Mladen Vranic, MD, DSc, O.C., O.Ont, FRSC, FRCP(C), FCAHS, Canadian Medical Hall of Fame MHFApril 3, 1930 – June 18, 2019, was a

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n-born

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

researcher, best known for his work in tracer methodology, exercise and stress in diabetes, the metabolic effects of hormonal interactions,

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...

physiology, extrapancreatic glucagon, the role of the direct and indirect metabolic effects of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

and the prevention of

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...

. Vranic was recognized by a number of national and international awards for his research contributions, mentoring and administration including the Orders of Canada (Officer) and Ontario.

Personal life and education

Vranic was born in 1930 to Vladimir Vranic and Ana Vranic in

Zagreb Zagreb ( , , , ) is the capital (political), capital and List of cities and towns in Croatia#List of cities and towns, largest city of Croatia. It is in the Northern Croatia, northwest of the country, along the Sava river, at the southern slop ...

, Croatia. His Jewish father converted to Christianity in 1920, and his mother converted upon marriage, but they were both non-observant. His father was a professor at the Faculty of Economics, Engineering, and Sciences, and Dean at the School of Economics and Engineering at the

University of Zagreb The University of Zagreb ( hr, Sveučilište u Zagrebu, ; la, Universitas Studiorum Zagrabiensis) is the largest Croatian university and the oldest continuously operating university in the area covering Central Europe south of Vienna and all of ...

. His mother ran a beauty salon in Zagreb. Vranic's immediate family escaped from the Holocaust due to the Italians' humane treatment of Jews. After the collapse of Italy, his family escaped with a partisan boat to Vis, an island governed by Allied Forces and Croatian partisans, and then on a British military ship to Taranto, Italy, which was already under supervision by the Allied Forces. During the last year of the war, his father joined the partisans. After the war, his family returned to Zagreb where Vranic completed high school, medical school (1955) and received a D.Sc. in physiology at the University of Zagreb in 1962. Vranic was invited to be the last post-doctoral fellow of Charles Best, a co-discoverer of

. He was promoted to assistant professor in 1965, associate professor in 1968 and full professor in 1972 at the University of Toronto Department of Physiology. Vranic was chair of the Department of Physiology from 1991 to 1995. In 1978 he was cross-appointed to professor in the Faculty of Medicine. In 1976-1977 he was an invited professor at the

University of Geneva The University of Geneva (French: ''Université de Genève'') is a public research university located in Geneva, Switzerland. It was founded in 1559 by John Calvin as a theological seminary. It remained focused on theology until the 17th centu ...

during a sabbatical leave and a visiting research fellow of

Merton College Merton College (in full: The House or College of Scholars of Merton in the University of Oxford) is one of the constituent colleges of the University of Oxford in England. Its foundation can be traced back to the 1260s when Walter de Merton, ch ...

at the

University of Oxford , mottoeng = The Lord is my light , established = , endowment = £6.1 billion (including colleges) (2019) , budget = £2.145 billion (2019–20) , chancellor ...

. From 1973 to 1978 he was appointed a member of the Institute of Biomedical Electronics and Engineering at the University of Toronto. He was an adjunct professor at the Karolinska Institute, Stockholm and at the

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. Vranic is also a member of the division of endocrinology and metabolism at the department of medicine and a fellow at the Senior Scholar's College at the University of Toronto. His first wife, Magda Vranic, was an assistant professor in rehabilitation medicine at the University of Toronto. She died of breast cancer at the age of 50. Together, they had two daughters (Iva and Maja (deceased). He married Linda Margaret Swallow in 1983. Together they had two daughters (Claire and Anne). Vranic died on June 18, 2019, in Toronto, Canada, of congestive heart failure.

Research

Vranic's research accomplishments reflect the supervision of a large number of graduate students and post-doctoral fellows, and wide collaboration with basic and clinical researchers who were crucial for interaction between basic science, molecular and cell biology, and clinical research. He has 214 peer-reviewed publications and is recognized for his research contributions in the following areas:

Tracer methodology

The treatment of

concentrates on the liver and/or the periphery. Vranic quantified hormonal and metabolic interactions involved in the physiology and

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of diabetes by developing tracer methods to separate the effects of diabetes on both. A large amount of his research accomplishments are due to measurement of non-steady state

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

kinetics. He collaborated in the first clinical tracer studies on insulin resistance,

hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and h ...

, and the

Cori cycle The Cori cycle (also known as the lactic acid cycle), named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactate, produced by anaerobic glycolysis in muscles, is transported to the liver and converte ...

Extrapancreatic glucagon

Diabetes reflects insulin deficiency and glucagon abundance. Vranic discovered extrapancreatic glucagon in dogs, which changed the prevailing dogma and permitted precise exploration of the roles of insulin and glucagon in physiology and diabetes, and provided conclusive evidence about the role of glucagon in diabetes. Before his research, glucagon was considered to have effects on many organs, but he was the first to measure the physiological role of glucagon, based on the effect of glucagon on glucose turnover. In contrast to prevailing beliefs, he was the first to indicate that glucagon only acts on the liver. He was also the first to quantify the physiological secretion of insulin.

Glucose metabolism

Vranic was the first to establish the critical role of glucagon-insulin interaction and the control of glucose metabolism during moderate exercise and of

catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a subst ...

s during strenuous exercise. He quantified the deficiencies in the release and effects of these hormones in diabetes. He also revealed how acute and chronic

hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

affects the expression of GLUT2 gene and protein in diabetes.

Exercise and stress

Vranic pioneered new concepts of the role of exercise in diabetes, leading to precise methods of controlling insulin, allowing type 1 diabetics to participate in the Olympics and clinicians to recommend exercise and healthy eating habits to prevent type 2 diabetes. He outlined molecular and physiological mechanisms whereby exercise training and adaptation to repetitive neurogenic stress can prevent diabetes in Zucker Diabetic Fatty (ZDF) rats.

Indirect effect of insulin

Vranic and others established that the indirect effect of insulin plays an important role in the regulation of glucose production in dogs. They confirmed this effect in humans and its role in

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

Mechanisms whereby the liver and muscle are protected against hypoglycemia

Vranic showed that because the muscle and the liver are protected against changes in glucose levels, these organs do not have diabetic complications.

Prevention of hypoglycemia

Vranic described the molecular mechanisms responsible for increased HPA axis in diabetes and for the diminished responses of HPA axis, catecholamines and glucagon to hypoglycemia. He proposed a new approach to decrease the threat of hypoglycemia by blocking the effect of

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...

. Vranic's research accomplishments and his main collaborators are summarized in a career retrospective entitled: "Odyssey between Scylla and Charybdis through storms of carbohydrate metabolism and diabetes: a career retrospective. Am J Physiol Endocrinol Metab 299: E849–E867, 2010".

Honours and awards

The Symposium to Honour Mladen Vranic for a Lifetime of Scientific Achievements and Mentoring, Toronto, Ontario, Canada (2010); he is a Laureate of the

Canadian Medical Hall of Fame __NOTOC__ The Canadian Medical Hall of Fame is a Canadian charitable organization, founded in 1994, that honours Canadians who have contributed to the understanding of disease and improving the health of people. It has an exhibit hall in London, O ...

(2009); the Canadian Diabetes Association Inaugural Life-Time Achievement Award for leadership in diabetes research and contribution to the Canadian diabetes community (2007); the honorary keynote speaker on Endocrinology and Diabetes; he is a member of The Society of Chinese Bioscientists of North America (2006); the Albert Renold Award from the American Diabetes Association for a distinguished career in the training of diabetes research scientists and facilitation of research (the only Canadian to receive this award) (2005); he is a Poll Visiting Scholar, University of Washington, Seattle, Washington (1995); the Novo Nordisk Lecture, Karolinska Institute, Stockholm (1995); the Solomon A. Berson Distinguished Lectureship of American Physiological Society - Endocrinology and Metabolism Section, FASEB, Atlanta (the first Canadian to receive this award) (1995); recognition for outstanding contributions to the Juvenile Diabetes Foundation, Canada (1994); the Mizuno Inaugural Lectureship and Award, Fourth International Symposium on Exercise and Diabetes - Osaka University, Japan (1992); the Banting Medal and Lectureship for Distinguished Scientific Achievement (American Diabetes Association) (1991); the R. Kroc Lectureship, University of Southern California School of Medicine, Los Angeles (1991); the Peter J. Laurie Memorial Lecture of Juvenile Diabetes Foundation Canada, Toronto (1991); the JDFI Mary Kugel Award (1989); the Inaugural Banting and Best Memorial Lecture and the Canadian Diabetes Association Award (1985); he is a Canada Council Killam Scholar (1988, 1989).

References

{{DEFAULTSORT:Vranic, Mladen 1930 births 2019 deaths Canadian diabetologists Croatian emigrants to Canada Fellows of the Royal Society of Canada Members of the Order of Ontario Officers of the Order of Canada Scientists from Toronto Scientists from Zagreb University of Zagreb alumni