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Novel Enteroendocrine Cell Receptors Regulating Incretin Secretion and Glucose Homeostasis

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Novel Enteroendocrine Cell Receptors Regulating Incretin Secretion and Glucose Homeostasis NOVEL ENTEROENDOCRINE CELL RECEPTORS REGULATING INCRETIN SECRETION AND GLUCOSE HOMEOSTASIS by Grace Beatrice Flock A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science, University of Toronto © Copyright by Grace Beatrice Flock 2012 NOVEL ENTEROENDOCRINE CELL RECEPTORS REGULATING INCRETIN SECRETION AND GLUCOSE HOMEOSTASIS Grace Beatrice Flock Doctor of Philosophy Institute of Medical Science University of Toronto 2012 ii Abstract The proglucagon‐derived peptides (PGDP) are expressed in islet alpha and gut enteroendocrine L cells. Although glucagon, glucagon‐like peptide‐1 (GLP‐1), and glucagon like peptide‐2 (GLP‐2) are derived from the same proglucagon gene, energy ingestion and nutrient assimilation represses proglucagon biosynthesis in the α‐cell, but stimulates the synthesis and secretion of GLP‐1 and GLP‐2 from the gut L cell. In the work presented in this thesis, I have identified novel G protein‐coupled receptors that stimulate GLP‐1 secretion and improve glucose homeostasis. G protein‐coupled receptor 119 (GPR119) is expressed in enteroendocrine cells and islets and is activated by nutrients (fatty acid derivatives) and small specific synthetic agonists. Activation of GPR119 enhances glucose‐ stimulated insulin secretion from islet β‐cells and promotes incretin release from enteroendocrine cells in a cyclic AMP (cAMP)‐dependent manner. To determine the importance of gut hormones for the glucoregulatory actions of GPR119, I examined GPR119 activation in normal mice, isolated islets, and in mice with inactivation of gut hormone receptors. GPR119 activation directly stimulates insulin secretion from islets in vitro, yet requires intact incretin receptor signaling and enteral glucose exposure for optimal improvement of glucose tolerance in vivo. In contrast, activation of GPR119 inhibits gastric emptying independent of incretin receptors through GPR119‐dependent pathways. Another important feature of β‐cell GPCRs coupled to cAMP generation is their ability to protect the β‐cell from external injury. I have shown that mice lacking GPR119 (GPR119‐/‐) are more susceptible to streptozotocin (STZ)‐induced apoptosis while pharmacological activation of GPR119 failed to protect the β‐cell from STZ‐induced injury. Furthermore, GPR119‐/‐ mice iii display impaired incretin secretion and beta cell function when chronically fed a high fat (HF) diet. Conversely, abrogation of GPR119 signaling does not affect the beta‐cell adaptation (increased islet number and size) to the metabolic demand of high‐fat feeding. Mechanisms to increase β‐cell mass and function may be useful tools for the treatment of type 2 diabetes. GLP‐1 stimulates insulin biosynthesis, β‐cell proliferation and exerts anti‐ apoptotic actions on β‐cells. To delineate novel mechanisms, important for the regulation of proglucagon gene expression and GLP‐1 secretion in the enteroendocrine L‐cell, I carried out a microarray‐based gene expression profiling and transcriptional networks analysis using RNA from murine gut GLUTag cells. To identify mechanisms unique to enteroendocrine L‐cells, I used the islet αTC1 cell line for comparative purposes. I identified a novel progesterone mediated signaling pathway involving activation of membrane GPCRs for the control of GLP‐1 secretion. In summary, these studies establish that GPR119 engages multiple complementary pathways for control of glucose homeostasis and suggest that endogenous GPR119 signaling plays a critical role in β‐cell adaptation to cytotoxic injury and nutrient excess. The studies provide evidence for a novel role for progesterone, regulating GLP‐1 secretion and controlling glucose homeostasis. iv Acknowledgments First, I would like to start thanking my dearest grandfather, “abuelo Guillermo”, who has supported and encouraged me to follow my dreams. Without him, I would have not been able to start this amazing journey. Since the first days upon arriving to Canada, without speaking any English and with very limited resources, he has been my model, always in my mind and in my heart, reminding me that failure is never an option. I am also grateful to my parents who always believed in me and supported my endeavors. I would like to give my sincere gratitude to my supervisor, Dr Daniel J. Drucker, who has supported and believed that it was important for me to complete my PhD studies. Without his support and understanding, becoming a Doctor in Philosophy would not have been possible. Furthermore, I am grateful to the members of my advisory committee, Dr Patricia Brubaker, Dr Adria Giacca and Dr Tony Lam for their thoughtful recommendations throughout my studies. I also like to thank profoundly Dr Bernardo Yusta who had planted in my mind the seed to pursue and finish my PhD, a project that came to a stall many years earlier due to life circumstances. He has provided me with helpful discussions, and valuable advice. Bernardo had supported me with kind and encouraging words during troubled times as I was moving forward in this journey. Many of the experiments could not have been done without the technical assistance of two very valuable members of Dr Drucker’s laboratory; Dianne Holland and Xiemin Cao and for that, I am very grateful to them. I would like to thank former members of the lab; Ms Meghan Sauve, who had always been very kind and had given her time to assist me with several experiments, and Ben Lamont and Adriano Maida for their advice with a series of experimental protocols. I am profoundly thankful to my dear friend, Theresa Kane, who did a masterful job in editing my thesis. v Finally but not least, it is very important for me to extend my gratitude to my dear husband, Alberto, who has been a wonderful partner and friend supporting my studies, working overtime at home, looking after our beloved son, keeping the house together during those times when I was consumed by my work and responsibilities. As well, I like to thank my son Axel, who has been so patient and understanding. Thanks Axel and remember that there is no limit for what you can become and never stop learning! vi Table of Contents Abstract .................................................................................................................................. iii Acknowledgments ................................................................................................................... v Table of Contents ................................................................................................................... vii List of Tables ........................................................................................................................... xi List of Figures ......................................................................................................................... xii List of Abbreviations .............................................................................................................. xv Author Contribution and Dissemination of Research ............................................................. xx Dedication ............................................................................................................................xxii Chapter 1 INTRODUCTION ....................................................................................................... 1 1.1 GLUCAGON‐LIKE PEPTIDE‐1 ............................................................................................ 2 1.1.1 The Incretin Effect .......................................................................................................... 2 1.1.2 The Proglucagon‐Derived Peptides................................................................................ 2 1.1.3 The GLP‐1 Receptor ....................................................................................................... 4 1.1.4 GLP‐1 actions, focus on the islet β‐cell .......................................................................... 7 1.1.5 GLP‐1 extra‐pancreatic effects .................................................................................... 13 1.2 GLUCAGON‐LIKE PEPTIDE‐1 (GLP‐1) SECRETION ........................................................... 14 1.2.1 The Enteroendocrine System ....................................................................................... 14 1.2.2 In vitro models for the study of GLP‐1 secretion regulation ....................................... 16 1.2.3 GLP‐1 secretion regulation .......................................................................................... 19 1.2.4 Indirect regulation of GLP‐1 secretion: First phase .................................................... 20 1.2.5 Direct regulation of GLP‐1 secretion: Second phase ................................................... 26 1.3 GPR119 ........................................................................................................................ 41 1.3.1 GPR119 expression ...................................................................................................... 41 1.3.2 GPR119 signal transduction ......................................................................................... 41 1.3.3 GPR119 endogenous ligands ....................................................................................... 42 vii 1.3.4 GPR119 insulinotropic actions ..................................................................................... 43 1.3.5 GPR119 agonists and GLP‐1 secretion ........................................................................
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