Insulin resistance in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects 8-18% of women, presenting a major public health and economic burden. Women with PCOS have insulin resistance (IR) independent of obesity. IR has an integral aetiological role in the reproductive and metabolic consequences of PCOS including obesity, type 2 diabetes (diabetes) and cardiovascular risk factors. Excess weight exacerbates IR and increases PCOS severity. PCOS combined with obesity presents a useful model to study IR before confounding hyperglycaemia occurs. Major PCOS research gaps include: i) methodological measurement of IR ii) effective lifestyle / exercise interventions iii) greater understanding of mechanisms underlying IR in PCOS Aims The body of work presented in this thesis on PCOS aims to explore: i) the literature on IR (Chapter 2, 3) ii) lifestyle change (Chapter 4) iii) assessment of IR (Chapter 5) iv) effects of an exercise intervention (Chapter 6) v) underlying aetiology of IR focusing on visceral fat (VF) (Chapter 6), mitochondrial function and intramyocellular lipid (Chapter 7) Methods Reviews : (Chapters 2-4) Literature regarding cardiometabolic complications and treatment of IR in PCOS was reviewed. A Cochrane systematic review of lifestyle interventions was completed. Study 1: Assessment of IR: Retinol-binding protein 4 (RBP4) in PCOS (Chapter 5.3) A retrospective sample analysis of 38 overweight PCOS and 17 non-PCOS women of comparable weight randomised to 6 months of higher dose oral contraceptive pill (OCP) or metformin, focused on IR and a novel potential marker of IR (RBP4). Study 2: Treatment and aetiology of IR in PCOS Part 1: Effects of exercise in PCOS and non-PCOS women and aetiology of IR: visceral fat (Chapter 6) A prospective 12-week intensified aerobic exercise intervention study of 20 overweight PCOS and 14 non-PCOS women of comparable weight explored outcomes including IR on euglycaemic hyperinsulinaemic clamp and body composition including VF. Part 2: Aetiology of IR: Mitochondrial function and intramyocellular lipid (Chapter 7) In a subset of 16 overweight PCOS and 13 non-PCOS women of comparable weight skeletal muscle mitochondrial protein and gene expression and computed tomography muscle attenuation, a surrogate of intramyocellular lipid, were explored pre- and post-exercise. Results Reviews: (Chapters 2-4) Key evidence gaps in PCOS and IR were identified and informed the original research in this thesis. The Cochrane review demonstrated that lifestyle change improved surrogate IR markers in PCOS. Study 1: RBP4 (Chapter 5) Overweight PCOS were more IR than non-PCOS but this was not reflected by RBP4 levels. RBP4 correlated with lipids but not with IR. RBP4 did not change when IR decreased with metformin or increased with OCP. Study 2: Part 1: Exercise, IR and visceral fat (Chapter 6) PCOS were more IR and had more VF than non-PCOS. IR correlated with VF. With exercise, both groups maintained weight but in PCOS, VF decreased. Triglycerides decreased in PCOS significantly more than non-PCOS. Despite exercise-induced improvement in IR, no relationship with decreased VF was found. Part 2: Mitochondrial function and intramyocellular lipid (Chapter 7) Despite greater IR, there were no baseline differences between the PCOS and non-PCOS women in mitochondrial function and no differences within or between groups with exercise despite improved fitness and IR. No relationship between IR and computed tomography muscle attenuation was found. There were differential changes between groups, suggesting increased muscle lipid content after exercise in PCOS women. Conclusions and future directions PCOS is an IR state and lifestyle intervention improves surrogate markers of IR, but further investigation of IR outcomes is required (Chapters 2-4). Measurement of IR remains challenging and novel simple markers are needed, yet RBP4 is not reflective of IR in PCOS (Chapter 5). Exercise-induced reductions in cardiometabolic risk factors including IR, within PCOS were observed in the absence of significant weight loss. Potentially, weight loss should not be the sole objective of exercise, yet this requires confirmation in future controlled trials. Triglycerides may be modulated more by exercise in PCOS than non-PCOS women (Chapter 6). Mechanistically, neither VF reduction (Chapter 6) nor mitochondrial functional changes correlated with improved IR with exercise in PCOS. Changes in muscle lipid content with exercise suggest increased capacity to store lipid in muscle in PCOS (Chapter 7). The changes in VF, muscle lipid content and triglycerides in PCOS compared to non-PCOS women mimic those seen in men when compared to non-PCOS women suggesting a possible “androgenic” pattern of lipid storage and response to exercise. Mechanisms of IR in PCOS are likely to be complex. We are currently exploring the role of insulin signalling pathways and further research is needed. This work has contributed significantly to the field of IR in PCOS, with an ongoing need for accurate assessment, improved treatment and better understanding of the mechanisms of IR to alleviate the increasing burden of PCOS.