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Strategies to Increase ß-Cell Mass Expansion This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents .................................................................................................. 2 Abstract ................................................................................................................. 6 List of abbreviations .............................................................................................. 7 List of figures....................................................................................................... 11 List of tables ........................................................................................................ 13 Acknowledgements ............................................................................................. 14 Chapter 1 ............................................................................................................ 15 Introduction ......................................................................................................... 15 1.1 β-cells and diabetes ...................................................................................... 16 1.1.1 Islets of Langerhans ............................................................................. 16 1.1.2 Insulin secretion and action .................................................................. 16 1.1.3 Diabetes ............................................................................................... 18 1.2 Hormonal control of β-cell adaptation to pregnancy ..................................... 20 1.2.1 Lactogenic hormones ........................................................................... 21 1.2.2 Hepatocyte Growth Factor signalling ................................................... 24 1.2.3 Glucocorticoids ..................................................................................... 25 1.2.4 Oestradiol ............................................................................................. 26 1.3 Placenta functions ........................................................................................ 27 1.4 The role of chemokines during pregnancy .................................................... 28 1.5 G protein-coupled receptors ......................................................................... 30 1.5.1 GPCR signalling ................................................................................... 31 1.5.2 G proteins............................................................................................. 34 1.5.3 Proteins modulating GPCR functions ................................................... 36 2 1.5.4 Signalling independent of G proteins ................................................... 37 1.6 WNT signalling ............................................................................................. 38 1.6.1 WNT proteins and their receptors ........................................................ 38 1.6.2 Canonical WNT/β-catenin signaling ..................................................... 38 1.6.3 Regulation of the WNT pathway by R-spondins ................................... 40 1.7 Aims and objectives ...................................................................................... 44 Chapter 2 ............................................................................................................ 45 Materials and methods ........................................................................................ 45 2.1 Animals ......................................................................................................... 46 2.1.1 Mice for pancreatic islet BrdU staining ................................................. 46 2.1.2 Mice for placental GPCR ligand secretome and GPCRome analysis .. 47 2.2 Immunofluorescence staining ....................................................................... 47 2.2.1 Analysis of pancreatic β-cell proliferation ............................................. 48 2.2.2 Analysis of pancreatic β-cell area ........................................................ 48 2.3 Isolation of mouse pancreatic islets .............................................................. 49 2.4 RNA isolation ................................................................................................ 49 2.4.1 Total RNA isolation from mouse pancreatic islets and pancreatic MIN6 β-cells.. ......................................................................................................... 50 2.4.2 Determination of RNA concentration .................................................... 50 2.5 cDNA synthesis ............................................................................................ 51 2.6 Quantitative real-time polymerase chain reaction (qRT-PCR) ...................... 52 2.6.1 Normalization against mouse housekeeping gene ............................... 53 2.6.2 Screening for mRNA expression .......................................................... 55 2.6.3 DNA agarose gel electrophoresis ......................................................... 56 2.6.4 Gene expression quantification ............................................................ 56 2.7 Analysis of RSPO4 protein concentration in mouse plasma during pregnancy……………………………………………………………………………….57 3 2.8 Culturing MIN6 β-cells .................................................................................. 57 2.9 MIN6 β-cell proliferation assay ..................................................................... 58 2.10 MIN6 β-cell apoptosis assay ....................................................................... 61 2.11 Measuring insulin secretion from MIN6 cells ............................................... 63 2.12 Insulin radioimmunoassay ........................................................................... 64 2.13 Statistical analysis ....................................................................................... 66 Chapter 3 ............................................................................................................ 67 Analysis of mouse pancreatic β-cell proliferation during pregnancy ................... 67 3.1 Introduction ................................................................................................... 68 3.2 Methods ........................................................................................................ 69 3.3 Results.......................................................................................................... 70 3.3.1 Changes in pancreatic β-cell replication during pregnancy .................. 70 3.3.2 Loss of β-cells post-partum .................................................................. 73 3.4 Discussion .................................................................................................... 75 Chapter 4 ............................................................................................................ 79 Analysis of the mouse placental GPCR ligand secretome and pancreatic islet GPCRome during pregnancy .............................................................................. 79 4.1 Introduction ................................................................................................... 80 4.2 Methods ........................................................................................................ 82 4.3 Results.......................................................................................................... 83 4.3.1 Analysis of the mouse placenta GPCR ligand secretome during pregnancy ..................................................................................................... 83 4.3.2 Analysis of the mouse pancreatic islet GPCRome during pregnancy .. 87 4.4 Discussion .................................................................................................... 96 Chapter 5 .........................................................................................................
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