Background. Metabolic syndrome (MetS) is a cluster of anthropometric, metabolic, and cardiovascular derangements that increase the risk for cardiovascular diseases and all- cause mortality. MetS has become a major public health problem worldwide with a prevalence of ~31% of the adult population in Spain. In individuals with some degree of insulin resistance (pre-diabetics) exercise-induced increases in CRF are associated with improvements in their insulin sensitivity. Epidemiological data reveals an inverse association between the prevalence of MetS and cardiorespiratory fitness (CRF) suggesting that both could be related. Some authors suggest that the attainment of a high CRF level could confer protection against developing hyperglycemia and insulin resistance. Thus, CRF could serve an index of the improvements in both cardiovascular and metabolic health with exercise-training. CRF is routinely evaluated using a graded exercise test (GXT) to volitional fatigue while collecting expired air to measure the maximal rate of oxygen consumption (i.e., VO2MAX). The main requisite to ensure that a VO2MAX has been reached, is the attainment of a steady-state in VO2 despite increases in workload. While for trained athletes it is usual to attain a maximal plateau in VO2 at the latter stages of a GXT, this attainment is uncommon in unfit individuals. As a result, in clinical populations, VO2PEAK instead of VO2MAX is habitually reported. However, it is unclear if VO2PEAK is an accurate measure of CRF. Muscle fatigue prevents the attainment of a VO2 plateau. Muscle fatigue has a bigger effect on preventing VO2MAX attainment when untrained than after several weeks of exercise-training. Thus, in unconditioned individuals, like in people with the metabolic syndrome, VO2MAX underscoring in the initial GXT testing, could inflate the gains in CRF attributed to training. In turn, this could lead to misinterpretations of the effects of a particular exercise-training program on CRF and disguise the strength of the association between CRF and insulin sensitivity. One of the most salient features of the MetS is the impaired fasting glucose (IFG) that reflects in hyperglycemia (i.e., blood glucose > 100 mg·dL-1), due to insulin resistance. Hyperglycemia is an important sign of the progression towards the MetS, since in its conception, insulin resistance was the triggering factor of the rest of the components of the MetS. Sustained hyperglycemia, leads to the erosion of the vasculature leading to cardiovascular diseases which are the main cause of mortality and disability among hyperglycemic individuals. Moreover, 70% of individuals with an initial stage of hyperglycemia (i.e., prediabetes) will progress to type 2 diabetes (T2D). Therefore, reducing hyperglycemia is one important clinical goal that would reduce cardiovascular diseases risk and delay the transition to T2D in this population. Lifestyle modification is the first line therapy to reduce the hyperglycemia of MetS. Lifestyle modifications include adoption of a hypocaloric diet and increases in physical activity. This could be accomplished by direct involvement in a supervised exercise training program that provides aerobic and/or resistance training. Both aerobic (AT) and resistance (RT) exercise-training have been shown to improve hyperglycemia and insulin resistance. It is however unclear which of the two exercise modes is more efficient on helping to regain glycaemic control in MetS patients. Within the different modes of AT, high-intensity interval aerobic training (HIIT) seems to be more effective than continuous mode to improve insulin resistance. Furthermore, the combination of AT and RT seems superior to reduce hyperglycemia than AT or RT separated. However, it is unclear if the improved effectivity of combining AT and RT, results simply from adding more total exercise dose and thus more caloric expenditure, being the type of exercise a secondary factor. Thus, studies using isocaloric sessions of AT and RT are needed to compare the efficacy of the exercise mode. Due to the high involvement of the anaerobic energy system in RT, it is difficult to fully assess energy expenditure during this mode of training. An alternative is to substitute parts of AT by RT that matches the aerobic energy expended in that workout portion. Metformin is the most common drug prescribed in the world for the treatment of hyperglycemia and insulin resistance. A study from the diabetes prevention program research group in 3234 hyperglycemic individuals, demonstrated that lifestyle change with exercise is as strong as metformin treatment on reducing the incidence of T2D. That data led exercise scientists to wonder if the combination of metformin and exercise-training could produce additive effects on reversing insulin resistance and hyperglycemia. However, the first researchers trying that combination reported that surprisingly, metformin blunted the gains in insulin sensitivity induced by an exercise program combining AT and RT. However, in their experimental model exercise-training and pharmacological treatment with metformin were initiated simultaneously. This does not reflect the real situation were users of metformin wonder if adding exercise training to a background of metformin use, could improve further their insulin sensitivity. So, it is possible that exercise on top of an ongoing metformin intake may result in normal exercise responses/adaptations. The interactions of metformin use with a bout of AT, with a bout of RT and then with a 16 weeklong training program will provide enough information to advice patients on the combination of both therapies (i.e., exercise and metformin). Aims. This dissertation encompasses seven studies with the main aim of exploring if exercise could contribute to the effects of metformin on lowering fasting hyperglycemia, insulin resistance and improving 24-h glycemic control in individuals with the MetS. First, we studied if the combination of AT and RT improved fasting hyperglycemia more than an isocaloric AT alone. Following, we investigated the separated and combined effects of exercise and metfomin in 24-h glycemic control of hyperglycemic MetS individuals. To study exercise- metformin interactions we used several exercise modes and durations. Initially we study the interactions between patient's chronic metformin treatment and two bouts of AT, and one bout of RT. Then, the interactions between metformin use and 48 sessions of high intensity AT. Finally, we attempted to improve CRF assessment using VO2MAX to confirm if the reported metformin interference with exercise gains in VO2MAX were associated with the blunting in exercise improvements in insulin sensitivity. Main findings. Cross sectional data supports that CRF level is positively associated with improved insulin sensitivity. Maximal oxygen uptake (VO2MAX) is the gold standard for CRF assessment. Maximal incremental exercise test (GXT) until exhaustion is typically used to assess VO2MAX with a primary criterion of attainment of a VO2 plateau. However, VO2 plateau attainment with GXT is rare in untrained populations and researchers report VO2PEAK as a surrogate of VO2MAX while not giving enough consideration to the potential error that this assumption can create. In study 1, by using a supramaximal verification test (VerT) after GXT recovery to find that VO2MAX was by 3% underestimated when not using a VerT. In 40% of participants, VO2MAX underestimation grew to 9% using only GXT. Thus, in a population of unfit MetS individuals, a VerT avoids gross underestimation of their initial level of cardiorespiratory fitness. In study 2, we explored if training-induced improvements in VO2MAX varied when using only GXT compared to when using VerT in initially unfit MetS individuals. Surprisingly, in average, VO2MAX gains with training were similar when tested by GXT only or when adding VerT. However, in 41% of the sample, GXT almost doubled the training improvements in VO2MAX compared with the "real" increases measured by VerT. These findings highlight the need for conducting a VerT to appropriately determine the individual training-induced improvements in VO2MAX in unfit subjects with MetS. In study 3, we randomly assigned MetS patients to two 16-week exercise training programs, one only using HIIT and the other using HIIT+RT. Exercise programs were isocaloric by substituting the last 10 min of each training bout of HIIT by RT (i.e., HIIT+RT). We found that this apparently minor incorporation of RT in HIIT+RT (20% substitution) have a significant effect on lowering fasting hyperglycemia. Of note this happened despite similar exercise duration and energy expenditure in both experimental groups. The results suggests that introduction of RT on a training base of AT benefits patients with prediabetes and hyperglycemia. The purpose of study 4 was to address if concurrent training (AT and RT in a single session) elicits leg muscular adaptations beyond the ones obtained by AT alone in sedentary individuals with MetS. It was found that concomitant AT and RT improves muscle performance beyond the effects of AT alone following 16 weeks of training. Specifically, substitution of 20% of AT by RT improved movement velocity at high loads and performance in countermovement jump, which could have improved the functional capacity of those MetS individuals. Furthermore, this substitution does not detract the improvements in MetS factors observed with more prolonged AT program. Thus, MetS individuals could get more benefits through combination of AT and RT without having to add more training volume. There is evidence of interfering effects of metformin on the insulin-sensitizing effects of exercise. In contrast, data from our lab using intravenous glucose tolerance test (IVGTT) supports that exercise and metformin could have additive effects on insulin sensitivity in patients under chronic metformin treatment. In study 5 we explore the interactions between metformin and two bouts of AT on fasting hyperglycemia and insulin sensitivity measured by HOMA and IVGTT. Insulin sensitivity increased in the metformin condition alone, as well in the combined intervention but not with only exercise. We added 24-h glycemic control and found that the combination of metformin and aerobic exercise reduced the frequency of hyperglycemic peaks. The findings suggest that aerobic exercise and metformin have additive effects on improving 24-h glycemic control. In study 3 we found that RT added to AT helped to lower hyperglycemia in pre-diabetic MetS individuals. In study 6, we determined the interactions between metformin and a bout of RT on insulin sensitivity and glycemic control in a sample of pre-and T2D individuals with MetS. We found that a bout of RT is insufficient to improve glycemic control (i.e., 24-h glucose monitoring). On the positive side, our data suggests that a bout of 50 min of RT does not blunt, neither aid to the antidiabetic effect of metformin in pre-and-T2D individuals. Thus, resistance exercise could be safely advised to prediabetic patients taking metformin, although it does not help acutely to improve glycemic control. Finally, Study 7, is a prospective intervention (HIIT training for 4 months) parallel group study with two arms: a) MetS patients taking metformin and b) MetS patients not taking medicines. The aim was to determine if chronic metformin use interferes with the improvement of 16 weeks of AT on insulin resistance and CRF in patients with hyperglycemia and MetS. We found that metformin treatment does not blunt the beneficial effects of 16 weeks of AT on improving insulin resistance (i.e., HOMA-IR). However, we coincided with other studies in that metformin treatment attenuated the CRF improvements (i.e., VO2MAX) elicited by 16 weeks of AT in MetS individuals. Contrary to the cross-sectional epidemiological studies, the associations between gains in CRF and insulin sensitivity were very poor in our intervention study. Our data suggests that metformin blunting of exercise-induced improvements in VO2MAX does not limit in parallel the exercise induced improvements in insulin sensitivity. Thus, the benefits of adding exercise-training in decreasing insulin resistance and MetS factors overweight the drawbacks (i.e., blunted development of VO2MAX) in people chronically medicated with metformin.