McIlvenna, Luke (2021) Polycystic Ovary Syndrome and Insulin Resistance: Dysregulation of Transforming Growth Factor Beta Signalling and the Effects of Exercise Training. PhD thesis, Victoria University.

Abstract

Polycystic Ovary Syndrome (PCOS) is primarily thought of as a reproductive condition, although it has profound effects on metabolic health, with 38-80% of women with PCOS presenting with insulin resistance. This underlying insulin resistance occurs independently of obesity and has negative effects on other features of the condition. The identification of peripheral insulin resistance in PCOS occurred in 1989, and despite several advances in this area, the molecular mechanisms responsible for peripheral insulin resistance in women with PCOS remain unclear. In addition, interventional studies from women with PCOS have identified impaired responses to insulin-sensitizing therapies. A possible explanation for the underlying insulin resistance and poor response to insulin-sensitizing treatments may be the dysregulation of Transforming Growth Factor-beta (TGF-beta) signalling. The dysregulation of TGF-beta signalling is responsible for remodelling in the ovarian tissues and reproductive dysfunction. Due to the systemic action of TGF-beta signalling, it may be conceivable that these effects extend beyond the reproductive tissues to the peripheral tissues. This presents a possible mechanism that could contribute to the development of insulin resistance in women with PCOS. Understanding the underlying mechanisms of insulin resistance will allow for improvements in diagnosis and for targeted therapies to be developed, which are currently lacking for women with PCOS. The overall aim of this thesis was to determine if dysregulated TGF-beta signalling plays a role in skeletal muscle insulin resistance and can influence metabolic responses to exercise in women with PCOS. This was achieved through a combination of in vivo and in vitro studies focusing on skeletal muscle metabolism. Study 1 explored the role of TGF-beta ligands, TGF-beta 1 and Anti-müllerian hormone (AMH), on glucose uptake and insulin signalling in myotubes from women with PCOS and healthy controls. In line with previous studies, we showed that in vivo metabolic phenotype was not accurately retained in cultured myotubes from women with PCOS, suggesting that a combination of the in vivo environmental factors and intrinsic defects lead to the development of insulin resistance. TGF-beta 1 and AMH had distinct metabolic effects. TGF-beta 1 increased basal and insulin-stimulated glucose uptake, while AMH decreased glucose uptake and PI3K-p110 expression, which was accompanied by an increase in inhibitory IRS-1ser312 phosphorylation. Study 2 assessed the response of myotubes from women with PCOS and healthy controls to an in vitro model of contraction with and without TGF-beta 1 or AMH. It was found that myotubes from women with PCOS and healthy controls display minimal differences in exercise-induced signalling transduction. Myotubes from healthy women showed an increase in the phosphorylation of p38 MAPK and CREB, which appeared to be absent in the myotubes from women with PCOS. The TGF-beta ligands AMH and TGF-beta 1 do not appear to influence in vitro skeletal muscle exercise-like signalling responses. In Study 3, a cross-sectional approach was used to assess skeletal muscle TGF-beta and insulin signalling in women with PCOS compared to overweight and lean controls. Insulin sensitivity, as determined by euglycemic–hyperinsulinemic clamp, confirmed previous findings that women with PCOS have a significant reduction in insulin sensitivity compared to controls. This insulin resistance occurred in the absence of any identifiable defects in skeletal muscle insulin signalling and did not appear to be related to TGF-beta signalling. Women with PCOS had greater levels of basal phosphorylation of p38 MAPK, suggesting that excessive reactive oxygen species and/or inflammation may contribute to insulin resistance. In Study 4, overweight women with PCOS participated in a 12-week exercise training intervention. We aimed to determine if changes in insulin sensitivity following 12 weeks of moderate or high-intensity exercise training were related to aberrant TGF-beta signalling and collagen deposition in the skeletal muscle. Exercise training of high and moderate intensities resulted in improvements in insulin sensitivity and cardiorespiratory fitness, with the metabolic benefits being more noticeable following the high-intensity intervention. Improvements in insulin sensitivity occurred independently of changes in body composition, TGF-beta signalling and other clinical measures. Collectively, the results from these studies demonstrate the role of TGF-beta ligands and signalling dysregulation in skeletal muscle metabolism in vitro. However, these findings do not appear to translate in vivo where insulin sensitivity was not related to TGF-beta signalling in women with or without PCOS. There was no apparent evidence of dysregulation of TGF- beta signalling or insulin signalling in women with PCOS. Furthermore, improvements in insulin sensitivity following 12 weeks of high- or moderate-intensity exercise training occurred independently of changes in TGF-beta signalling.

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