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Strategies to increase -cell mass expansion

Drynda, Robert Lech

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King's College London

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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
1.1.1Islets of Langerhans............................................................................. 16

1.1.2Insulin secretion and action.................................................................. 16 1.1.3Diabetes............................................................................................... 18
1.2 Hormonal control of β-cell adaptation to pregnancy ..................................... 20
1.2.1Lactogenic hormones........................................................................... 21

1.2.2Hepatocyte Growth Factor signalling ................................................... 24 1.2.3Glucocorticoids..................................................................................... 25 1.2.4Oestradiol............................................................................................. 26
1.3 Placenta functions ........................................................................................ 27 1.4 The role of chemokines during pregnancy.................................................... 28 1.5 G protein-coupled receptors ......................................................................... 30
1.5.1GPCR signalling................................................................................... 31

1.5.2G proteins............................................................................................. 34 1.5.3Proteins modulating GPCR functions................................................... 36

2

1.5.4Signalling independent of G proteins ................................................... 37
1.6 WNT signalling ............................................................................................. 38
1.6.1WNT proteins and their receptors ........................................................ 38

1.6.2Canonical WNT/β-catenin signaling ..................................................... 38 1.6.3Regulation 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
2.1.1Mice for pancreatic islet BrdU staining................................................. 46

2.1.2Mice for placental GPCR ligand secretome and GPCRome analysis .. 47
2.2 Immunofluorescence staining....................................................................... 47
2.2.1Analysis of pancreatic β-cell proliferation............................................. 48

2.2.2Analysis of pancreatic β-cell area ........................................................ 48
2.3 Isolation of mouse pancreatic islets.............................................................. 49 2.4 RNA isolation................................................................................................ 49
2.4.1Total RNA isolation from mouse pancreatic islets and pancreatic MIN6 β-cells........................................................................................................... 50 2.4.2Determination of RNA concentration.................................................... 50

2.5 cDNA synthesis ............................................................................................ 51 2.6 Quantitative real-time polymerase chain reaction (qRT-PCR)...................... 52
2.6.1Normalization against mouse housekeeping gene............................... 53

2.6.2Screening for mRNA expression.......................................................... 55 2.6.3DNA agarose gel electrophoresis......................................................... 56 2.6.4Gene 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
3.3.1Changes in pancreatic β-cell replication during pregnancy.................. 70

3.3.2Loss 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
4.3.1Analysis of the mouse placenta GPCR ligand secretome during

pregnancy..................................................................................................... 83 4.3.2Analysis of the mouse pancreatic islet GPCRome during pregnancy .. 87
4.4 Discussion .................................................................................................... 96 Chapter 5.......................................................................................................... 109 A potential role for R-spondin 4 in β-cell adaptations to pregnancy.................. 109 5.1 Introduction................................................................................................. 110 5.2 Methods...................................................................................................... 112

4

5.3 Results........................................................................................................ 113 5.4 Discussion .................................................................................................. 121

Chapter 6.......................................................................................................... 125 General discussion ........................................................................................... 125 6.1 General discussion..................................................................................... 126 6.2 Future perspectives.................................................................................... 130

Appendix I......................................................................................................... 132 Appendix II........................................................................................................ 133 Appendix III....................................................................................................... 148 Appendix IV....................................................................................................... 160

References…………………………………………………………………………….184

5

Abstract

Aim: Failure of the functional β-cell mass to adapt to compensate for peripheral insulin resistance leads to the development of type 2 diabetes and gestational diabetes. The overall aim of this thesis was to study mechanisms regulating β-cell mass expansion, using pregnancy in mice as an experimental model in which the β-cell mass increases during gestation and returns to normal levels post-partum. The mechanisms underlying this adaptation are not well understood, although placental signals are thought to be involved. The first objective of the project was to analyse changes in the β-cell mass during pregnancy, and post-partum. The second objective was to quantify the expression of islet β-cell G protein-coupled receptors (GPCRs) and their placental ligands to identify novel placental signals potentially involved in β-cell adaptation to pregnancy. The third objective was to examine the effects of one of the novel placental signals, R-spondin 4 (RSPO4), on β-cell function. Methods: β-cell proliferation was quantified using immunohistochemical staining of pancreatic sections labelled with 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue. β-cell identity was confirmed by co-immunostaining for insulin and quantified by morphometric analysis. Islet GPCR and placental ligand mRNAs were quantified using a non-biased quantitative real time PCR (qRT-PCR) array

approach. The effects of RSPO4 on insulin secretion, β-cell proliferation and

survival were evaluated using radioimmunoassay, BrdU incorporation and caspase 3/7 apoptosis assays, respectively. Results: Mouse β-cells proliferated during pregnancy, peaking around gestational day 12, are the newly-formed β-cells which were not selectively lost post-partum. Placental expression of GPCR ligands was upregulated on day 12, and islet GPCR expression was differentially regulated during pregnancy. One candidate placental GPCR ligand, RSPO4, had pro-proliferative and insulinotropic effects in β-cells, consistent with an adaptive function during pregnancy. Conclusion: The placenta synthesizes many GPCR ligands, such as RSPO4, which have the potential to influence β-cell function during pregnancy, and which may have therapeutic potential in treating diabetes.

6

List of abbreviations

AKAP AKT (PKB) AP-2

A kinase anchoring protein Protein kinase B β2-adaptins

ATP

Adenosine triphosphate

Bcl6

B-cell lymphoma 6 protein Body mass index

BMI BrdU cAMP CaSR CCL11 CCL21 CCL7 CDK1 CDK4 CHOP C-MET C-MYC CNS

5-bromo-2'-deoxyuridine Cyclic adenosine monophosphate Calcium sensing receptor Eotaxin Chemokine (C-C motif) ligand 21 Chemotactic protein-3 Cyclin-dependent kinase 1 Cyclin-dependent kinase 4 CCAAT-enhancer-binding homologous protein Hepatocyte growth factor receptor V-Myc avian myelocytomatosis viral oncogene homolog Central nervous system

CPT-1 CX3CL1 DAG

Carnitine palmitoyltransferase 1 Fractalkine Diacylglycerol

EDTA ELISA ER

Ethylenediaminetetraacetate Enzyme-linked immunosorbent assay Endoplasmic reticulum

ERK

Extracellular signal–regulated kinase (MAPK) Fibroblast growth factor

FGF FITC

Fluorescein isothiocyanate

7

FoxO1 GAD65 GAPs GDM

Forkhead box protein O1 Glutamic acid decarboxylase GTPase-activating proteins Gestational diabetes mellitus

GH

Growth hormone

GLP1 GLUT GPCR GR

Glucagon-like peptide 1 receptor Glucose transporter G protein coupled receptor Glucocorticoid receptor

GSIS

Glucose stimulated insulin secretion Glycated haemoglobin

HbA1c HCC-1 HCC-4 HGF

Hemofiltrate CC chemokine-1 Hemofiltrate CC chemokine-4 Hepatocyte growth factor Human pituitary growth hormone Human placental growth hormone Hepatocyte nuclear factor-4α Human placental lactogen

hGH-N hGH-V HNF-4α hPL HTR1D

Serotonin receptor 1d (5-hydroksytryptamine receptor 1d)

HTR2B

Serotonin receptor 2b (5-hydroksytryptamine receptor 2b)

IGF-1 IHC

Insulin-like growth factor 1 Immunohistochemistry

Interleukin 1β

IL-1β INF-γ IPGTT IP3

Interferon γ

Intraperitoneal glucose tolerance test Inositol 1,4,5-trisphosphate Insulin receptor substrate

IRS

8

Jak2

Janus kinase 2

LTB4 LTB4R1 MafA

Leukotriene B4 Leukotriene B4 receptor 1 V-Maf masculoaponeurotic fibrosarcoma oncogene homologue A

MAPK

Mitogen activated protein kinase Macrophage-derived chemokine Major histocompatibility complex Macrophage inflammatory protein-1β Dual-specificity phosphoprotein phosphatase 1 Neurogenic differentiation 1

MDC MHC MIP-1β MKP-1 NeuroD1 NHERF2 NOD mice

Na+/H+ exchanger regulatory factor 2 Non-obese diabetic mice (type 1 diabetes mellitus model)

p18

Cyclin-dependend kinase 4 inhibitor C (CDKN2C) Cyclin-dependent kinase inhibitor 1 Cyclin-dependent kinase inhibitor 1B Cyclin-dependent kinase inhibitor 1C Pancreatic and duodenal homebox

p21 p27 p57 Pdx-1 PGC-1α

Peroxisome proliferator-activated receptor γ coactivator

1-α

PA

Phosphatidic acid

PDZ

Post-synaptic density of 95 kDa (PSD95)-disc large-zona occludens (PDZ)

PI

Phosphatidylinositol

PIP2 PI3K PIBF PKA PKC

Phosphatidylinositol 4,5-bisphosphate Phosphatidylinozytol 3-kinase Progesterone induced blocking factor 1 Protein kinase A Protein kinase C

9

PL

Placental lactogen

PLD

Phospholipase D

PPARα

PRL

Peroxisome proliferator-activated receptor α Prolactin

PRLR PTH1R PTH2R Rasd1 RSPO4 SAT

Prolactin receptor Parathyroid hormone 1 receptor Parathyroid hormone 2 receptor Dexamethasone-induced ras-related protein 1 R-spondin 4 Subcutaneous adipose tissue Standard error of the means Sarcoendoplasmic reticulum Ca2+-ATPase 2 SH2-plekstrin homology domain Signal transducer and activator of transcription 3 Signal transducer and activator 5 Type 1 diabetes mellitus

SEM SERCA2 SHC STAT3 STAT5 T1DM T2DM T3DM TGF-β1 TNF-α TPH1/2 TRB3 Tris

Type 2 diabetes mellitus Type 3 diabetes mellitus

Transforming growth factor β Tumour necrosis factor α

Tryptophan hydroxylase 1 and 2 Tribble 3 Tris(hydroxymethyl)aminomethane Under-carboxylated osteocalcin Uncoupling protein 2

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  • Pathophysiology of Gestational Diabetes Mellitus: the Past, the Present and the Future

    Pathophysiology of Gestational Diabetes Mellitus: the Past, the Present and the Future

    6 Pathophysiology of Gestational Diabetes Mellitus: The Past, the Present and the Future Mohammed Chyad Al-Noaemi1 and Mohammed Helmy Faris Shalayel2 1Al-Yarmouk College, Khartoum, 2National College for Medical and Technical Studies, Khartoum, Sudan 1. Introduction It is just to remember that “Pathophysiology” refers to the study of alterations in normal body function (physiology and biochemistry) which result in disease. E.g. changes in the normal thyroid hormone level causes either hyper or hypothyroidism. Changes in insulin level as a decrease in its blood level or a decrease in its action will cause hyperglycemia and finally diabetes mellitus. Scientists agreed that gestational diabetes mellitus (GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. From our experience most women with GDM in the developing countries are not aware of the symptoms (i.e., the disease will be symptomless). While some of the women will have few symptoms and their GDM is most commonly diagnosed by routine blood examinations during pregnancy which detect inappropriate high level of glucose in their blood samples. GDM should be confirmed by doing fasting blood glucose and oral glucose tolerance test (OGTT), according to the WHO diagnostic criteria for diabetes. A decrease in insulin sensitivity (i.e. an increase in insulin resistance) is normally seen during pregnancy to spare the glucose for the fetus. This is attributed to the effects of placental hormones. In a few women the physiological changes during pregnancy result in impaired glucose tolerance which might develop diabetes mellitus (GDM). The prevalence of GDM ranges from 1% to 14% of all pregnancies depending on the population studied and the diagnostic tests used.
  • VU Research Portal

    VU Research Portal

    VU Research Portal Genetic architecture and behavioral analysis of attention and impulsivity Loos, M. 2012 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Loos, M. (2012). Genetic architecture and behavioral analysis of attention and impulsivity. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 28. Sep. 2021 Genetic architecture and behavioral analysis of attention and impulsivity Maarten Loos 1 About the thesis The work described in this thesis was performed at the Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. This work was in part funded by the Dutch Neuro-Bsik Mouse Phenomics consortium. The Neuro-Bsik Mouse Phenomics consortium was supported by grant BSIK 03053 from SenterNovem (The Netherlands).