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oai:gupea.ub.gu.se:2077/645442020-08-25T01:39:24Zcom_2077_282com_2077_17com_2077_10556col_2077_544col_2077_310col_2077_10557

Miranda, Caroline 2020-06-12T13:50:29Z 2020-06-12T13:50:29Z 2020-06-12 978-91-7833-952-5 (PRINT) 978-91-7833-953-2 (PDF) http://hdl.handle.net/2077/64544 ABSTRACT The mechanisms controlling glucagon secretion by α-cells in islets of Langerhans were studied. We generated mice with the light-activated ion channel ChR2 specifically expressed in β-, α-, and δ-cells, and explored the spatio-temporal relationship between cell activation and glucagon release. In paper I, ChR2 was expressed in β-cells and photoactivation of these cells rapidly depolarized neighbouring δ-cell but produced a more delayed effect on α-cells. We showed that these effects were mediated via electrical signalling from the β- to δ-cells via gapjunction. Once activated, the δ-cells released somatostatin which repolarized the αcells following its intercellular diffusion from the δ- to the α-cells. In paper II we used a novel antibody for detection of somatostatin, which showed great efficiency compared with commercially available antibodies. Immunostaining of intact islets showed an islet-wide network involving α- and δ-cells. Furthermore, we used immunostaining to compare the islet architecture as pertaining to δ-cell number, and morphology between islets from healthy human donors and type 2 diabetic donors and found that the number of δ-cells in type 2 diabetic islets is reduced. In paper III we expressed ChR2 in α- and δ-cells in two novel mouse models. We showed that photoactivation of α-cells depolarized the α-cells and evoked action potential firing, effects that were associated with stimulation of glucagon secretion regardless of the glucose concentration. In islets exposed to 1 mM glucose, photoactivation of δ-cells transiently hyperpolarized α-cells, produced a long-lasting inhibition of glucagon exocytosis and inhibited glucagon secretion at 1 mM glucose but had no additional inhibitory effect at 6 or 20 mM glucose. The effect of somatostatin was so strong that it was possible to suppress glucagon secretion by photoactivation of δ-cells even when measurements were performed using the perfused mouse pancreas. eng I. Briant, L. Reinbothe, T. Spiliotis, J. Miranda, C. Rodriguez, B. Rorsman, P. δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin. J. Physiol. 2018, Jan 15: 596(2): 197-215 ::DOI::10.1113/JP274581 II. Miranda, C. Kothegala, L. Lundequist, A. G. Belekar, P. Krieger, J-P. Presto, J. Rorsman, P. Gandasi, N.R. Structural correlations influencing regulation of somatostatin-releasing δ-cells (Manuscript) III. Miranda, C. Tolö, J. Santos, C. Kothegala, L. Mellander, L. Hill, T. Briant, L. Tarasov, A.I. Zhang, Q. Gandasi, N.R. Rorsman, P. Dou, H. Intraislet paracrine crosstalk between islet cells unveiled by optogentic activation of α- and δ-cells. (Manuscript) Type 2 Diabetes Glucagon α-Cell Optogenetics Paracrine control of glucagon secretion in the pancreatic α-cell: Studies involving optogenetic cell activation text Doctoral thesis Doctor of Philosophy (Medicine) caroline.miranda@gu.se University of Gothenburg. Sahlgrenska Academy Institute of Neuroscience and Physiology. Department of Physiology Torsdagen den 3 september 2020, Kl 13.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg https://gu-se.zoom.us/j/66671958661?pwd=Qlpka3NKUHVmenJVYnFKemlXMFM3Zz09 2020-09-03 SA open.access