Diabetes mellitus is one of the most common non-communicable diseases in the world. It is a syndrome of metabolic disturbances, usually due to a combination of hereditary and environmental causes, resulting in chronic hyperglycaemia.
In 2000, there were 171 million people diagnosed with diabetes globally (World Health Organisation, 2006). Within the U.K. there are 2.3 million people diagnosed with diabetes, 3.66% of the population, and approximately 2 million of these have Type 2 diabetes, while a further 500,000 people are estimated to have undiagnosed Type 2 diabetes (Diabetes UK, 2008). The Department of Health (2007) estimates that there will be more than 4 million people with diabetes in the U.K. by 2025.
The World Health Organisation (2009) states that "diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot, effectively use the insulin it produces". Insulin plays a crucial important role in maintaining the homeostasis of glucose within the body following postprandial increases, by stimulating the uptake of glucose from the blood in the muscle, liver and adipose cells. Insulin release from the B-cells in the islets of langerhans of the pancreas cause the intracellular translocation of Glut-4 glucose transporters from the Golgi-apparatus to the cell membrane for facilitated diffusion, along with the secretion of glycogen synthase, causing glycogenesis and storage of glucose as triglycerides. Collectively, these changes result in reductions in glucose levels.
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Research from Peirce (1999) highlights the importance of physical inactivity as a major risk factor to diabetes, by stating "exercise has an crucial role to play in reducing the significant worldwide burden of diabetes". Hardman and Stensel (2003) states that physical inactivity is one of three main modifiable risk factors for diabetes, with others being obesity, and cigarette smoking. Non-modifiable risk factors of diabetes include genetic predisposition, age, and race.
There are two main forms of diabetes. Type 1 diabetes is commonly known as insulin-dependent diabetes mellitus (IDDM). It is autoimmune condition caused by the cell-mediated destruction of the pancreatic B-cells, by the body's own white blood cells. Although the environmental and genetic factors that trigger this destruction are poorly defined, Frayn (1996) states that the inheritance of the human histocompatible lymphocyte antigen (HLA) complex accounts for 30-60% of all cases. As a result of this autoimmune destruction, the pancreas is unable to produce insulin and this hormone must be injected regularly to control blood glucose levels. Type 1 diabetes usually occurs before adulthood and therefore it is also termed juvenile-onset diabetes (Hardman & Stensel, 2003). On a global scale, type 1 diabetes accounts for less than 5% of all diabetic cases.
Type 2 diabetes is often referred to as non-insulin dependent diabetes mellitus. In contrast to type 1 diabetes, the pancreatic cells of type 2 diabetics are able to produce insulin, but the body's cells are unresponsive to insulin. This is termed insulin resistance. Insulin resistance (IR) is defined as 'a decline in the ability of insulin to increase glucose uptake'. This means for a given concentration of insulin, less glucose is cleared to the target cells than would be experienced in healthy individuals. Ivy et al (1999) states that while type 2 diabetes is mostly due to environmental factors, there is evidence for mutations in genes such as hepatocyte nuclear factor ~4ï¡. Although type 2 diabetes is commonly thought of as a disease which afflicts only adults, cases are now occurring in children with increasing frequency (Hardman & Stensel, 2003). Type 2 diabetes accounts for more than 95% of all diabetes cases worldwide.
Hardman & Stensel (2003) suggests that cells become insensitive to the actions of insulin due to elevated body fat levels. This is plausible since most people with type 2 diabetes are overweight and obese. Obesity may desensitise muscle cells and adipocytes to the effects of insulin thereby reducing GLUT-4 translocation and thus glucose transport into the cells. Defects in muscle sensitivity are thought to be the main reason for impaired glucose uptake in diabetics. As the cells become insulin insensitive the response of the muscle and adipocyte cells to insulin is compromised. In the liver, postprandial glucose production continues as a result of gluconeogenesis.
Insulin resistance initially causes the pancreas to secrete more insulin, which will counteract the diminishing function of the cells and allow blood glucose concentration to remain normal (O'Gorman & Nolan, 2005). Overtime, however, insulin resistance increases further and eventually the pancreas cannot maintain this hyperinsulinaemic state. A drop in insulin secretion and subsequent increases in blood glucose concentrations is likely to result in glycosuria. In the case of type 1 diabetes this may be severe enough to cause significant loss in weight. Those with type 2 diabetes, do not normally excrete enough glucose in the urine to lose weight.
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In addition to elevated blood glucose concentrations, type 2 diabetics exhibit raised non-esterfied fatty acid (NEFA) concentrations as a result of insulin resistance. Since the adipocytes have become insensitive they are immune to the antilipolytic effects of insulin. Thus, the catabolism of triglycerides within the adipocytes results in elevated NEFA's, which can interfere with the ability of muscle to uptake glucose thereby exaberating insulin resistance. Some of these NEFA's are oxidised in the liver resulting in the production of ketone bodies (ketogenesis) and a dangerous condition known as ketoacidosis (reduction in pH). Although this condition is rare in those with type 2 diabetes, it is one of the distinguishing features between type 1 and type 2 diabetes clinically (Hardman & Stensel, 2003).
Ceriello & Motz (2004) states that oxidative stress generation is proposed as the common persistent pathogenic factor which can lead to type 2 diabetes. When caloric intake exceeds energy expenditure as a result of over nutrition and physical inactivity, substrate-induced (glucose, free fatty acids) increase in the kreb's cycle generates an excess of mitochondrial NADPH/FADH2 and reactive oxygen species (ROS). When excess NADH /FADH2 cannot be dissipated by oxidative phosphorylation, the mitochondrial proton gradient increases and single electrons are transfered to oxygen, leading to the formation of free radicals, particularly super oxide anion (Maechlen et al. 1999). Consequences of oxidative stress are damage to DNA, lipids, proteins, disruption in cellular homeostasis and accumulation of damaged molecules (Jakus, 2000). These consequences of oxidative stress can promote the development of complications of diabetes mellitus.
B-cells and endothelial cells are particularly susceptible to damage by ROS due to the low content of antioxidant enzymes such as catalase, glutathione peroxidase, and super oxide dismutase. Glucose and free fatty acids do not require GLUT's in these cells, and therefore cannot down-regulate their entry. Prolonged exposure to ROS exacerbates metabolic consequences, leading to diabetes. The key role of glucose metabolism in producing impaired B-cell function through oxidative stress has recently been confirmed by a study by Sakai et al (2003), which showed that intracellular ROS increased 15 minutes after exposure to high glucose concentrations.
Common symptoms of diabetes mellitus include excessive thirst, tiredness, muscle wasting, and blurred vision. It is important to note that although the symptoms are generally similar for both type 1 and type 2 diabetes, symptoms of type one diabetes develops suddenly over weeks or a few days.
Although the main cause of morbidity and premature mortality with diabetes is cardiovascular disease (Hardman & Stensel, 2003), there are a number of other complications, including atherosclerosis, nephropathy, and neuropathy. In addition, diabetes is also the major cause of blindness (retinopathy and cataracts), as well as the leading cause of nontraumatic lower-extremity amputation and end-stage renal disease (Votey &Peters, 2007). The risk of these occurring is related to the extent and duration of hyperglycaemia.
There are several plausible biologic mechanisms through which exercise has been hypothesised to delay the pathogenic onset or development of diabetes.
Peirce (1999) states that "exercise can increase glucose uptake by increasing insulin sensitivity and lowering body adiposity. Both alone and when combined with diet and drug, physical activity can result in improvements in glycaemic control in type 2 diabetics".
Following exercise there is a prolonged and persistent increase in glucose uptake by skeletal muscle (Ivy & Holloszy, 1981; Ren et al., 1993). Henriken (2002) states that single or repeated bouts of exercise have been shown to increase the translocation and concentration of GLUT-4 protein in skeletal muscle, facilitating increased glucose transport into muscle cells. Moreover, Hardman & Stensel (2003) states that an increase in glucose delivery to muscle is aided by the increased cardiac output and stroke volume, and increased muscle blood flow that occurs during and following exercise. Glucose delivery, storage, and utilisation would further be enhanced via adaptations to exercise training such as increased skeletal muscle capillarisation, increased muscle mass, and an increased concentration of oxidative and non-oxidative enzymes.
Hawley & Lessard states that the acute increase in glucose transport in response to a single bout of whole-body exercise is mediated by a variety of intramyocellular signalling events including increased insulin receptor signalling, activation of the AMP-activated protein kinase pathway (AMPK), protein kinase B phosphorylation, nitric oxide production and calcium mediated mechanisms involving ca2+/caMK and protein kinase C (PKC) (Jessen &Goodyear, 2005).
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Bruce et al (2006) suggests that exercise training may improve muscle insulin sensitivity by increasing the proportion of lipids targeted for utilization and oxidation (increased lipoprotein lipase concentration), thereby reducing the accumulation of lipid species that are known to inhibit insulin signal transduction. In direct support for this contention, Lessard et al (2007) have shown that 4 weeks of exercise training attenuated high-fat, diet-induced increases in muscle lipid storage.
Exercise may also improve hepatic insulin sensitivity through the reduction of NEFA's, leading to a reduced level of gluconeogenesis. This is particularly important in a fasted state since hepatic glucose concentration is the main determinant of fasting blood glucose concentration.
In addition, exercise results in a reduction in oxidative stress, through a decrease in the levels of autoxidation, NADPH oxidase, and leukocytes. Physical activity also restores B-cell function, Nitric Oxide induced vasodilation and increased mobilisation of protective antioxidants such as superoxide dimutase. Lappalainen et al (2009) "Regular exercise plays an important preventative and therapeutic role in oxidative stress-associated diseases such as diabetes and its complications."
It must be noted that the insulin-sensitising effects of an acute exercise bout are short-lived and persist for only 48 hr if another bout of exercise is undertaken (Etgan et al, 1993). This indicates that exercise must be performed regularly for the maintenance of insulin sensitivity.
There is now considerable evidence from epidemiological studies to show that increased levels of physical activity is associated with a decrease in the risk of diabetes (Manson et al. 1992; Pan et al, 1997; Hu et al. 2001; Tuomilehto, 2001; Lambers et al, 2008; Marcus et al, 2008; Yokuyama et al. 2007).
One example is the Physicians' Health Study (Manson et al. 1992), which highlighted that a lower risk of type 2 diabetes was observed in active men with evidence of dose response, when 21,000 US male physicians aged 40-84 years were followed for 5 years. Consistent with the Physicians Health Study, the Nurses Health Study (Hu et al., 2000) found a dose-response between activity status and diabetes risk, when 85,000 women were followed over a 16 year period. Moreover, the importance of taking a holistic approach to diabetes prevention was emphasised by the finding that the relative risk of developing type 2 diabetes was only 0.1 in nurses characterised by the following combination: good diet, low body mass index, and high physical activity levels.
Although these cohort studies are convincing they have some limitations. As with cross-sectional studies physical activity is assessed via questionnaire. Moreover, diabetes is determined by self-report and this may lead to inaccuracies due to undiagnosed cases (Hardman & Stensel, 2003). These difficulties are overcome by intervention studies.
The Malmo prevention study (Eriksson & Lingarde, 1991), a non-randomised intervention study, showed reduced mortality in patients with impaired glucose tolerance and a 50% reduction in type 2 diabetes following a five year exercise and diet programme. The findings of the Malmo feasibility study have been confirmed by the Da Quing impaired glucose tolerance study (Pan et al, 1997). This study followed 577 subjects with impaired glucose tolerance for six years, and found that exercise led to a 46% reduction in the risk of developing diabetes.
In addition, the Finnish Prevention Study (Tuomilehto, 2001), a randomised study involving 522 middle aged, overweight males and females with impaired glucose tolerance, found the incidence of diabetes was more than halved in the intervention group who participated in exercise 30 minutes per day. These results have been supported by studies conducted by Yokoyama et al (2007) and Marcus et al(2008).
A recent review by Gill & Cooper (2008), which incorporated data from 20 longitudinal cohort studies on the effects of exercise on diabetes, presents the consistent picture that regular physical activity substantially reduces the risk of type 2 diabetes. Gill & Cooper conclude "while 150 minutes per week of moderate activity confers benefits, higher levels of activity may be necessary to maximise diabetes risk reduction in those at high baseline risk of the disease". They also claim that a high level of physical activity is associated with a 20-30% reduction in diabetes risk.
Since the typical type 2 diabetics are middle-aged, obese and sedentary, exercise must be carefully implemented to minimise risk. The ACSM (2006) exercise guidelines for diabetics is 30 minutes of continuous moderate exercise, equivalent to brisk walking 5 or 6 days a week.
In conclusion, the strengths and consistency of the evidence has led researchers to conclude that physical activity reduces the risk of diabetes, as Hawley and Lessard (2008) states "there is indisputable evidence that exercise training is an effective therapeutic intervention to increase insulin action in skeletal muscle from diabetic individuals". Peirce (1999) states that "although recent studies have improved our understanding of the acute and long term physiological benefits of physical activity, the precise duration, intensity, and type of exercise have yet to be fully elucidated." Further research is required to help refine the exercise prescription for diabetes prevention, as well as comparing the effects of exercise on diabetes with a variety of drugs and supplementary therapies such as insulin sensitisers and antioxidants (vitamin C, vitamin E, ï¡-lipoid acid). In addition, further investigations are needed to investigate diabetes at a molecular level. This research may focus on gene expression, heat shock proteins, free radicals and pro/anti inflammatory markers (such as CRP, adiponectin, & leptin). An investigation of these questions is likely to lead to novel approaches to pharmacotherapy and exercise rehabilitation for patients with diabetes mellitus.