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Unravelling the Link Between Insulin Resistance and Androgen Excess

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Unravelling the Link Between Insulin Resistance and Androgen Excess Unravelling the link between insulin resistance and androgen excess by Michael O’Reilly A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Clinical and Experimental Medicine College of Medical and Dental Sciences The University of Birmingham August 2015 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Abstract Insulin resistance and androgen excess are the cardinal phenotypic features of polycystic ovary syndrome (PCOS). The severity of hyperandrogenism and metabolic dysfunction in PCOS are closely correlated. Aldoketoreductase type 1C3 (AKR1C3) is an important source of androgen generation in human adipose tissue, and may represent a link between androgen metabolism and metabolic disease in PCOS. We performed integrated in vitro studies using a human preadipocyte cell line and primary cultures of human adipocytes, coupled with in vivo deep phenotyping of PCOS women and age- and BMI-matched controls. We have shown that insulin upregulates AKR1C3 activity in primary female subcutaneous adipocytes. AKR1C3 mRNA expression increased with obesity. Androgens were found to increase lipid accumulation in human adipocytes. In clinical studies, androgen exposure induced relative suppression of adipose lipolysis in PCOS women, supporting a role for androgens in lipid accumulation. Androgens were detectable in adipose fluid from PCOS women, and correlated with systemic markers of androgen metabolism. Using comprehensive in vivo, ex vivo, and in vitro techniques, we have shown regulation of adipose androgen generation through AKR1C3, with evidence of a vicious circle of hyperinsulinaemia, adipose androgen generation and lipid accumulation. These data identify AKR1C3 as a promising therapeutic target in PCOS. II Acknowledgements Acknowledgements I would like to thank my supervisors, Professor Wiebke Arlt and Professor Jeremy Tomlinson, for their guidance, availability and mentorship in both academic and clinical medicine throughout this thesis. You have fuelled my appetite for endocrinology and encouraged me to always strive for excellence. I am grateful to the Arlt research group and colleagues in CEDAM, without whom the work presented in this thesis would not have been possible. I hope that the friendships forged during my time here will continue long into the future. I am most grateful to past and present members of the Shadow Ninja running fraternity, who motivate ruthlessly and refuse to accept mediocrity. I would particularly like to thank past and present CEDAM stalwarts Craig Doig, Ian Rose, Laura Gathercole, Iwona Bujalska, Stuart Morgan and Rachel Crowley for their help over the years. A special thanks to my father, John, who has taught me all I know about being the best person and professional I can be, to my sister Maeve and brother David who support me in everything I do, and to my mother, Marguerite, who sadly is no longer with us, but who has moulded me into the person I am today. I would like to dedicate this thesis to my wife Laura and son Senan, who made their life with me in Birmingham to support my career, and who have stood by me through tough times, bad moods and sleepless nights. Without you, none of this would have been possible. III Table of contents Table of contents 1 General Introduction ............................................................................................................. 1 1.1 Introduction .............................................................................................................................. 2 1.2 An introduction to polycystic ovary syndrome (PCOS) ........................................................ 4 1.2.1 Diagnostic criteria ............................................................................................................... 4 1.2.2 Clinical features ................................................................................................................... 7 1.3 Physiology of insulin action and insulin resistance .............................................................. 13 1.3.1 Insulin structure and secretion ........................................................................................... 13 1.3.2 Insulin signaling ................................................................................................................ 16 1.3.3 Metabolic actions of insulin .............................................................................................. 18 1.3.4 Molecular features of insulin resistance ............................................................................ 20 1.3.5 Monogenic disorders of insulin resistance ........................................................................ 21 1.4 Physiology of androgen secretion and androgen excess in females .................................... 25 1.4.1 Androgen biosynthesis ...................................................................................................... 25 1.4.2 Peripheral (pre-receptor) androgen metabolism ................................................................ 31 1.4.3 The role of androgens in female health and development ................................................ 35 1.4.4 Monogenic disorders of androgen excess ......................................................................... 42 1.5 Links between insulin resistance and androgen excess ....................................................... 47 1.5.1 Evidence for regulation of androgen metabolism by insulin ............................................ 48 1.5.2 Evidence linking primary androgen excess with insulin resistance ................................. 53 1.6 Adipose tissue .......................................................................................................................... 58 1.6.1 Adipose tissue embryology and morphology .................................................................... 58 1.6.2 Adipose tissue proliferation .............................................................................................. 59 1.6.3 Adipose tissue differentiation ............................................................................................ 61 1.6.4 Adipocyte lipid metabolism .............................................................................................. 64 1.7 Adipose tissue and androgens ................................................................................................ 73 1.7.1 Effects of androgens on adipose tissue function ............................................................... 74 IV Table of contents 1.7.2 Pre-receptor androgen metabolism in adipose tissue ........................................................ 82 1.8 Summary, hypotheses and aims ............................................................................................ 87 1.8.1 Adipose tissue is a key organ of androgen generation in PCOS ....................................... 87 1.8.2 Insulin is a key regulator of adipose and systemic androgen metabolism ........................ 88 1.8.3 Androgens play a crucial role in adipose tissue function, including adipogenesis and lipid metabolism ..................................................................................................................................... 88 2 General Methods ............................................................................................................... 90 2.1 Primary human preadipocyte and adipocyte isolation ....................................................... 91 2.1.1 Principle ............................................................................................................................ 91 2.1.2 Solutions ............................................................................................................................ 91 2.1.3 Method .............................................................................................................................. 92 2.2 Preadipocyte cell line .............................................................................................................. 93 2.2.1 Solutions ............................................................................................................................ 93 2.3 MIN6 mouse insulinoma cell line .......................................................................................... 94 2.4 Realtime quantitative PCR .................................................................................................... 95 2.4.1 RNA extraction and quantification ................................................................................... 95 2.4.2 Complementary DNA synthesis and amplification – reverse transcription ...................... 95 2.4.3 Realtime PCR .................................................................................................................... 96 2.5 Steroid extraction and measurement by liquid chromatography/tandem mass spectrometry (LC-MS/MS) ............................................................................................................
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