Physical inactivity has been identified as a stronger predictor of chronic diseases even when compared with traditional risk factors, such as hypertension, hyperlipidaemia, diabetes and obesity. Moreover, regular physical activity appears to protect against premature death, independently of obesity.
Several studies, clinical and experimental, have been assessing the role of regular physical activity (training) on cardiovascular and cardiometabolic disorders, including on diabetes. Although results from studies using animals cannot be directly extrapolated for humans, animal models of T2DM could offer excellent opportunities to evaluate experimental conditions and to assess tissues that cannot be tested in humans, thus improving the knowledge about the endocrine, metabolic and morphological changes underlying the pathogenic mechanisms of the disease and the treatment options.
In the following topics we will review the benefits of a particular physical exercise (training) in the wide pathophysiological aspects associated with T2DM, focusing on antioxidant and anti-inflammatory properties, based on the information already available in the literature, from both clinical and experimental studies, and in particular on the data obtained from our own experiments using an animal model of obese T2DM, the Zucker Diabetic Fatty (ZDF fa/fa) rats.
In order to not repeat the information alongside the text, the physical exercise program performed by us, which will be mentioned during the review, was a regular and moderate intensity aerobic exercise (defined as training), consisting of 12 weeks (1 h/day, 3 times/week) of swimming program, voluntary, for both the male obese diabetic rats (ZDF fa/fa) and the male control lean animals (ZDF +/+), between 8 and 20 weeks of age [32–34]. In brief, the protocol used was: the animals, maintained under controlled temperature (22°C), humidity (60%) and lighting (12 h of light) conditions, given a rodent maintenance chow (A-04 Panlab, Barcelona, Spain) adjusted to their respective weights (100 mg/g of weight) and distilled water ad libitum, perform their exercise in a cylindrical tank, 120 cm in diameter and 80 cm in height, containing water with a controlled temperature (30 -32°C); the animals were placed in the tank every day at the same hour (09.00 -10.00 h) under the supervision of the same person; the swimming period was initially for 15 min/d and was gradually increased such that the rats were able to perform exercise for 60 min/d, which was achieved in 1 wk; after 1 wk of this training period, the rats were made to swim for 1 h, three times a week; at the end of each exercise session, the animals were dried and kept in a warm environment; the sedentary rats were kept in the container where the swimming sessions were held for a period of 60 min to ensure that these control rats underwent the same amount of stress as the test animals that performed exercise. The animals that practiced exercise were sacrificed 48 h after the end of the last training session to minimize the acute effects of the exercise. The night before sacrifice, food was removed from the animal cages.
Physical activity, obesity and body fat distribution
Our studies showed that exercised diabetic rats presented, when sacrificed 48 h after the last bout training session, a trend to increase body weight, which might be due to an increase in muscle mass . Despite the lack of measurement of the animal body fat amount, a reduction in total visceral or subcutaneous fat in exercised animals cannot be excluded. Similar effect was observed by other studies in humans, confirming that after the training there was an increase in muscle mass with decrease in fat mass [35, 36].
In the same work, Teixeira de Lemos et al.  showed that the weight of some organs or tissues (heart, liver, kidneys and muscle) were heavier in the exercised diabetic rats when compared with the sedentary animals, thus confirming that training leads to important morphological and physiological adaptations to maintain body homeostasis, as previously suggested by others [37, 38]. In addition, the results suggest that the maintenance in time of training is an important factor for the appearance of those adaptations.
The study conducted by Tuomilehto et al. (2001) provided evidence that T2DM, in both women and man at high cardiovascular risk, can be prevented by lifestyles modifications, with a decrease of overall incidence of diabetes of 58% . Regarding physical exercise practice, which has included components designed to improve both cardiorespiratory fitness and muscle strength, the results showed that more than 4 h/week of exercise was associated with a significant reduction in risk of diabetes even without weight loss . Some of the key beneficial effects of an exercise program include visceral obesity reduction and muscle mass increase. Randomized control trials conducted in individuals with normal body mass index (BMI), as well as in patients with abdominal obesity and T2DM, demonstrated that physical exercise regularly practiced contributes to diminish total, visceral and subcutaneous fat, even without weight loss, together with improvement of glycaemia and with increase of FFA oxidation and, thus, to an amelioration of the diabetes [40–42].
Physical exercise and glycaemia and insulinaemia control
The first aim of T2DM treatment is hyperglycaemia control, as a way of reducing chronic diabetic complications, namely of cardiovascular nature. The American Diabetes Association (ADA) recommends a value of HbA1c above 7%. Our group demonstrated, using the training protocol above described in ZDF (fa/fa) rats, that hyperglycaemia was prevented by exercise, together with a significantly lower value of HbA1c (-6,6%), when compared to sedentary counterpart, reinforcing the idea of a effect maintained over time [33, 34]. This results were corroborated by Kyraly et al. (2008) in ZDF rats submitted to forced swim training (1 h/day; 5 days/week during 13 weeks) . Additionally, in our study the hiperinsulinaemia was partially, but significantly, corrected in the trained rats, which was accompanied by reduction of insulin resistance, given by the lower HOMA (homeostasis model assessment), and index of insulin resistance. Thu, we hypothesize that swimming training was able to improve peripheral insulin resistance, although the less action on hepatic resistance, suggesting that hyperinsulinaemia could be a reflex of insulin resistance in the liver, not improved by exercise [33, 34].
Concerning studies in humans, in a meta-analysis which reviewed the studies concerning exercise intervention of at least 8 weeks in type 2 diabetic individuals, regular aerobic exercise showed a statistically and clinically significant effect on HbA1c, suggesting that this non-pharmacological intervention improve glycaemic control, while having little effect on body weight . Similar results were encountered in another meta-analysis on the effect of exercise practice, which included 14 studies (12 with aerobic exercise and 2 with resistance exercise) , demonstrating that the effect of exercise on HbA1c (the major marker of glycemic control), is a well established finding.
The amelioration on glucose metabolism by exercise training may occur primarily through three distinct mechanisms: i) stimulation of glucose transport to muscle; ii) increased in insulin action on cells of the organs involved in the exercise; iii) positive regulation of signaling pathway stimulated by insulin as a result of regular exercise.
Exercise has been indicated as an "insulin-like" activity because of the increase of muscle's capacity to capture circulating glucose, due to decreased intramuscular fat reserves . Christ-Roberts et al. (2004) found that exercise training significantly increased expression of GLUT4 glucose transporter in overweight nondiabetic and diabetic subjects, by 38% and 22%, respectively [46, 47]. Akt protein expression, which was decreased by about 29% in the diabetic subjects before training, when compared to the nondiabetics, increased significantly in both groups . Furthermore, it was also observed that in skeletal muscle exercise training affects the transcriptional regulation of the gene of the IRS-1 and the post-transcriptional regulation of the PI3-kinase expression [48, 49]. The increased capacity of the muscle to oxidize fat in response to aerobic exercise is also a major mechanism by which exercise training improves insulin sensitivity in the muscle . Taken together, the above mentioned actions of exercise (training) on skeletal muscle contribute to regulate blood glucose levels.
Exercise and dyslipidaemia
Chronic exercise (training) has favorable effects on lipid profile [34, 51], being nowadays viewed as one of the best non-pharmacological strategies for the prevention or attenuation of diabetic dyslipidaemia. Our group demonstrated that aerobic exercise training improved dyslipidaemia in ZDF rats, namely by reducing the total-cholesterol (T-Chol) and triglycerides (TGs) . Among other benefits, exercise stimulates lipolytic activity (with decreased plasma TG), promotes the use of FFA as an energy source and increases HDL concentration. Furthermore, favorable changes in the quantity and composition of LDL particles were also shown, as well as on the quality of HDL [52, 53]. The primary mediator mechanism of these changes seems to be the beneficial influence of regular exercise on the activity of peripheral enzymes, such as lipoprotein lipase (LPL), lecithin-cholesterol acyltransferase (LCAT) and hepatic lipase (HL) . In addition to the regulation of the mechanism of hepatic lipid transformation, moderate physical exercise increases the oxidative capacity of several tissues, including the skeletal muscle, which is under low oxidative capacity in situations of insulin resistance. Physical exercise increases the number of capillaries and oxidative fibers in muscle, increasing lipolysis, which allows free flow of fatty acid to the tissue, reducing its concentration in plasma, which is an indicator of its uptake and oxidation by tissues .
It seems clear now that regular exercise training is able to improve lipid metabolism. But is this evident in human studies? Type 2 diabetes populations have been shown to improve fasting blood lipid profile following long-term exercise interventions, with or without dietary restriction [55, 56]. Furthermore, exercise practice in Type 2 diabetes patients showed improved glycemic control, body composition, blood pressure, muscle strength, and workload capacity, together with attenuated progressive increase in exogenous insulin requirements . In accordance with earlier reports, the randomized trial conducted by Sigal et al. (2007) showed that, despite an unaltered body weight, combined endurance and resistance type of exercise training is able to induce regional changes in fat and lean muscle mass in obese T2DM patients . Furthermore, Lira et al. (2007) also reported that low and moderate exercise intensities (training) appear to promote clear benefits on lipid profile .
The exercise is also able to activate an alternative pathway: the AMPK . This enzyme acts on the liver, muscle and adipocytes by increasing fatty acid oxidation, decreasing cholesterol synthesis, lipogenesis and lipolysis, and even modulating insulin secretion on pancreatic islets . Apart from the effect that AMPK appears to have on lipid oxidation, it also plays an important role in decreasing the glucose levels, being able to stimulate GLUT-4 increment .
Considering the data above mentioned, it seems obvious that the regular practice of an exercise program has a positive effect on the dyslipidaemic profile displayed by patients with T2DM whic could not be neglected.
Physical exercise and blood pressure
It is widely accepted that the exercise practiced on a regular basis has an antihypertensive effect in humans [63, 64]. Indeed, regular exercise (training) is able to reduce heart rate, improving the sensitivity of aortic baroreceptors, which contributes to a more efficient regulation of blood pressure . The beneficial effects on hypertension (blood pressure lowering, either systolic or diastolic) due to decreased activity of both the sympathetic nervous system and the renin-angiotensin system was also documented. Other mechanisms responsible for the antihypertensive effect of training include the decrease in peripheral arterial resistance caused by vasodilatation . Besides improving glycaemic control, a meta-analysis showed that structured exercise intervention studies in non-insulin-dependent Type 2 diabetes patients reduce systolic blood pressure of about -4.16 mmHg . Such reduction in mean blood pressure are clinically relevant and similar to the effects produced by combined therapy of an angiotensin-converting enzyme (ACE) inhibitor and an thiazide diuretic .
Also in animals, as shown by our studies using the ZDF rats as model of type 2 diabetes, training (swimming) has promoted a decrease in systolic and mean blood pressure and in heart rate, together with a diminishment of differential pressure [33, 34], suggesting an improvement of vascular arterial compliance, with reduction in cardiac work and a left ventricular hypertrophy amelioration. The increased arterial stiffness appears to be one of the factors that best combine cardiovascular risk and atherosclerosis. Differential pressure has been indicated as an indirect measure of arterial stiffness and a better predictor of coronary risk. By preventing the increasing of differential pressure regular exercise training positively influence the cardiovascular diabetic complications, such as diabetic ischemic heart disease, which is often asymptomatic.