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Α-Cell Signalling in Glucose- Regulated Glucagon Secretion

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Α-Cell Signalling in Glucose- Regulated Glucagon Secretion Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1478 α-Cell signalling in glucose- regulated glucagon secretion QIAN YU ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0387-1 UPPSALA urn:nbn:se:uu:diva-356478 2018 Dissertation presented at Uppsala University to be publicly examined in B21, Biomedical Centre, Husargatan 3, Uppsala, Thursday, 13 September 2018 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor David W Piston (Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, U.S.A). Abstract Yu, Q. 2018. α-Cell signalling in glucose-regulated glucagon secretion. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1478. 49 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0387-1. Glucagon is a blood glucose-elevating hormone released from α-cells in the islets of Langerhans during hypoglycaemia. Glucagon is critical for glucose homeostasis and inappropriate regulation of its secretion underlies both impaired counter-regulation of hypoglycaemia and chronic hyperglycaemia in diabetes patients. The mechanisms by which glucose controls glucagon secretion are poorly understood, but have been suggested to involve both direct effects of the sugar on α-cells and indirect effects mediated by paracrine factors released within the islet, including insulin and gamma-hydroxybutyrate (GHB) from β-cells, and somatostatin from δ-cells. This thesis addresses the role of the intracellular messengers ATP, Ca2+ and cAMP in glucose-regulated glucagon secretion. Various fluorescence microscopy techniques were used to monitor changes of these messengers in single, dispersed α-cells and those in situ within intact islets, and glucagon secretion from islets was measured with an immunoassay. Glucose induced elevations of α-cell ATP, which were smaller and showed a left- shifted concentration-dependence compared to those in β-cells, consistent with α-cells being less dependent on oxidative metabolism and optimized for sensing hypoglycaemia. α-Cells showed Ca2+ oscillations with little glucose dependence. Surprisingly, these oscillations became synchronized in phase with Ca2+ oscillations in β-cells at high glucose. Since Ca2+ is a main trigger of exocytosis in both cell types, and since insulin and glucagon secretion is pulsatile in opposite phase, the results indicate that factors other than Ca2+ are more important for shaping glucagon secretion. Consistent with a key role of cAMP for the regulation of glucagon release, the concentration of the messenger was relatively high in α-cells at low glucose concentrations, and elevations of glucose suppressed cAMP in parallel with glucagon secretion. This effect was independent of paracrine signalling from insulin and somatostatin. The glucose-induced suppression of glucagon secretion was prevented by cAMP-elevating agents and mimicked by inhibitors of protein kinase A. GHB lacked effects both on Ca2+, cAMP and glucagon secretion from mouse islets, but tended to stimulate glucagon secretion by a somatostatin- receptor-dependent mechanism in human islets. The data indicate that GHB is not an inhibitor of glucagon secretion and that α-cell-intrinsic glucose sensing involves signalling via cAMP and protein kinase A. Keywords: Islets, glucagon, insulin, somatostatin, ATP, cAMP, Ca2+ , GHB, oscillations, α- cell, β-cell, δ-cell Qian Yu, Department of Medical Cell Biology, Box 571, Uppsala University, SE-75123 Uppsala, Sweden. © Qian Yu 2018 ISSN 1651-6206 ISBN 978-91-513-0387-1 urn:nbn:se:uu:diva-356478 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-356478) Dedicated to my dearest family List of Papers This thesis is based on the following papers. I. Li, J., Yu, Q., Ahooghalandari, P., Gribble, F.M., Reimann, F., Tengholm, A., and Gylfe, E. Sub-membrane ATP and Ca2+ kinetics in -cells: unexpected signaling for glucagon secretion. FASEB J. 2015; 29:3379-3388. II. Yu, Q., Shuai, H.Y., Ahooghalandari, P., Gylfe, E., and Tengholm, A. Glucose controls glucagon secretion by directly modulating cAMP in α-cells. Submitted manuscript. III. Yu, Q., Gylfe, E., and Tengholm, A. Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion. Manuscript. IV. Yu, Q., Lai, BK., Ahooghalandari, P., Helander, A., Gylfe, E., Gilon, P., Tengholm, A. γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion. Manuscript. Reprints were made with permission from the publisher. Contents Introduction ................................................................................................... 11 Pancreatic islets ........................................................................................ 12 Glucose-dependence of islet hormone secretion ...................................... 12 Pulsatile release of islet hormones ........................................................... 13 Stimulus-secretion coupling and oscillatory signalling in β-cells ....... 13 Glucose regulation of glucagon secretion ................................................ 15 Glucose metabolism in α-cells ............................................................. 15 Neural regulation ................................................................................. 15 Paracrine regulation by β-cell factors .................................................. 15 Paracrine inhibition by somatostatin from δ-cells ............................... 16 Juxtracrine control of glucagon secretion ............................................ 17 α-cell-intrinsic regulation of glucagon secretion ................................. 17 Role of cAMP in insulin and glucagon secretion ..................................... 19 cAMP production and degradation ...................................................... 19 cAMP effector proteins ........................................................................ 20 Measurements of cAMP ...................................................................... 21 Aims .............................................................................................................. 22 Methods ........................................................................................................ 23 Islet isolation, culture, virus infection ...................................................... 23 Measurements of ATP, Ca2+ and cAMP .................................................. 23 Fluorescence microscopy ......................................................................... 25 Measurements of glucagon and insulin secretion ..................................... 26 Signal processing and statistics ................................................................ 27 Results and discussion .................................................................................. 28 Identification of α- and β-cells within intact islets ................................... 28 2+ Glucose increases [ATP]pm in opposite phase to [Ca ]pm in α- and β- cells .......................................................................................................... 28 2+ High glucose synchronizes the [ATP]pm and [Ca ]pm oscillations between α- and β-cells .............................................................................. 29 Somatostatin shapes pulsatile glucagon secretion independently of 2+ [Ca ]pm ..................................................................................................... 30 Dual effects of glucose on cAMP regulation in α-cells ............................ 31 Glucose lowers [cAMP]pm via an α-cell intrinsic pathway independent of paracrine effects of somatostatin and insulin ....................................... 32 Phosphodiesterase activation contributes to glucose suppression of α-cell [cAMP]pm ....................................................................................... 32 Glucose regulation of α-cell [cAMP]pm does not seem to involve the Ca2+-store operated mechanism ................................................................ 33 cAMP regulation of glucagon secretion is mediated by protein kinase A ............................................................................................................... 33 γ-hydroxybutyrate does not mediate glucose inhibition of glucagon secretion ................................................................................................... 34 Conclusions ................................................................................................... 36 Acknowledgements ....................................................................................... 37 References ..................................................................................................... 39 Abbreviations AC Adenylyl cyclase ADP Adenosine diphosphate ATP Adenosine triphosphate [ATP]pm Sub-plasma membrane ATP concentration 2+ 2+ [Ca ]pm Sub-plasma membrane Ca concentration cAMP 3’,5’-cyclic adenosine monophosphate [cAMP]pm Sub-plasma membrane cAMP concentration FRET Förster resonance energy transfer GABA γ-aminobutyric acid GHB γ-hydroxybutyrate + KATP channel ATP-sensitive K channel PDE Phosphodiesterase PFK1 Phosphofructokinase-1 PKA Protein kinase A SOC Store-operated Ca2+ channel SSTR Somatostatin receptor TIRF Total internal reflection fluorescence Introduction Blood glucose homeostasis is maintained mainly by the glucose-elevating and –reducing hormones glucagon
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