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Dissertation Facklam 2017.Pdf Aus der Universitätsfrauenklinik Rostock Direktor Professor Dr. med. habil. B. Gerber DER EINFLUSS DER ORALEN ANTIDIABETIKA METFORMIN UND THIAZOLIDINDION AUF DIE HORMONEXPRESSION HUMANER TROPHOBLASTZELLEN Inauguraldissertation zur Erlangung des akademischen Grades Doktor der Medizin der Medizinischen Fakultät der Universität Rostock vorgelegt von Anna Facklam geboren am 09.01.1986 in Schwerin Rostock, 2016 1 Dekan: Professor Dr. med. univ. E. C. Reisinger Medizinische Fakultät, Universität Rostock 1. Gutachter: Professor Dr. med. V. Briese Universitätsfrauenklinik und Poliklinik, Klinikum Südstadt Rostock 2. Gutachter: Professor Dr. rer. nat. B. Hinz Institut für Pharmakologie und Toxikologie, Universität Rostock 3. Gutachter: Professor Dr. med. E. Schleußner Klinik für Frauenheilkunde und Geburtshilfe, Friedrich-Schiller-Universität Jena Datum der Einreichung: 11. Juni 2016 Datum der Verteidigung: 20. Dezember 2016 2 Inhaltsverzeichnis Abkürzungsverzeichnis .............................................................................................................. 6 Abbildungs- und Tabellenverzeichnis ........................................................................................ 9 1. Einleitung ............................................................................................................................. 10 1.1 Plazenta ........................................................................................................................... 10 1.1.1 Aufbau und Entwicklung der Plazenta..................................................................... 10 1.1.2 Funktion der Plazenta............................................................................................... 14 1.1.3 Trophoblastzellen ..................................................................................................... 15 1.2 Veränderungen der Plazenta durch Diabetes mellitus in der Schwangerschaft ............ 18 1.3 Gestationsdiabetes und Diabetes mellitus in der Schwangerschaft ................................ 18 1.3.1 Definition und Epidemiologie .................................................................................. 18 1.3.2 Riskofaktoren und Pathophysiologie ....................................................................... 20 1.3.3 Maternale und fetale Risiken des Gestationsdiabetes .............................................. 21 1.3.4 Diagnose des Gestationsdiabetes ............................................................................. 23 1.3.5 Nichtmedikamentöse Therapie ................................................................................ 25 1.3.6 Medikamentöse Therapie ......................................................................................... 27 1.3.7 Insulin ...................................................................................................................... 29 1.3.8 Orale Antidiabetika .................................................................................................. 30 1.4 Metformin und Thiazolidindion ..................................................................................... 32 1.4.1 Metformin ................................................................................................................ 32 1.4.2 Thiazolidindione ...................................................................................................... 34 1.5 Plazenta und Hormone (Östrogen und Progesteron) ...................................................... 36 1.5.1 Östrogen ................................................................................................................... 38 1.5.2 Progesteron .............................................................................................................. 39 2. Zielstellung ........................................................................................................................... 41 3. Hypothesen ........................................................................................................................... 42 4. Material ................................................................................................................................ 43 4.1 Plazenta ........................................................................................................................... 43 4.2 Antibiotika und Antikoagulantien für die Aufbewahrung der Plazenten ....................... 43 4.3 Lösungen, Puffer und Chemikalien zur Trophoblastisolierung siehe Anhang 1 ............ 43 4.4 Zellkulturmedium ........................................................................................................... 43 4.5 Medikamente .................................................................................................................. 43 4.5.1 Medikamentenverdünnungen ................................................................................... 44 4.6 Biochemische Assays ..................................................................................................... 44 3 4.7 Immunhistochemische Assays ........................................................................................ 45 5. Methoden .............................................................................................................................. 46 5.1 Isolierung der Trophoblastzellen .................................................................................... 46 5.2 Zellzählung und Erstellung der Zellkonzentration ......................................................... 49 5.3 Methodischer Ablauf ...................................................................................................... 51 5.4 Charakterisierung der Trophoblastzelle .......................................................................... 52 5.5 Biochemische Assays ..................................................................................................... 53 5.5.1 LDH-Zytotoxizitätstest ............................................................................................ 53 5.5.2 CellTiter-Blue® -Zytotoxizitätstest ......................................................................... 55 5.5.3 PlGF-Immunoassay .................................................................................................. 56 5.6 Statistik ........................................................................................................................... 57 6. Ergebnisse ............................................................................................................................ 59 6.1 Charakterisierung der Trophoblastzellen ........................................................................ 59 6.2 Mikroskopische Vitalitätsprüfung .................................................................................. 60 6.3 LDH-Zytotoxizitätstest ................................................................................................... 70 6.4 CellTiter-Blue® -Zytotoxizitätstest ................................................................................ 75 6.5 Glukose, Östrogen und Progesteron unter dem Einfluss von Metformin ....................... 77 6.5.1 Einfluss von Metformin auf die Glukosekonzentration im Überstand .................... 77 6.5.2 Einfluss von Metformin auf die Östrogenkonzentration im Überstand ................... 78 6.5.3 Einfluss von Metformin auf die Progesteronkonzentration im Überstand .............. 81 6.6 Glukose, Östrogen und Progesteron unter dem Einfluss von Thiazolidindion .............. 82 6.6.1 Einfluss von Thiazolidindion auf die Glukosekonzentration im Überstand ............ 83 6.6.2 Einfluss von Thiazolidindion auf die Östrogenkonzentration im Medium.............. 84 6.6.3 Einfluss von Thiazolidindion auf die Progesteronkonzentration im Überstand ...... 85 6.7 Ergebnisse des PlGF-Immunoassay ............................................................................... 86 7. Diskussion ............................................................................................................................ 90 7.1 Die zytotoxische Wirkung von Metformin und Thiazolidindion .................................. 90 7.2 Der Einfluss von Metformin und Thiazolidindion auf die Glukosekonzentration im Zellkulturmedium ................................................................................................................. 99 7.3 Der Einfluss von Metformin und Thiazolidindion auf die Hormonexpression ............ 100 7.4 Der Einfluss von Metformin und Thiazolidindion auf die PlGF-Expression ............... 104 7.5 Orale Antidiabetika in der Therapie des Gestationsdiabetes und Diabetes mellitus in der Schwangerschaft ................................................................................................................. 107 7.6 Ausblick: orales Insulin ................................................................................................ 111 4 7.7 Methodenkritik ............................................................................................................. 112 8. Zusammenfassung .............................................................................................................. 114 9. Thesen ................................................................................................................................ 117 10. Literaturverzeichnis .......................................................................................................... 119 11. Anhang ............................................................................................................................
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