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Age-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic beta cells

dc.contributor.advisorRupnik, Marjan Prof. Dr.
dc.contributor.authorTsiaze, Ernest Beaudelaire
dc.titleAge-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic beta cellsde
dc.contributor.refereeMoser, Tobias Prof. Dr.
dc.description.abstractengATP-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
dc.contributor.coRefereeSchwappach, Blanche Prof. Dr.
dc.subject.engKATP channelsde
dc.subject.engKir6.2 ablated micede
dc.subject.engPersistent Hyperinsulinaemia Hypoglycaemia of Infancyde
dc.subject.engPancreatic tissue slicede
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullPhysiologie / Pathophysiologie - Allgemein- und Gesamtdarstellungen (PPN619875283)de

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