Non-invasive extracellular recordings of electrical activity from whole intact islets of Langerhans and the development of the medium throughput BetaScreen device

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Dokumentart: Dissertation
Date: 2020-08-06
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Pharmazie
Advisor: Drews, Gisela (Prof. Dr.)
Day of Oral Examination: 2018-06-08
DDC Classifikation: 570 - Life sciences; biology
610 - Medicine and health
Keywords: Diabetes , Insulin , Elektrophysiologie
Other Keywords: KATP-Kanal
Beta Zellen
Langerhans Inseln
Islets of Langerhans
Beta cells
License: Publishing license including print on demand
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Type-2 diabetes mellitus (T2DM) is a tremendous health problem worldwide. The present work demonstrates that the microelectrode array (MEA) technique is an excellent tool to study in vitro the molecular basis of functional changes in beta-cells during the development of T2DM. I have provided the “proof-of-principle” that electrical activity can be reproducibly recorded using intact single islets and extracellular electrode arrays. The results revealed with the MEA technology are comparable to results obtained with traditional electrophysiological techniques, like e.g. the patch clamp technique or recordings with intracellular electrodes (Pfeiffer et al., 2011). Moreover, I established an in vitro model that allows for the first time long-term investigations of beta-cell function through repetitive electro-physiological recordings of the same culture using the MEA technology (Schönecker et al., 2014). Further, I have shown that the application of oxidative stress which is crucial in the development of T2DM has a strong effect on the electrical behaviour of the single islets in vitro and that a SOD mimetic protects beta-cells against acute oxidative stress demonstrating the central role of SOD as an antioxidant defence mechanism within pancreatic islets (Schönecker et al., 2014). The next fundamental achievement was to show for the first time that the MEA technique allows measurements of electrical activity of islets isolated from human biopsies. Human islets exhibit glucose-dependent electrical activity and the electrical activity was increased by tolbutamide and inhibited by diazoxide. The Na+ channel inhibitor tetrodotoxin markedly reduced electrical activity in hu-man islets, but does not affect electrical activity of mouse islets (Schönecker et al., 2015). Within the scope of the BMBF-program KMU innovative (Biotechnol-gie-BioChance, #0316162B) and in cooperation with the company Multi Channel Systems (MCS) this study presents for the first time the development of the Be-taScreen device which allows to record semi automatically from up to 25 islets simultaneously. Importantly, the throughput of the acute recordings is now in-creased by a factor of 25 and paves the way for pharmaceutical medium-through-put drug screenings. Furthermore, I could show that the BetaScreen device is also suitable to record electrical activity from human islets.

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