Mladen Vranic

Mladen Vranic, MD, DSc, O.C., O.Ont, FRSC, FRCP(C), FCAHS, Canadian Medical Hall of Fame[CMHF] April 3, 1930 — June 18, 2019,[1] was a Croatian-born diabetes researcher, best known for his work in tracer methodology, exercise and stress in diabetes, the metabolic effects of hormonal interactions, glucagon physiology, extrapancreatic glucagon, the role of the direct and indirect metabolic effects of insulin and the prevention of hypoglycemia. 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.

Mladen Vranić
Born(1930-04-03)3 April 1930
Zagreb, Croatia
Died18 June 2019(2019-06-18) (aged 89)
NationalityCroat Canadian
Alma materUniversity of Zagreb

Personal life and education

Vranic was born in 1930 to Vladimir Vranic and Ana Vranic in Zagreb, 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. 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.[2]

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 insulin.[2] 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 during a sabbatical leave and a visiting research fellow of Merton College at the University of Oxford. From 1973-1978 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 University of Zagreb, Croatia. 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.[3]

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.[4]

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 diabetes concentrates on the liver and/or the periphery. Vranic quantified hormonal and metabolic interactions involved in the physiology and pathogenesis 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 kinetics. He collaborated in the first clinical tracer studies on insulin resistance, hypertriglyceridemia, and the Cori cycle.[5][6]

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.[7][8][9][10]

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 catecholamines 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 affects the expression of GLUT2 gene and protein in diabetes.[11][12][13][14][15]

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.[16][17][18][19][20][21][22][23][24][25]

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.[15][26][27][28][29]

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.[30][31][32][33][34][35]

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.[36][37][38][39][40][41][42][43][44][45][46][47] 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".[48]

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 (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).[3]

References
  1. "Mladen Vranic MD DSc". Canadian Medical Hall of Fame. Retrieved January 1, 2020.
  2. Jiménez, Marina (Jun 4, 2009). "'I don't give up easily'". The Globe and Mail. Archived from the original on 4 March 2016. Retrieved 21 January 2014.
  3. Department of Physiology, University of Toronto. "Mladen Vranic". Archived from the original on March 4, 2014. Retrieved January 26, 2014.
  4. The Globe and Mail, July 18, 2019
  5. Radziuk, J., Norwich, K.H. and Vranic, M. (1978). "Experimental validation of measurements of glucose turnover in nonsteady state". American Journal of Physiology. 234: E84–E93.CS1 maint: multiple names: authors list (link)
  6. Finegood, D.T., Bergman, R.N. and Vranic, M. (1987). "Estimation of endogenous glucose production during hyperinsulinemic euglycemic glucose clamps: Comparison of unlabeled and labeled exogenous glucose infusates". Diabetes. 36 (8): 914–924. doi:10.2337/diabetes.36.8.914.CS1 maint: multiple names: authors list (link)
  7. Vranic, M., Pek, S. and Kawamori, R. (1975). "Increased "glucagon immunoreactivity" in plasma of totally depancreatized dogs". Diabetes. 23 (11): 905–912. doi:10.2337/diab.23.11.905.CS1 maint: multiple names: authors list (link)
  8. Vranic, M., Kawamori, R., Pek, S., Kovacevic, N. and Wrenshall, G.A. (1975). "The essentiality of insulin and the role of glucagon in regulating glucose turnover during strenuous exercise". Journal of Clinical Investigation. 57 (2): 245–255. doi:10.1172/jci108275. PMC 436648. PMID 1254723.CS1 maint: multiple names: authors list (link)
  9. Muller, W.A., Girardier, L., Seydoux, J., Berger, M., Renold, A.E. and Vranic, M. (1978). "Extrapancreatic glucagon and glucagon-like immunoreactivity in depancreatized dogs: a quantitative assessment of secretion rates and anatomical delineation of sources". Journal of Clinical Investigation. 62 (1): 124–132. doi:10.1172/jci109096. PMC 371745. PMID 659625.CS1 maint: multiple names: authors list (link)
  10. Doi, K., Prentki, M., Yip, C., Muller, W., Jeanrenaud, B. and Vranic, M. (1979). "Identical biological effects of pancreatic glucagon and a purified moiety of canine gastric glucagon. J". Journal of Clinical Investigation. 63 (3): 525–531. doi:10.1172/jci109331. PMC 371982. PMID 429572.CS1 maint: multiple names: authors list (link)
  11. Vranic, M., Morita, S. and Steiner, G. (1980). "Insulin resistance in obesity analyzed by the response of glucose kinetics to glucagon infusion". Diabetes. 29 (3): 169–176. doi:10.2337/diabetes.29.3.169.CS1 maint: multiple names: authors list (link)
  12. Wajngot, A., Roovete, A., Vranic, M., Luft, R. and Efendic, S. (1982). "Insulin resistance and decreased insulin response to glucose in lean Type II diabetics". Proceedings of the National Academy of Sciences. 79 (14): 4432–4436. Bibcode:1982PNAS...79.4432W. doi:10.1073/pnas.79.14.4432. PMC 346686. PMID 6750603.CS1 maint: multiple names: authors list (link)
  13. Kemmer, F.W., Sirek, A., Sirek, O.V., Perez, G. and Vranic, M. (1983). "Glucoregulatory mechanisms following hypophysectomy in diabetic dogs with residual insulin secretion". Diabetes. 32 (1): 26–34. doi:10.2337/diab.32.1.26. PMID 6129169.CS1 maint: multiple names: authors list (link)
  14. Wajngot, A., Giacca, A., Grill, V., Vranic, M. and Efendic, S. (1992). "The diabetogenic effects of glucocorticoids are more pronounced in low than in high insulin responders". Proceedings of the National Academy of Sciences. 89 (13): 6035–6039. Bibcode:1992PNAS...89.6035W. doi:10.1073/pnas.89.13.6035. PMC 402133. PMID 1631088.CS1 maint: multiple names: authors list (link)
  15. Giacca, A., Fisher, S., Gupta, R., Shi, Z.Q., Lickley, L. and Vranic, M. (1992). "Importance of peripheral mechanisms of insulin action for the regulation of hepatic glucose production in diabetes". Journal of Clinical Investigation. 90 (5): 1769–1777. doi:10.1172/JCI116051. PMC 443235. PMID 1430203.CS1 maint: multiple names: authors list (link)
  16. Kawamori, R.; Vranic, M. (1977). "Mechanisms of exercise-induced hypoglycemia in depancreatized dogs maintained on long acting insulin". Journal of Clinical Investigation. 59 (2): 331–337. doi:10.1172/jci108645. PMC 333364. PMID 833280.
  17. Issekutz, B.; Vranic, M. (1980). "Role of glucagon in the regulation of glucose production in exercising dogs". American Journal of Physiology. 238: E13–E20.
  18. Wasserman, D.H., Lickley, H.L.A. and Vranic, M. (1984). "Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs". Journal of Clinical Investigation. 74 (4): 1404–1413. doi:10.1172/jci111551. PMC 425308. PMID 6148356.CS1 maint: multiple names: authors list (link)
  19. Bjorkman, O., Miles, P., Wasserman, D., Lickley, L. and Vranic, M. (1988). "Regulation of glucose turnover during exercise in pancreatectomized, totally insulin deficient dogs: effects of ß-adrenergic blockade". Journal of Clinical Investigation. 81 (6): 1759–1767. doi:10.1172/jci113517. PMC 442622. PMID 3290252.CS1 maint: multiple names: authors list (link)
  20. Challis, R.A.J., Vranic, M. and Radda, G.K. (1989). "Bioenergetic changes during contraction and recovery in diabetic rat skeletal muscle". American Journal of Physiology. 256: E129–E137.CS1 maint: multiple names: authors list (link)
  21. Miles, P., Yamatani, K., Lickley, L. and Vranic, M. (1991). "Mechanism of glucoregulatory responses to stress and their deficiency in diabetes". Proceedings of the National Academy of Sciences. 88 (4): 1296–1300. Bibcode:1991PNAS...88.1296M. doi:10.1073/pnas.88.4.1296. PMID 1996330.CS1 maint: multiple names: authors list (link)
  22. Marliss EB, Vranic M (2002). "Intense exercise has unique effects on both insulin release and its role in glucoregulation: Implications for diabetes". Diabetes. 51 (Suppl 1): S271–S283. doi:10.2337/diabetes.51.2007.s271.
  23. Kaniuk NA, Kiraly M, Bates HE, Vranic M, Volchuck A, Brumell JH (2007). "Ubiquitinated-protein aggregates form in pancreatic β-cells during diabetes-induced oxidative stress and are regulated by autophagy". Diabetes. 56 (4): 930–939. doi:10.2337/db06-1160. PMID 17395740.
  24. Kiraly MA, Bates HE, Kaniuk N, Yue JT, Brummel J, Matthews SG, Riddell MC, Vranic M (2008). "Swim training prevents hyperglycemia in ZDF rats: Mechanisms involved in partial maintenance of β-cell function". American Journal of Physiology. Endocrinology and Metabolism. 294 (2): E271–E283. doi:10.1152/ajpendo.00476.2007. PMID 18029442.
  25. Bates HE, Sirek AS, Kiraly MA, Yue JT, Goche Montes D, Matthews SG, Vranic M (2008). "Adaptation to mild, intermittent stress delays development of hyperglycemia in the ZDF rat independent of food intake: role of habituation of the HPA axis". Endocrinology. 149 (6): 2990–3001. doi:10.1210/en.2007-1473. PMID 18325996.
  26. Giacca, A., Fisher, S., McCall, R.H., Shi, Z.Q. and Vranic M. (1997). "Direct and indirect effects of insulin in suppressing glucose production in depancreatized dogs: Role of glucagon". Endocrinology. 138 (3): 999–1007. doi:10.1210/en.138.3.999. PMID 9048601.CS1 maint: multiple names: authors list (link)
  27. Lewis, G.F., Vranic, M., Harley, P., and Giacca A. (1997). "Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans". Diabetes. 46 (7): 1111–1119. doi:10.2337/diabetes.46.7.1111.CS1 maint: multiple names: authors list (link)
  28. Lewis, G.F., Giacca, A., Vranic, M. and G. Steiner. (1998). "Acute direct and indirect effects of insulin on hepatic glucose and very low density lipoprotein (VLDL) production". Current Opinion in Endocrinology, Diabetes and Obesity. 5: 235–245. doi:10.1097/00060793-199811000-00001.CS1 maint: multiple names: authors list (link)
  29. Lewis, G.H., Carpentier, A., Vranic, M. and Giacca, A. (1999). "Resistance to insulin's direct hepatic effect in suppressing steady state glucose production in individuals with type 2 diabetes mellitus". Diabetes. 48: 570–576. doi:10.2337/diabetes.48.3.570.CS1 maint: multiple names: authors list (link)
  30. Efendic, S., Wajngot, A., Vranic, M. (1985). "Increased activity of the glucose cycle in the liver: early characteristic of Type II diabetes". Proceedings of the National Academy of Sciences. 82 (9): 2965–2969. Bibcode:1985PNAS...82.2965E. doi:10.1073/pnas.82.9.2965.CS1 maint: multiple names: authors list (link)
  31. Yamatani, K., Shi, Z., Giacca, A., Gupta, R., Fisher, S., Lickley, L. and Vranic, M. (1992). "Role of FFA-Glucose cycle in glucoregulation during exercise in total absence of insulin". American Journal of Physiology. Endocrinology and Metabolism. 263 (26): E646–E653. doi:10.1152/ajpendo.1992.263.4.e646.CS1 maint: multiple names: authors list (link)
  32. Marette, A., Richardson, J.M., Ramlal, T., Balon, T.W., Vranic, M., Pessin, J.F. and Klip, A. (1992). "Abundance, localization, and insulin-induced translocation of glucose transporters in red and white muscle of rat hind limb". American Journal of Physiology. Cell Physiology. 263 (32): C443–C452. doi:10.1152/ajpcell.1992.263.2.c443.CS1 maint: multiple names: authors list (link)
  33. Shi, Z.Q., Giacca, A., Fisher, S., Hubert Vidal, van de Werve, G. and Vranic, M. (1994). "Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog". Diabetes. 43 (11): 1284–1290. doi:10.2337/diabetes.43.11.1284.CS1 maint: multiple names: authors list (link)
  34. Tsakiridis, T., Vranic, M. and Klip, A. (1994). "Disassembly of the actin network inhibits insulin-dependent stimulation of glucose transport and prevents recruitment of glucose transporters in plasma membrane". Journal of Biological Chemistry. 269: 29934–29942.CS1 maint: multiple names: authors list (link)
  35. Mathoo, J.M.R., Shi, Z.Q., Klip, A. and Vranic, M. (1999). "Opposite effects of acute hypoglycemia and acute hyperglycemia on glucose transport and glucose transporters in perfused rat skeletal muscle". Diabetes. 48 (6): 1281–1288. doi:10.2337/diabetes.48.6.1281. PMID 10342817.CS1 maint: multiple names: authors list (link)
  36. Lickley, H.L.A., Kemmer, F.W., El-Tayeb, K.M.A. and Vranic, M. (1987). "Importance of glucagon in the control of futile cycling as studied in alloxan-diabetic dogs". Diabetologia. 30 (3): 175–182. doi:10.1007/bf00274224.CS1 maint: multiple names: authors list (link)
  37. Efendic, S., Karlander, S. and Vranic, M. (1988). "Mild Type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity". Journal of Clinical Investigation. 81 (6): 1953–1961. doi:10.1172/jci113543.CS1 maint: multiple names: authors list (link)
  38. Rastogi, K.S., Lickley, L., Jokay, M., Efendic, S. and Vranic, M. (1990). "Paradoxical reduction in pancreatic glucagon with normalization of somatostatin and decrease in insulin in normoglycemic alloxan-diabetic dogs: a putative mechanism of glucagon irresponsiveness to hypoglycemia". Endocrinology. 126 (2): 1096–1104. doi:10.1210/endo-126-2-1096. PMID 1967577.CS1 maint: multiple names: authors list (link)
  39. Shi, Z.Q., Rastogi, K.S., Lekas, M., Efendic, S., Drucker, D.J. and Vranic, M. (1996). "Glucagon response to hypoglycemia is improved by insulin-independent restoration of normoglycemia in diabetic rats". Endocrinology. 137 (8): 3193–3199. doi:10.1210/en.137.8.3193.CS1 maint: multiple names: authors list (link)
  40. Chan O, Chan S, Inouye K, Vranic M, Matthews SG (2001). "Molecular regulation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-induced diabetes: effects of insulin treatment". Endocrinology. 142: 4872–4879. doi:10.1210/en.142.11.4872.
  41. Inouye K, Shum K, Chan O, Mathoo J, Matthews SG, Vranic M (2002). "Effects of recurrent hyperinsulinemia with and without hypoglycemia on counterregulation in diabetic rats". American Journal of Physiology. Endocrinology and Metabolism. 282 (6): E1369–E1379. doi:10.1152/ajpendo.00480.2001. PMID 12006368.
  42. Chan O, Chan S, Inouye K, Shum K, Bilinski D, Matthews SG, Vranic M (2002). "Diabetes impairs hypothalamic-pituitary-adrenal (HPA) responses to hypoglycemia and insulin treatment normalizes HPA, but not epinephrine responses". Diabetes. 51 (6): 1681–1689. doi:10.2337/diabetes.51.6.1681. PMID 12031953.
  43. Inouye K, Yue JT, Chan O, Burdett E, Kim T, Akirav EM, Park E, Riddel MC, Matthews SG, Vranic M (2006). "Effects of insulin treatment without and with recurrent hypoglycemia on hypoglycemic counterregulation and adrenal catecholamine-synthesizing enzymes in diabetic rats". Endocrinology. 147 (4): 1860–1870. doi:10.1210/en.2005-1040. PMID 16396986.
  44. Yue JT, Burdett E, Giacca A, Efendic S, Vranic M (2012). "Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats". Diabetes. 61 (1): 197–207. doi:10.2337/db11-0690. PMC 3237655. PMID 22106159.
  45. Gaisano HY, MacDonald PE, Vranic M (2012). "Review article: Glucagon secretion and signaling in the development of diabetes". Frontiers in Physiology. 3: 1–12. doi:10.3389/fphys.2012.00349. PMC 3432929. PMID 22969729.
  46. Yue JT, Burdett E, Coy DH, Efendic S, Riddell M, Vranic M (2013). "Amelioration of hypoglycemia via somatostatin receptor type 2 antagonism in recurrently hypoglycemic diabetic rats". Diabetes. 62 (7): 2215–2222. doi:10.2337/db12-1523. PMC 3712070. PMID 23434929.
  47. Yue JT, Goche MD, Bates HE, Kiraly MA, Matthews SG, Vranic M (2007). "Recurrent stress attenuates expression of genes regulating hypoglycemic and restraint stress responses in diabetic rats". Diabetes. 56 (Suppl 1): A101.
  48. Vranic, M. (2010). "Odyssey between Scylla and Charybdis through storms of carbohydrate metabolism and diabetes: a career retrospective". American Journal of Physiology. Endocrinology and Metabolism. 299 (6): E849–E867. doi:10.1152/ajpendo.00344.2010. PMID 20823450.
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