The prevalence of high numbers of metabolic risk factors (HiMF) associated with the metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) has increased considerably over the past two decades. Lifestyle factors including physical inactivity are major components in the development of HiMF. Middle-aged individuals with HiMF and T2DM are commonly characterised by reductions in muscle strength, muscle mass and also lower capacities to perform activities of daily living (ADL's), compared to individuals with low numbers of metabolic risk factors (LoMF). As such, changes to physical activity levels should improve the functional capacities and clinical profiles for individuals with HiMF.

Study One. The purpose of this study was to investigate differences in some characteristics between individuals with HiMF and LoMF. These included conventional metabolic risk factors:​ waist circumference, blood pressure, lipids profile and fasting glucose levels and emerging metabolic risk factors:​ inflammatory markers, the hepatic enzymes gammaglutamyltransferase (GGT) and alanine aminotransferase (ALT) and brain-derived neurotrophic factor (BDNF). This study also examined whether HiMF in the absence of symptomatic heart disease is linked to reductions in capacities to perform ADL's and/or impaired quality of life (QoL). Fifty-five middle-aged (50.8+6.1 yr) men (n=28) and women (n=27) participated in the study. Each participant was classified as HiMF (n of risk factors > 2) or LoMF (n of risk factors < 1) as defined by the International Diabetes Federation (IDF). Multivariate analysis of variance (MANOVA) was used to assess differences between HiMF and LoMF groups. Spearman Rho correlations were conducted to assess the relationship between selected variables. Participants with HiMF (both men and women) diverged more from healthy clinical profiles than individuals with LoMF. This included both conventional and emerging risk factors. In men, despite the higher numbers of risk factors for HiMF, compared to men with LoMF, no differences between groups were observed for aerobic power, muscle strength relative to body mass, the capacity to perform ADL's or QoL. Women with HiMF however, tended to have lower relative muscle strength (-14%, p=0.06) and longer time to complete their ADL's (10%, p=0.07), and they also reported higher level of bodily pain (p=0.02), compared to women with LoMF. In women, but not in men, the actual number of metabolic risk factors was positively correlated with the time taken to perform ADL's (r=0.50, p=0.01) and negatively correlated with aerobic power (r= - 0.52, p<0.01), and the physical components of the QoL questionnaire (SF-36) (p=-0.40, p=0.04). Muscle strength relative to body mass, was also negatively correlated with the risk profile (r=-0.50, p=0.01) for women only. The findings from this study may provide an explanation as to why women are more likely to consult a healthcare practitioner than men. As women's clinical profiles have negative associations with bodily pain and the capacity to perform ADL's, they may be more likely to seek medical intervention before risk factors progress to heart disease, compared to men. In men, impaired functional capacities or reduced QoL may not serve as early warnings of future disease. This emphasises the importance of regular medical check-ups, combined with education and motivation strategies, to promote health outcomes.

Study Two. The purpose of this study was to compare the effects of 10 weeks of resistance exercise training (RT) on the capacity to perform ADL's and QoL for middle- aged individuals with HiMF and LoMF. Following the initial allocation to HiMF or LoMF, (see Study One), participants were randomised to either training or control within their groups, as follows:​ HiMF training (HiMFT), HiMF non-exercise control (HiMFC), LoMF training (LoMFT) and LoMF non-exercise control (LoMFC). The training data were analysed by the repeated measures ANOVA model. No changes were observed in total energy intake or energy macronutrient composition within or between groups (p>0.20). For both HiMFT and LoMFT, training improved lean body mass (LBM, 2.6% and 2.1%), both p=0.03), total muscle strength (25.0% and 23.7% p<0.01) and the capacity to perform ADL's (9.7%) and 8.8%) p<0.01), compared to corresponding controls. RT did not reduce whole body fat content or improve aerobic power (V02peak) for HiMFT, but did improve QoL. In contrast, there was a reduction in whole body fat and improved aerobic power for LoMFT, in the absence of improvements in QoL. Changes to total muscle strength were negatively correlated with changes to total time to complete the ADL's for both HiMF (pooled HiMFT and HiMFC, r=-0.53, p<0.01) and LoMF (pooled LoMFT and LoMFC, r=-0.47, p=0.02). However, changes to total muscle strength for the HiMF group only (pooled data), correlated with changes to self-reported physical and mental health (r=0.59, p<0.01 and 0.45, p=0.02 respectively). The main finding of Study Two was that for HiMF, the improvements in the capacity to perform ADL's and improvements to self-perceived QoL were associated with increases in muscle strength, and not related to changes in body fat levels or aerobic capacity.

Study Three. The purpose was to examine the effect of RT on conventional and emerging metabolic risk factors for individuals with HiMF and LoMF. The participants and the randomisation to subgroups (i.e. HiMFT, HiMFC, LoMFT and LoMFC) were identical to Study Two. Ten weeks of RT did not change any metabolic risk factors for HiMF, including blood pressure, lipid profiles, and fasting glucose levels. In addition, training did not change plasma levels of inflammatory markers, hepatic enzymes or BDNF (all p>0.05). For HiMFT, training increased insulin levels compared to baseline (from 46.1±28.5 to 71.2+48.8 pmol-L"\ p<0.05) and also tended to increase insulin resistance, as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) (from 1.6±1.1 to 2.6+2.0, p=0.07). The data suggest that RT as a single intervention has little or no influence on conventional and emerging metabolic risk factors and may even have an adverse effect on insulin levels and insulin resistance in middle-aged individuals with clusters of metabolic abnormalities in the absence of overt T2DM or CVD. As such, RT may not be sufficiently efficacious as a therapeutic mode of exercise to improve metabolic risk profiles in middle-aged individuals who are yet to develop overt disease. It is possible however, that longer RT duration or the inclusion of aerobic training and/or dietary interventions may be needed in order to elicit improvements in metabolic risk factors in this population.

Study Four. This study was an investigation of the effects of RT on the insulin- signalling proteins, Akt (protein kinase B) and Akt substrate of 160 kDa (AS 160), and muscle glycogen stores for individuals with HiMF or LoMF. In addition, correlations of the insulin-signalling proteins with metabolic risk factors were analysed. Thirty-two men (n=15) and women (n=17) who participated in Studies Two and Three also volunteered to undergo muscle biopsies and other anthropometric and clinical measures before and after RT. At baseline, no significant differences were found between HiMF and LoMF groups in regard to glycogen stores, and total and phosphorylated Akt and AS 160. At baseline, IL6 and IL8 were negatively correlated with total AS 160 (r=-0.51 and r=-0.52, p=0.02) and phosphorylated AS 160 (r=-0.49 and r=-0.45, p<0.05) and insulin resistance was negatively correlated with phosphorylated Akt (r=-0.44, p=0.05) for the total HiMF group, (training and control pooled together). For both HiMFT and LoMFT, training increased muscle glycogen stores, compared to baseline (by 22.3%, p=0.06 and 34.4%, p=0.03, respectively). For HiMFT, training significantly increased total Akt by 25.1%) but phosphorylated Akt tended to reduce, compared to the HiMFC group (p=0.08), and phosphorylated AS 160 was significantly reduced by 24.8%) (p<0.05). No significant changes in Akt or AS 160 (total or phosphorylated) were observed for LoMF groups (training and control). For HiMFT, the percentage change in phosphorylated AS 160 was negatively correlated with the number of metabolic risk factors (r=-0.81, p<0.01). RT increased skeletal muscle glycogen content, while it reduced phosphorylated Akt and phosphorylated AS 160 for HiMFT. The increases in the number of metabolic risk factors and levels of inflammatory markers may serve to inhibit insulin-signalling protein phosphorylation and possibly contribute to the insulin resistance evident in these individuals.

Conclusion. Study One showed that women with HiMF have higher perception of bodily pain, compared to their LoMF peers, and the number of metabolic risk factors is correlated with the capacity to perform ADL's and the physical aspect of the SF-36. Men with HiMF however, have similar capacities to perform ADL's and QoL, compared to men with LoMF. This may partly explan why women are more likely to consult a healthcare practitioner than men, especially early in the disease progression. It may also indicate that functional capacity and self-perceived QoL may not serve as early warnings of future disease in men. As such, routine medical check-ups and adoption of healthier lifestyle are recommended before risk factors progress to symptomatic disease. Study Two showed that RT can improve the capacity to perform ADL's and QoL in individuals with HiMF even in the absence of change in aerobic power or body fat mass. Study Three showed that despite these improvements, RT had limited effects on conventional and emerging metabolic risk factors and Study Four showed that RT can increase muscle glycogen content, but may also adversely affect insulin-signalling. Reductions in phosphorylated AS 160 and phosphorylated Akt may also be related to increases in inflammatory marker levels.

The results of this thesis suggest that middle-aged individuals should perform RT as it improves muscle strength, mass, muscle glycogen stores and the capacity to perform ADL's and QoL. However, it appears that in order to target the metabolic risk and improve insulin-signalling proteins (especially the phosphorylated proteins) for individuals with clusters of metabolic risk factors, this form of training may need to be combined with aerobic training and other lifestyle interventions such as diet.