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MEDICAL FACULTY UNIVERSITY OF ZAGREB
UNIVERSITY CLINIC FOR DIABETES, ENDOCRINOLOGY AND METABOLIC DISEASES
VUK VRHOVAC

e-mail: boris.rocic@idb.hr

1970. - Researcher, Vuk Vrhovac University Clinic
1971. - Diploma, Faculty of Technology (BTO), University of Zagreb
1972. - Head, Radioisotope laboratory, Vuk Vrhovac University Clinic
1979. - Dr.Sc. Thesis, Faculty of Biotechnology, University of Zagreb
1980. - Head, Laboratory of Biological Chemistry, Vuk Vrhovac University Clinic
1980. - Head, Laboratory of Endocrinology, Vuk Vrhovac University Clinic
1981. - Scientific Associate, Faculty of Biotechnology, University of Zagreb
1981. - 1997. - Guest scientist, Oxford University, Oxford, UK (ALIS award, British Council)
1982. - Head, Department of Laboratory Medicine, Vuk Vrhovac University Clinic
1985. - Scientific Asociate, Faculty of Technology, University of Zagreb
1991. - Vice-director of the Vuk Vrhovac scientific Institute
1992. - Assistant Professor, Departmrnt of Internal Medicine, Medical Faculty, Zagreb
1998. - Associate Professor, Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Medical Faculty, Zagreb
1999. - Scientific Advisor , Medical Faculty, Zagreb
2004. - Full Professor, Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Medical Faculty, Zagreb

Member

Section for Diabetes of the Croatian Medical Association
Croatian society of Medical Biochemists
New York Academy of Sciences
American Diabetes Association
European Association for the study of Diabetes
WHO Member on Laboratory Aspects of the Joint Programme on      
European Diabetes Care

Research projects

# Biogenesis of diabetogenic compounds and etiology of diabetes (Principal investigator: B. Ročić)

# The role of guanidines and purines in the etiology of diabetes (Principal investigator: B. Ročić)

# Specific toxic mechanisms in the etiology of diabetes mellitus (Principal investigator: B. Ročić)

# Oxidative Transformations of Purines and Etiology of Diabetes Mellitus (Investigators: M. Poje, # B. Ročić /Zagreb/ and S.J.H. Ashcroft /Oxford/; ALIS, British Council)

# Cytotoxic mechanisms in the etiology of diabetes mellitus (Principal investigator: B. Ročić)

Biogenetic hypothesis on the etiology of diabetes is associated with the discovery of chemical experimental diabetes provoked after application of alloxan (Dunn,McLetchie, Lancet, 1943). Specific diabetogenic effect of alloxan on the pancreatic B-cells of the islets of Langerhans, and a possibility that alloxan  could be derived from purines (uric acid) suggested the relation between diabetes and abnormalities in purine metabolism (Poje,Ročić,Škrabalo, Diab.Croat., 1980). Experimental evidences have permanently renovated the interest for biogenetic hypothesis, however,  until recently, the idea that diabetes is the consequence of oxidative transformation of purines to alloxan was speculative. The main problem  in the critical evaluation of biogenetic hypothesis was the scanty knowledge of chemistry of the oxidative transformation of purines. In                       

our previous research we have synthetized the key intermediates of uric acid oxidation what is prerequisite for the chemistry of unknown quinonoide systems (Poje,Ročić, Tetrahedron  Lett., 1979; Poje,Paulus,Ročić, J.Org.Chem., 1980; Poje, Ročić, Vicković, Bruvo, J.Chem.Soc.Chem. Commun., 1982; Poje,Ročić,Sikirica,Vicković,Bruvo, J.Med.Chem., 1983) with the specific diabetogenic activity (Poje,Ročić, Experientia, 1980;  Tait,Poje,Ročić,Ashcroft, Diabetologia, 1983; Dominis,Ročić,Ashcroft,Poje,ibid.,1984; Ročić,Harrison,Ashcroft,Poje ,Diab.Res.Clin. Practic,1985;Harrison,Poje,Ročić,Ashcroft, Biochem.J.,1986; Ashcroft,Harrison, Ročić,Poje, Br.J.Pharmac., 1986). Recent hypothesis indicate that diabetes (type I) developes as a consequence of the deleterious autoimmune destruction mediated  by toxic oxygen radicals, however, the question of the initial B-cell damage remained obscure. It was first demonstrated that uric acid has an important biological role as the main antioxidant in primates, with high efficiecy in protection against free oxygen radicals what indicate  a new dimension in biological redox-processes of uric acid, and suggest mechanisms of B-cell destruction compatible with biogenetic In our recent investigations we have rigorously examined the model of  the antioxidant capacity of uric acid (Vučić,Ročić,Božikov,Pavlić-Renar,Mesić,et al.,Diabetologia, 1995; Vučić,Ročić, Knežević-Ćuća,Profozić,Pavlić-Renar et al., ibid., 1996; Vučić,Ročić,Božikov,Ashcroft, Horm.Metab.Res., 1997; Ročić,Vučić,Knežević-Ćuća,Radica,Pavlić-Renar et al., Exp.Clin.Endocrinol.Diabetes, 1997).These investigations  presented evidence on the specific diabetogenic activity of intermediates in oxidative uric acid degradation, with a strong suggestion that uric acid itself might play a key role in regulation of glucose homeostase (Ročić,Vučić,Poje, Bioorg.Med.Chem.Lett. 2005). Oxidative transformations of purines are still a controversal research sphere, although there is an increasing interest for purine transformation in DNA, degenerative diseases, and aging processes (Chem.Rev.,1998). Only few reports have indicated the damage of DNA bases in diabetes suggesting that these effects are connected with oxidative stress and toxicity of  oxygen radicals It is speculated, so far, that the main course of DNA damage  comprises the conversion of guanine to 8-oxoguanine, an 2-N-analogon of uric acid (Nucleic Acid Res., 1999).

Results of these investigations should present more information on the role of urate in the etiology of diabetes, with the far reaching importance in understanding of mutagenesis and the progress of diseases which are a direct consequence of DNA damage.

Scientific and professional activities

Consultant:  Laboratory of Organic Chemistry, Faculty of Sciences, Zagreb; Pharmacia AB, Uppsala,Sweden.  Collaborative projects with: The Nuffield Department of Clinical Biochemistry,  University of Oxford, UK; R. Bošković Institute, Zagreb;  Department of Medicine, Medical School, The University of Newcastle, UK;  The Diabetes Institute, Norfolk, USA;  Medical Department, County Hospital, Aarhus, Danska;  Department of Endocrinology and Metabolism, Karolinska Sjukhuset, Stockholm, Švedska;  Asta Medica, Medical Department, Frankfurt, Njemačka;  Shire, Pharmaceutical Development, Hampshire, UK;  Hoechst/Aventis, Medical Department, Frankfurt, Germany;  Thomae/Boehringer, Biberach, Germany;  Viatris, Drug Development, Frankfurt, Germany;  Zentaris AG, Frankfurt, Germany;  Institute of Experimental Endocrinology, Centre of Physiologycal Sciences, Bratislava,Slowakia;  Diabetes Institute, Madras, India;  University Medical School, Szeged, Hungary;  Laboratoires de Recherches Metaboliques, Universite de Geneve,Switzerland;  Islet Processing Facility, Istituto Scientifico S. Raffaele, Milano, Italy. Teaching: From 1972 - Medical Faculty University of Zagreb. Postgraduate teaching from  1976. Invited lecturer: WHO/IDF International Teaching Seminar on Appropriate Laboratory Technology, Cordoba, Spain; Boston, Stockholm, Zagreb International Postgraduate Course on Diabetology, Dubrovnik; CEEPUS Summer School of Medical Biochemistry, Dubrovnik. Mentor of 5 MSc Thesis, 2 DSc Thesis i 4 undergraduate diploma works. Other activities: Secretary general of the European Postgraduate Course on Diabetology (1972., 1975., 1978) i I WHO/IDF International Teaching Seminar on Appropriate Laboratory Technology (1983.); Member of the Editorial board of  Diabetologia Croatica; First Secretary general of the Croatian Section for Diabetes of the Croatian Medical Association; Member of the professional board for medical biochemistry of the Croatian Ministry of Health; Member of the Project Council of the Croatian Ministry of Science,etc.

Selected publications

Ročić B, Vučić Lovrenčić M, Poje M, and Ashcroft SJH: Effect of creatine on the pancreatic β-cell. Exp Clin Endocrinol Diabetes 2007;115:29-32

Ročić B, Vučić Lovrenčić M, Poje N, Poje M, and Bertuzzi F. Uric acid may inhibit glucose-induced insulin secretion via binding to an essential arginine residue in rat pancreatic β-cell. Bioorg Med Chem Lett 2005;15:1181-1184

Miličević Z, Knežević J, Sabioncello A, Roglic G, and Ročić B: β-Cell secretory function and CD25+ lymphocyte subsets in the early stage of type 1 diabetes mellitus.  Exp Clin Endocrinol Diabetes 2004;112:181-186

Lipovac V, Gavella M, Vučić M, Mrzljak V, and Ročić B: Effect of creatine on erythrocyte rheology in vitro. Clin Rheolog Microcirculation  2000;22:45-52

Vučić M, Ročić B, Božikov V, and Ashcroft SJH: Plasma uric acid and total antioxidant status in patients with diabetes mellitus.  Horm Metab Res 1997;29:355-357

Ročić B, Vučić M, Knežević Ćuća J, Radica A, Pavlić Renar I, Profozić V, and Metelko Ž: Total plasma ntioxidants in first-degree relatives of patients with insulin-dependent diabetes. Exp Clin Endocrinol Diabetes 1997;105:213-217

Ročić B, Turk Z, Mišur I, and Vučić M: Effect of creatine on glycation of albumin in vitro. Horm Metab Res 1995;27:511-512

Ročić B, Breyer D, Granić M, and Milutinović S: The effect of guanidino substances from uremic plasma on insulin binding to erythrocyte receptors in uremia. Horm Metab Res 1991;23:490-494

Ashcroft SJH, Harrison D, Poje M, and RočićB: Structure-activity relationships of alloxan-like compounds derived from uric acid. Br J Pharmac 1986;89:469-472

Harrison D, Poje M, Ročić B, and Ashcroft SJH: Effects of dehydrouramil on protein phosphorylation and insulin secretio0n in rat islets of Langerhans. Biochem J 1986;237:191-196

Dominis M, Ročić S, Ashcroft SJH, Ročić B, and Poje M: Diabetogenic action of alloxan-like compounds: cytotoxic effects of 5-hydroxy-psuedouric acid and dehydrouramil hydrate hydrochloride on rat pancreatic β-cells. Diabetologia 1984;27:403-406

Poje M, Ročić B, Sikirica M, Vicković I, and Bruvo M: Oxidation of uric acid. 4. Synthesis, structure, and diabetogenic action of 5-imino-2,4,6(1H, 3H,5H)-pyrimidinetrione salts and their alloxan-like covalent aducts. J Med Chem 1983;26:861-864

Breyer D, Cvitković P, Škrabalo Z, Pedersen O, and Ročić B: Decreased insulin binding to erythrocytes in subjects with Klinefelter's syndrome. J Clin Endocrinol Metab 1981;83:654-655

Poje M, Paulus EF, and Ročić B: Oxidation of uric acid. 1. Structural revision of uric acid glycols. J Org Chem 1980;45:65-68

Poje M and Ročić B: Diabetogenic action of alloxan-like derivatives of uric acid. Experientia 1980;36:78

Poje M and Ročić B: A reinvestigation of alloxan-like compounds derived from uric acid. Tetrahedron Lett 1979;1979:4781-4782

B. Rocic, N. Bedernjak Bajuk, P. Rocic, D.S. Weber, J. Boras and M. Vucic Lovrencic, Comparison of antihyperglycemic effects of creatine and Metformin in type II diabetic patients; Clin. Invest. Med., 32, 322-326 (2009).