medical collaborators in both basic science and of type 2 diabetes (7–12). Through his Hall of Fame (2009), and Officer of the clinical investigation. His first major con- work, he founded the first international (2010). Dr. Vranic is tribution was to implement the use of symposium on exercise and diabetes, additionally the recipient of 18 honorary new tracer methods in physiological which still has a major impact today. As degrees, including ones from Karolinska studies that enabled accurate measure- an additional consequence, his work in University and the University of Toronto. ment of steady- and nonsteady-state the exercise field led toprecise methods glucose turnover for the first time (2, of controlling insulin administration Mladen’s First Graduate Student 3). This work opened the field to iden- during exercise in the individual with By Alan Cherrington tification of the effects of hormonal and diabetes, thereby enabling athletes with I was Mladen’s first graduate student and metabolic perturbations on glucose me- type 1 diabetes to participate at the began work in his laboratory in 1968. I tabolism in both the normal and diabetic highest level in various sports. decided to go to graduate school after state, including some of the first clinical Mladen also went on to open up a new working in a research laboratory at the tracer studies relating to insulin resis- field in the area of stress and diabetes. He Food and Drug Directorate in Ottawa. In tance, hypertriglyceridemia, and the Cori delineated the physiological and molecu- fact, I was fascinated by physiology and cycle in humans. In the latter half of his lar mechanisms responsible for increased couldhaveworkedinanyareaofthe career, he fine-tuned our understanding stimulation of the hypothalamic-pituitary- discipline, but as fate would have it of defects in glucose and insulin metab- adrenal (HPA) axis in type 2 diabetes and Mladen had just been appointed to the olism in diabetes at the cellular and how it leads to defects in glucose turnover faculty at the University of Toronto and molecular levels, demonstrating impair- and , as well as interven- he was looking for a graduate student. I ments in GLUT2 expression during acute tions that effectively ameliorate it (13–16). knew very little about diabetes, but that hyperglycemia and, along with others, In opposition to the deleterious effects of quickly changed. I was involved in Mladen’s separating the direct and indirect effects chronic stress, he strikingly showed that early studies of glucagon action and the of insulin on the liver (4). intermittent neurogenic stress prevents discovery of nonpancreatic glucagon. Another early important finding was the onset of type 2 diabetes, similar to Mladen was a terrific mentor, not only Mladen’s discovery of extrapancreatic exercise (17–19). Paradoxically,in his later teaching me the meaning of first-rate glucagon (5,6), which changed the pre- years, he identified the molecular mech- science but also showing me how to vailing dogma at the time that any given anisms responsible for the diminished balance research and family life. He hormone is only produced in one spe- response of the HPA axis, catecholamines, was indeed a wonderful spouse and cific gland. His early studies of glucagon cortisol, and glucagon to insulin-induced parent, something I try to emulate and action on glucose production provided hypoglycemia in diabetes (20–21). He then instill in my own trainees. Mladen care.diabetesjournals.org Cherrington and Rashid 1999

explained that Mladen was one of the Charybdis...: A Career Retrospective” foremost pioneers in the study of ex- (24). He had a genuine interest in the ercise physiology in diabetes, among a background and cultures of his very di- multitude of other areas of research verse research groups over the years, excellence in diabetes. Needless to say, something that was reflected in his varied my interview with Mladen went well. collection of heirloom books of ancient He gave me a publication of his on the cultures. Consistent with this interest, he impact of stress on the development of learned to speak six languagesdEnglish, hyperglycemia in diabetes, which had Italian, French, Russian, Croatian, and a strong impact on me. It became my Germandand did quite well in Latin, ’ research focus in his laboratory and led also. Mladen Vranic and Alan Cherrington upon Alan s fi Outstanding Research as a Young Investigator to my initial rst-authored article on the Mladen would probably also say not to Award from ADA amelioration of hyperglycemia from stress “just take the road not taken” but to just in diabetes through hyperinsulinemia and take the road and move forward with b-blockade, published in Diabetes (16) and determination according to his own supported me in many ways through my highlighted by Reuters news agency as a motto: “I don’t give up easily. In fact, I career and I continued to visit him even as major find in 2000. never give up at all.” This maxim applied his health declined. I was by chance in Through the years, our relationship to his tenacious approach to probing for Toronto when Mladen passed and had grew from mentor-mentee to collaborator- answers in science and to his life, a life the honor of being a pallbearer at his colleague and then friends. Mladen had well lived but not without struggle. Many funeral. Two things were most striking to many wonderful personal attributes. of his scientific breakthroughs came after me on that occasion: first, the number of As a mentor and adviser, he was always his recovery from a stroke in later life, people whose lives he had touched and patientandpersonable, teachingbyhand including acquiring a patent during his who were present for the celebration of with ruler and pencil in tow the impor- final years on a putative new method for his life; second, the warmth with which tance of reading and interpreting raw alleviating hypoglycemia in diabetes, one his daughters and his wife, Linda, spoke experimental data and graphs. Given his of the most frequent and serious acute of him. His was truly a life well lived. prolific scientific writings, he always had complications of insulin-treated diabe- an instructional journal article, text chap- An Introduction to Quality Scientific tes. The new approach involved blocking ter, or book of his, his mentees, and Research the effect of somatostatin to lower the collaborators in hand from the full shelves potential of hypoglycemia. This discovery By Shirya Rashid of his office. He was even-tempered and later went into drug development with I first met Mladen when he was Chair of remained calm in the midst of conflicts start-up Zucara Therapeutics in conjunc- the Department of Physiology at the and crises and was optimistic about the tion with MaRS, University of Toronto, University of Toronto in the 1990s. My outcomes. He recommended the same and the Centre for Drug Research and introduction to scientific research excel- for his trainees, valuable advice when Development (CDRD). lence was through Mladen, as it was for experiments inevitably initially failed and Despite such challenges in life, Mladen countless other scientists and leaders in grant and manuscript deadlines were in was well known for a personality that diabetes that had the good fortune to be near sight. mentored by him. Mladen considered Very apparent was his curiosity for all the success and impact of (his) students things scientific and, in this respect, he and fellows to represent the most im- was an inventive thinker. At honorary portant achievement of (his) scientific speeches, he would often quote Robert career. Frost’s “The Road Not Taken” as the route My first encounter with Mladen was in to originality, which he felt was a key to an interview for a graduate studentship his success and to success in the arts and in his laboratory. I had been carrying out a science: research stint at Penn State University in the Department of Exercise Physiology I shall be telling this with a sigh andwishedtoreturntoCanadato Somewhere ages and ages hence: pursue a master’s degree in physiology. Two roads diverged in a wood, and Id I knew that the University of Toronto’s I took the one less traveled by, Department of Physiology was the lead- And that has made all the difference. ing program in Canada and wished to apply to Mladen, who was Chair of the His curiosity also extended to a love of department. If I didn’t know his legend- classical music, literature, theater, and ary status at the time, I soon became cultures. His speeches over the years are aware of it. Mladen’s call to me at Penn liberally filled with quotes from global fi State was routed through the of ce of works of great literature. Indeed, the title Mladen during a visit to Zagreb, , where Penn State’s Chair of Exercise Physiology of his autobiography is taken from Greek he received an award from the Croatian Academy (my supervisor) at that time. He later mythology: “Odyssey Between Scylla and of Medical Sciences 2000 Profiles in Progress Diabetes Care Volume 43, September 2020

exhibited great humor, wit, and charm inulin as tracer and tracee. Can J Physiol Phar- 15. Lekas MC, Fisher SJ, El-Bahrani B, van and a great deal of generosity. He not macol 1974;52:508–521 Delangeryt M, Vranic M, Shi ZQ. Glucose uptake only trained multiple generations of di- 3. Vranic M, Wrenshall GA. Matched rates of during centrally induced stress is insulin inde- insulin infusion and secretion and concurrent pendent and enhanced by adrenergic blockade. J abetes scientists and leaders but also tracer-determined rates of glucose appearance Appl Physiol (1985) 1999;87:722–731 supported them throughout their ca- and disappearance in fasting dogs. Can J Physiol 16. Rashid S, ShiZQ,Niwa M, etal. Beta-blockade, reers. In terms of myself, he advised Pharmacol 1968;46:383–390 but not normoglycemia or hyperinsulinemia, me throughout my career in translational 4. Mathoo JM, Shi ZQ, Klip A, Vranic M. Opposite markedly diminishes stress-induced hyperglyce- – metabolism and cardiology research, pro- effects of acute hypoglycemia and acute hyper- mia in diabetic dogs. Diabetes 2000;49:253 262 glycemia on glucose transport and glucose trans- 17. Bates HE, Kiraly MA, Yue JT, et al. Recurrent vided me with ready letters of support and porters in perfused rat skeletal muscle. Diabetes intermittent restraint delays fed and fasting recommendations, and accepted fea- 1999;48:1281–1288 hyperglycemia and improves glucose return to tured lectures at my university during 5. Vranic M, Engerman R, Doi K, Morita S, Yip CC. baseline levels during glucose tolerance tests in my professorships. While it was usually Extrapancreatic glucagon in the dog. Metabolism the Zucker diabetic fatty ratdrole of food intake Mladen who generously nominated in- 1976;25(Suppl. 1):1469–1473 and corticosterone. Metabolism 2007;56:1065– 6. Ross G, Lickley L, Vranic M. Extrapancreatic 1075 vestigators for awards, I was honored to glucagon in control of glucose turnover in de- 18. Bates HE, Sirek AS, Kiraly` MA, et al. Adap- have cosponsored an honorary doctor- pancreatized dogs. Am J Physiol 1978;234:E213– tation to mild, intermittent stress delays de- ate for him granted by McMaster Uni- E219 velopment of hyperglycemia in the Zucker versity (2013) during my tenure there. 7. Zinman B, Vranic M, Albisser AM, Leibel BS, diabetic Fatty rat independent of food intake: Mladen died of congestive heart fail- Marliss ED. The role of insulin in the metabolic role of habituation of the hypothalamic-pituitary- – ure 18 June 2019 at the age of 89. He response to exercise in diabetic man. Diabetes adrenal axis. Endocrinology 2008;149:2990 1979;28(Suppl. 1):76–81 3001 leaves behind his wife Linda Vranic, di- 8. Minuk HL, Hanna AK, Marliss EB, Vranic M, 19. Bates HE, Sirek A, Kiraly MA, et al. Adaptation rector at Magnus Associates, with whom Zinman B. Metabolic response to moderate to intermittent stress promotes maintenance of he has two daughters, Claire Vranic, a exercise in obese man during prolonged fasting. beta-cell compensation: comparison with food director at the Canadian Imperial Bank Am J Physiol 1980;238:E322–E329 restriction. Am J Physiol Endocrinol Metab 2008; – of Commerce, and Anne Vranic, a commu- 9. Vranic M, Berger M. Exercise and diabetes 295:E947 E958 mellitus. Diabetes 1979;28:147–163 20. Chan O, Chan S, Inouye K, Shum K, Matthews nications specialist at the Royal Ontario 10. Minuk HL, Vranic M, Marliss EB, Hanna AK, SG, Vranic M. Diabetes impairs hypothalamo- Museum. His daughter Iva Vranic, from Albisser AM, Zinman B. Glucoregulatory and pituitary-adrenal (HPA) responses to hypoglyce- his first marriage to his late wife Magda metabolic response to exercise in obese non- mia, and insulin treatment normalizes HPA but Vranic (who herself was an Assistant insulin-dependent diabetes. Am J Physiol 1981; not epinephrine responses. Diabetes 2002;51: Professor of Rehabilitation Medicine at 240:E458–E464 1681–1689 11. Douen AG, Ramlal T, Rastogi S, et al. Exercise 21. Inouye K, Chan O, Riddell MC, Akirav E, the University of Toronto), is a securities induces recruitment of the “insulin-responsive Matthews SG, Vranic M. Mechanisms of im- lawyer and director with the Bank of glucose transporter.” Evidence for distinct in- paired hypothalamic-pituitary-adrenal (HPA) Nova Scotia. tracellular insulin- and exercise-recruitable function in diabetes: reduced counterregula- For many of us, his exceptional work transporter pools in skeletal muscle. J Biol tory responsiveness to hypoglycaemia. Diabe- and wonderfully larger-than-life person- Chem 1990;265:13427–13430 tes Nutr Metab 2002;15:348–355; discussion ´ – ality will continue to inspire us as the 12. Kiraly MA, Campbell J, Park E, et al. Exercise 355 356, 362 maintains euglycemia in association with de- 22. YueJT,BurdettE,Coy DH,GiaccaA,EfendicS, years go by. creased activation of c-Jun NH2-terminal kinase Vranic M. Somatostatin receptor type 2 antag- and serine phosphorylation of IRS-1 in the liver of onism improves glucagon and corticosterone ZDF rats. Am J Physiol Endocrinol Metab 2010; counterregulatory responses to hypoglycemia in 298:E671–E682 streptozotocin-induced diabetic rats. Diabetes Duality of Interest. fl No potential con icts of 13. Miles PD, Yamatani K, Lickley HL, Vranic M. 2012;61:197–207 interest relevant to this article were reported. Mechanism of glucoregulatory responses to 23. Yue JT, Riddell MC, Burdett E, Coy DH, stress and their deficiency in diabetes. Proc Efendic S, Vranic M. Amelioration of hypoglyce- References Natl Acad Sci USA 1991;88:1296–1300 mia via somatostatin receptor type 2 antagonism 1. Vranic M. The effects of cortisol in guinea pigs 14. Miles PD, Yamatani K, Brown MR, Lickley HL, in recurrently hypoglycemic diabetic rats. Di- with normal and atrophic exocrine pancreas. VranicM.Intracerebroventricularadministration abetes 2013;62:2215–2222 Diabetes 1965;14:194–200 of somatostatin octapeptide counteracts the 24. Vranic M. Odyssey between Scylla and 2. Norwich KH, Radziuk J, Lau D, Vranic M. hormonal and metabolic responses to stress Charybdis through storms of carbohydrate metab- Experimental validation of nonsteady rate mea- in normal and diabetic dogs. Metabolism 1994; olism and diabetes: a career retrospective. Am J surements using a tracer infusion method and 43:1134–1143 Physiol Endocrinol Metab 2010;299:E849–E867