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Molecular Effects of Polyphenols in Experimental Type 2 Diabetes Mellitus and Metabolic Syndrome

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Molecular Effects of Polyphenols in Experimental Type 2 Diabetes Mellitus and Metabolic Syndrome Molecular Effects of Polyphenols in Experimental Type 2 Diabetes Mellitus and Metabolic Syndrome DISSERTATION zur Erlangung des naturwissenschaftlichen Doktorgrades der Julius-Maximilians-Universität Würzburg vorgelegt von Stoyan Dinkov Dirimanov aus Sofia Würzburg 2019 Eingereicht bei der Fakultät für Chemie und Pharmazie am: ........................................... Gutachter der schriftlichen Arbeit: 1. Gutachter: ................................................................. 2. Gutachter: ................................................................. Prüfer des öffentlichen Promotionskolloquiums: 1. Prüfer: .................................................................. 2. Prüfer: .................................................................. 3. Prüfer: .................................................................. Datum des öffentlichen Promotionskolloquiums: .................................................................. Doktorurkunde ausgehändigt am: .................................................................. 3 Die vorliegende Arbeit wurde auf Anregung von Frau Professor Dr. Petra Högger am Lehrstuhl für Pharmazeutische Chemie des Instituts für Pharmazie und Lebensmittelchemie der Julius-Maximilians-Universität Würzburg angefertigt. Meiner Eltern 3 Poster Presentations Dirimanov S., Xiao J., Högger P. Role of polyphenols in vascular health ISPMF 2015, 2nd International Symposium on Phytochemicals in Medicine and Food, June 26-29, 2015, Shanghai, China Dirimanov S., Xiao J., Högger P. The protective role of polyphenols in diabetes related vascular complications ICNPU 2015, 2nd International Conference on Natural Products Utilization: from Plant to Pharmacy Shelf, October 14-17, 2015, Plovdiv, Bulgaria 4 5 „Nicht durch die kraft höhlet der tropfen den stein, sondern durch häufiges fallen.” „Gutta cavat lapidem, non vi, sed saepe cadendo.” Ovid 5 Acknowledgments First of all, I would like to express my sincere gratitude to Prof. Dr. Petra Högger for accepting me as a doctoral student and giving me the opportunity to get involved in a project regarding intriguing and socially significant topic. In addition, I am very grateful for her awesome supervision, original ideas, understanding and readiness to discuss openly every challenge that occurred during the project. I would like to thank Prof. Ing. Zdeňka Ďuračková (Comenius University in Bratislava) and the Horphag Research for organizing and carrying out the clinical study and for kindly providing volunteers’ samples for the present investigations. Special thanks are due to Prof. Dr. Christoph Sotriffer for the opportunity to collaborate with his working group and to learn a lot about in silico models. I am very grateful to Mr. Mathias Diebold for his time, support, discussions, and also for supplying me with several compound databases for virtual screenings. I would like to gratefully acknowledge the organizations BAYHOST and FAZIT-Stiftung for providing me a financial support, and thus making the completion of this work possible. Furthermore, I would like to thank the persons who positively assessed my progress and supported me for obtaining and prolonging my funding: Prof. Dr. Petra Högger, Prof. Dr. Michael Decker, and PD Dr. med. Asparouh Iliev. Moreover, I would like to thank to: • The present and former members from the working groups of Prof. Högger (Roswitha Scheblein, Dr. Frederic Vollmers, Dr. Martin Haas, Dr. Melanie Mülek, Dr. Steffen Jeßberger, Dr. Maike Scherf-Clavel, Dr. Jianbo Xiao, Dr. Hui Cao, Dr. Lisa Schaaf, Andreas Pospiech, Linda Volpp, Florian Lang, Charlotte Beier, Theresa Häfner, Arthur Felker, Jasmin Bayer) and Prof. Scherf-Clavel (Prof. Dr. Oliver Scherf-Clavel, Bettina Friedl, Sebastian Zimmermann, Maximilian Stapf) for the positive attitude, friendship, and helpfulness. Danke für alles! • Prof. Dr. Jianbo Xiao for providing me the opportunity to present parts of my work on the ISPMF 2015 conference in China • The colleagues from the Chair for Drug Formulation and Delivery (working group Prof. Meinel) who readily shared their equipment and discussed intriguing scientific issues with me, especially: Dr. Marcus Gutmann, Dr. Gabriel Jones, Dr. Fang Wu, and Dr. Alexandra Braun. • My colleagues for the pleasant time during the teaching activities (5. Semester): Theresa, Christine, Klaus, Daniela, Maike, Melanie, Felix, David and Frederic. • Dr. Stefan Ivanov, Vania Dirimanova and Eng. Liubomir Bambov who checked some parts of the present thesis for spelling. Special thanks to Stefan for our talks and his expert opinion regarding a variety of scientific topics. 6 7 Furthermore, I am very thankful to my family and friends who supported me and encouraged me all the time. Last but not least, I would like to thank you Giovanna for staying by my side and for sharing every single moment of sadness and joy during the years of my study. 7 Table of Contents A Introduction ........................................................................................... 14 1 Diabetes mellitus .................................................................................................. 14 1.1 Background ........................................................................................................... 14 1.2 Types of diabetes .................................................................................................. 14 1.2.1 Type 1 diabetes ..................................................................................................... 14 1.2.2 Type 2 diabetes ..................................................................................................... 15 1.2.3 Further types of diabetes ....................................................................................... 15 1.3 Prediabetes ............................................................................................................ 15 1.4 Insulin resistance .................................................................................................. 16 1.5 Endothelial dysfunction and vascular complications ........................................... 17 1.6 Management of T2DM ......................................................................................... 17 2 Diabetes and cell signaling ................................................................................... 19 2.1 PI3K/Akt ............................................................................................................... 19 2.1.1 Protein structure of Akt kinase ............................................................................. 20 2.1.2 Akt isoforms ......................................................................................................... 21 2.1.3 Regulation of Akt activity .................................................................................... 21 2.1.4 Akt substrates ....................................................................................................... 23 2.1.5 Akt and the cardiovascular system ....................................................................... 25 2.1.6 Akt inhibitors ........................................................................................................ 26 2.2 AMPK ................................................................................................................... 27 2.2.1 AMPK – protein structure and regulation ............................................................ 27 2.2.2 AMPK – cellular functions and substrates ........................................................... 28 2.3 MAPK ................................................................................................................... 30 3 Polyphenolic compounds ...................................................................................... 31 3.1 Background ........................................................................................................... 31 3.2 Classification ........................................................................................................ 31 3.3 Beneficial effects .................................................................................................. 33 3.3.1 Polyphenols and diabetes...................................................................................... 34 3.3.2 Polyphenols and cardiovascular diseases ............................................................. 36 3.4 Safety of polyphenols ........................................................................................... 38 3.5 Pycnogenol® ......................................................................................................... 41 3.5.1 Pycnogenol® – beneficial effects .......................................................................... 41 3.5.2 Pycnogenol® – pharmacokinetics ......................................................................... 42 3.5.3 Pycnogenol® – pharmacodynamics ...................................................................... 42 4 Aims of the thesis ................................................................................................. 44 Table of Contents B Results and Discussion ........................................................................ 45 1 Cellular effects of Pycnogenol® in healthy individuals ........................................ 45 1.1 Pycnogenol® effects on active GLP-1, DPP IV, relaxin-2, and adiponectin ........ 45 1.2 Effects of Pycnogenol® on GLP-1 (active) ........................................................... 46 1.2.1 Background:
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