dc.contributor.advisor | Rupnik, Marjan Prof. Dr. | |
dc.contributor.author | Tsiaze, Ernest Beaudelaire | |
dc.date.accessioned | 2014-03-31T08:53:01Z | |
dc.date.available | 2014-04-09T22:50:04Z | |
dc.date.issued | 2014-03-31 | |
dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-5E73-D | |
dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4437 | |
dc.language.iso | eng | de |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.subject.ddc | 610 | de |
dc.title | Age-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic beta cells | de |
dc.type | doctoralThesis | de |
dc.contributor.referee | Moser, Tobias Prof. Dr. | |
dc.date.examination | 2014-04-02 | |
dc.description.abstracteng | ATP-sensitive K<sup><sup>+</sup></sup> channels (K<sub<ATP</sub> channels) regulate cellular energy metabolism in control of membrane excitability. The K<SUB>ATP</SUB> channel of pancreatic β-cells is composed of SUR1 and Kir6.2 subunits. Kir6.2<sup>-/-</sup> mice have a defective K<SUB>ATP</SUB> channel and can mimic the phenotype of persistent hyperinsulinaemia hypoglycaemia of infancy (PHHI) where the stimulus-secretion coupling underlying insulin secretion is disrupted. In this study, a transient hypoglycaemia in young (2 - 4 weeks old) and a progressive hyperglycaemia in ageing (5 - 60 weeks old) Kir6.2<sup>-/-</sup> mice were observed compared to control. Furthermore, a pancreatic tissue slice preparation was used as a novel technique to reassess islets morphology and to study the electrophysiological properties of Kir6.2<sup>-/-</sup> β-cells in a near native environment. Using this novel approach, age-linked differences in cyto-architecture reflecting the defective glucose homeostasis were seen in Kir6.2<sup>-/-</sup> mice. Moreover, the coupling of membrane excitation to exocytosis was verified using the patch clamp technique that enables a high resolution measurement of membrane capacitance (C<sub>m</sub>) changes upon exocytosis of hormone. I observed a more efficient stimulus-secretion coupling in β-cells of young Kir6.2<sup>-/-</sup> mice compared to ageing Kir6.2<sup>-/-</sup> mice. This enhanced stimulus-secretion coupling was further verified by the application of repetitive trains of stimulation. To test if the more efficient stimulus-secretion coupling was due to enhanced calcium (Ca<sup>2+</sup>) sensitivity of exocytosis, the efficacy of Ca<sup>2+</sup> to trigger secretion was analyzed and found to be increased. Additionally, the constitutive bursting and spiking electrical activity as well as the larger high voltage activated (HVA) Ca<sup>2+</sup>current density monitored in pancreatic β-cells from Kir6.2<sup>-/-</sup> mice may explain the known elevated basal [Ca<sup>2+</sup>]<sub>c</sub> and provide more insight in clarifying the late steps of stimulus-secretion coupling during glucose metabolism in Kir6.2<sup>-/-</sup> β-cells. These findings should also promote the understanding of the pathophysiology of PHHI and other K<SUB>ATP</SUB> channels related pancreatic diseases. | de |
dc.contributor.coReferee | Schwappach, Blanche Prof. Dr. | |
dc.subject.eng | KATP channels | de |
dc.subject.eng | Kir6.2 ablated mice | de |
dc.subject.eng | Persistent Hyperinsulinaemia Hypoglycaemia of Infancy | de |
dc.subject.eng | Pancreatic tissue slice | de |
dc.subject.eng | Patch-clamping | de |
dc.subject.eng | Exocytosis | de |
dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5E73-D-3 | |
dc.affiliation.institute | Medizinische Fakultät | de |
dc.subject.gokfull | GOK-MEDIZIN | de |
dc.subject.gokfull | Physiologie / Pathophysiologie - Allgemein- und Gesamtdarstellungen (PPN619875283) | de |
dc.description.embargoed | 2014-04-09 | |
dc.identifier.ppn | 781978025 | |