- Title
- Long-chain omega-3 polyunsaturated fatty acids, sex hormones, and insulin resistance
- Creator
- Abbott, Kylie Anne
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Type 2 diabetes (T2D) is the fastest growing chronic health condition, driven by obesity-related insulin resistance (IR). Obesity accounts for 50% of the total diabetes burden in Australia and worldwide. As the global prevalence of obesity increases, diabetes-related health care costs will continue to rise. Interventions that prevent or delay the onset of diabetes can potentially reduce the overall diabetes burden and associated health care costs. Weight loss is clinically effective in ameliorating IR and reducing T2D risk, however long-term weight loss remains difficult to achieve and maintain, and research into adjunct therapies are warranted. Previous studies reported a sex-dependent association between long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) eicosapentaenoic acid (EPA; c20:5n-3) and docosahexaenoic acid (DHA; c22:6n-3) and T2D. Sex hormones are known to regulate synthesis of DHA from α-linolenic acid (ALA; c18:3n-3), though precise mechanisms through which they do so are not well understood. Sex hormones also affect T2D risk differentially in men and women. Interactions between sex hormones and LCn-3PUFA may in part explain some of the differential T2D risk in men and women. Therefore, this thesis aimed to investigate the interactions between sex hormones and LCn-3PUFA for the prevention of obesity-associated IR and subsequent development of T2D. A systematic review and meta-analysis was undertaken to review the existing evidence to determine whether currently available literature supported the prevailing hypothesis, that LCn-3PUFA reduce IR in a sex-dependent manner. The literature was searched to identify randomised controlled trials (RCT) which used a dietary or supplemental n3-PUFA intervention and included measures of IR or insulin sensitivity as an outcome. Thirty-two studies including n=1848 participants were included, with two studies conducted in men, seven in women and the rest in mixed population. Meta-analysis showed that interventions with LCn-3PUFA in females ≥6 weeks duration displayed a reduction in IR, with no change in IR in studies in male populations. However, few intervention studies were conducted in males and significant heterogeneity was present that could not be explained in our analysis, limiting conclusions that could be drawn. Furthermore, there were no studies in which men and women were exposed to an identical intervention protocol, necessitating development of a double-blind RCT. A cross-sectional study of n=2,092 older (55-85 years) Australians assessed relationships between LCn-3PUFA status and diabetes, with sub-group analyses used to investigate sex- and weight- related interactions. There was a significant three-way interaction between sex, weight status and LCn-3PUFA status in the prediction of T2D, therefore sub-group analysis was performed based on this. This demonstrated an inverse association between LCn-3PUFA and diabetes in overweight and obese women, which is consistent with previously reported findings. LCn-3PUFA was inversely correlated with HOMA-IR in men and women. However, this was attenuated when adjusted for BMI. A mediation analysis explored whether the observed association between LCn-3PUFA and T2D was mediated through inflammatory pathways, which demonstrated that interleukin-6, but not C-reactive protein, fibrinogen, or neutrophil-leukocyte ratio, was a partial mediator of the association in overweight and obese women. A double-blind RCT was designed and conducted to investigate the effects of a 12-week DHA-enriched fish oil supplementation on IR in men and women with abdominal obesity and no history of diabetes. This study found a significant reduction in IR in men and women with hyperinsulinaemia at baseline, with no significant interaction between sex and treatment. There was no change in fasting glucose or beta-cell function in any groups across the course of the study. Contrary to the hypothesis, there was a similar magnitude of change in both the males and females. Secondary analysis showed that there was a significant interaction between sex and treatment on testosterone across the course of the study, with fish oil increasing circulating testosterone levels in males compared with control, whilst no change was evident amongst females (p-interactionsex*treatment=p<0.001). Changes in testosterone in males were inversely associated with changes in omega-6 PUFA dihomo-γ-linolenic acid content in erythrocyte membranes, and change in testosterone was a significant predictor of changes to insulin and HOMA-IR in men across the 12 week intervention. Finally, an observational study in n=20 transgender individuals undergoing cross-sex hormone treatment (feminising therapy: n=10; masculinising therapy: n=10) investigated effects of testosterone, androgen blockers and oestradiol on erythrocyte DHA levels and body composition. This suggested that exogenous testosterone administration in trans-men acutely downregulates DHA concentrations, but inhibiting the action of testosterone with androgen receptor antagonists does not increase erythrocyte DHA, suggesting an indirect effect; however, these did not reach statistical significance. Masculinising therapy was associated with significant increases in skeletal muscle mass at 3- and 6- months; feminising therapy was associated with decreases in skeletal muscle mass at 3- and 6- months, and increases in % body fat after 6 months treatment. Observational studies with larger sample sizes are required to determine whether change to erythrocyte DHA composition modulates any change in metabolic functioning. This thesis provides further evidence of an inverse association between LCn-3PUFA and T2D in overweight and obese women. However, the sex-dependency of the association appears to be independent of a direct effect on IR, and may represent differences in the pathogenesis of T2D in men and women. Investigations between DHA and testosterone in obese men is deserving of further research, and if substantiated, may have clinical applications for men with mild hypogonadism for whom testosterone is not clinically indicated. The inverse association between DHA and diabetes in women may have biological significance for the development of gestational diabetes. Future research should focus on associations between DHA, inflammation and IR in pregnancy.
- Subject
- omega-3; type 2 diabetes; insulin resistance
- Identifier
- http://hdl.handle.net/1959.13/1416221
- Identifier
- uon:37017
- Rights
- Copyright 2019 Kylie Anne Abbott
- Language
- eng
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