Exercise and Type 2 Diabetes

The world is in the midst of a global diabetes epidemic. Its occurrence, particularly type 2 diabetes, continues to rise unrelentingly in most developed and developing nations (Simpson et al 2003). Current estimates of the global prevalence of type 2 diabetes calculate that approximately 250 million people are affected, and this number is expected to rise to some 380 million people by the year 2025 (Praet and Van Loon 2007). Diabetes is currently the 9^th leading cause of death worldwide (WHO 2012), and current epidemiological patterns show that the incidence of diabetes is progressively increasing in young and middle-aged people (Ehrman et al 2003). Death rates for young people with diabetes are staggeringly high in comparison to healthy individuals, with observations that in excess of 15% of people that develop diabetes before 30 years of age will die before they reach 40. The economic and social cost of this disease is huge, diabetes is associated with many severe clinical complications which result in disability and reduced life expectancy, placing an enormous burden on the economy in terms of healthcare costs and reduced productivity in the workplace (Simpson et al 2003). In Ireland alone, the cost of treating this disease accounts for 10% of the entire health budget totaling €1.4 billion per annum (Nolan et al 2006). Physical inactivity is one of the most important modifiable risk factors for primary prevention of type 2 diabetes. Exercise has long been considered to play a key role in the treatment and prevention of diabetes alongside diet and medication, however high-quality research on the importance of physical activity and exercise in this area was lacking until recently (Sigal et al 2006).  The focus of this article will be on the pathophysiology of the disease, the mechanisms through which exercise acts as a therapy, the role of exercise and in particular current recommendations in relation to the frequency, intensity, time, and type of exercise, as well as future recommendations to help combat this disease.

Figure 1. Increases in the prevalence of diabetes from 1995-2010 (Simpson et al 2003)

Pathophysiology

The pathophysiology of Type 2 Diabetes Mellitus (T2DM) is complex and controlled by many factors, including both genetic and environmental components that affect β-cell function and tissue insulin sensitivity (Frontera et al 2006). T2DM is characterized by defects in both insulin action and insulin secretion, which leads to a gradual increase in plasma glucose levels over time (Ehrman et al 2003). The role of insulin is to transport glucose into the cell. Insulin is a peptide hormone that is secreted by the β-cells in the islets of langerhans in the pancreas. Each time we eat, insulin is released into the bloodstream to induce the liver, muscles, and adipose tissue to remove glucose from the blood for metabolism or storage (Widmaier et al 2008). In a normal fed state there is an increase in blood glucose coming from the gut, insulin binds with its receptor which is embedded in the plasma membrane of the cell. Once insulin is bound to its receptor, it initiates the signaling pathway that causes the vesicles containing GLUT-4 to translocate to the plasma membrane and allow glucose to enter the cell.

In an insulin resistant state, where insulin action is not working properly, there is still the same or even an increased production of insulin from the pancreas in response to an increase in blood glucose but there is no translocation of the internal vesicle containing GLUT-4 to the plasma membrane, thus glucose cannot enter the cell (Frontera et al 2006). However, there is less glycogen synthesis because of the decreased uptake of glucose into the liver. Since insulin is not working effectively, the liver still maintains gluconeogenesis, thus there is already plenty of glucose in the blood but the liver is releasing even more causing hyperglycaemia (McArdle et al 2010). In a hyperglycaemic state glucose can attach to different proteins and glycosylate them. This glycosylation affects the proteins function and ability to work properly. De Novo lipogenesis still occurs because the effect of insulin to act on the cell is reduced, resulting in the uptake of fatty acids into the muscle causing a build-up of intra-myocellular lipid stores (Williams and Pickup 2004).

β-cell dysfunction can occur up to 10 years before hyperglycaemia takes place, this alteration is evident with a reduced insulin response to glucose (Scheen 2003). In the early stages of impaired β-cell function there is a reduced insulin response to glucose, causing increased postprandial hyperglycaemia. As the dysfunction progresses to its later stages, prolonged hyperglycaemia triggers insulin secretion to be sustained for a longer time, this has been hypothesized to overwork the β-cell and impair its function (Leahy 1996). A progression from IGT to T2DM occurs due to a combination of insulin resistance and β-cell dysfunction, increased β-cell insulin secretion can’t maintain its high rates in response to glucose and T2DM develops (Ehrman et al 2003). By the time the disease is diagnosed, β-cell function will typically already be reduced by approximately 50%, and a progressive linear decrease of β-cell insulin secretion capacity over subsequent years can explain the deterioration of blood glucose control (Bilous and Donnelly 2010, Scheen 2003).

There are a number of environmental and genetic risk factors that may contribute to the development on T2DM. Some of these are non-modifiable risk factors such as ethnic origin, age, and family history. However, there are several modifiable risk factors associated with lifestyle choices that can lead to the development of T2DM, namely, obesity, physical inactivity, and diet. In the majority of western populations, more than 60% of new cases of T2DM are occurring in obese patients (Watkins et al 2004). Obesity is achieved through overfeeding of modern calorie dense food, coupled with a sedentary lifestyle, resulting in prolonged positive net energy balance (Scheen 2003). While obesity has been recognized as an important determinant of insulin sensitivity, the distribution of body fat appears to be the decisive factor. The greatest risk of diabetes is associated with central obesity in which fat is deposited intra-abdominally (Williams and Pickup 2004). Excess fat in the visceral region releases greater amounts of non-esterified fatty acids (NEFAs) through lipolysis which increases gluconeogenesis in the liver and reduces glucose uptake at the muscular and hepatic sites (Scheen 2003). Long term positive energy balance not only increases fat stores in the adipose tissue but also results in an increase in intramuscular triglyceride storage. In addition, lipids can accumulate in other tissues and affect their normal function, hepatic steatosis is regular in obese subjects, and non-alcoholic fatty liver disease is now linked with insulin resistance (Ravussin and Smith 2002). The severity of insulin resistance in the tissues is related to the degree of intramuscular triglyceride deposits, and interestingly increased fatty deposits in the pancreatic islets has been reported as a contributing factor in β-cell dysfunction (Unger 2002).

Exercise as a Therapy

Skeletal muscle is the primary site for the disposal of glucose in the body. As discussed already, in the insulin resistant state this function is impaired. However, exercise, or more specifically, muscle contraction, has an insulin-like effect. Even though individuals with T2DM are resistant to insulin, they are not resistant to the effect that exercise has on glucose utilization (Sigal and Kenny 2004). Muscle contraction activates AKT independent of insulin, and invokes the translocation of the GLUT-4 receptor to the sarcolemma and t-tubules allowing glucose transport to take place (Henriksen 2002). The signal for translocation of GLUT-4 during exercise is different from the insulin mediated function, and does not require phosphorylation of the insulin receptor (Rockl et al 2008). A single bout of exercise can have a significant glucose lowering effect in individuals with T2DM, as well as lowering plasma insulin concentrations during the activity. There is one main difference between the insulin effect and exercise effect. Insulin has a half time in circulation of approximately 7 minutes, so as soon as it is produced, the body must utilize it. Once it is withdrawn, glucose uptake is suppressed. Exercise has a different effect, it has been shown that a single bout of exercise can have a residual effect on glucose uptake for up to 72 hours (Sigal and Kenny 2004).

Exercise increases energy expenditure, skeletal muscle is the largest organ in the body, much bigger than the liver and adipose tissue. The larger the amount of muscle mass engaged in exercise, the more glucose that will be taken up and metabolized. This helps to restore energy balance, and takes pressure off the β-cells to produce insulin because the amount of circulating glucose is decreased, thus reducing insulin resistance (Sigal and Kenny 2004). Post-exercise, the muscle and liver are more sensitive to insulin, glucose continues to be taken up into the muscle and stored as glycogen and glucose taken up by the liver is nonoxidatively metabolized (Hamilton et al 1996). Regular exercise causes a number of physical adaptations within the muscle that enables more efficient utilization of substrates for the generation of ATP. Increased GLUT-4 protein expression occurs alongside increased mitochondrial function, this helps to facilitate increased glucose uptake into the muscle cell. The highest levels of GLUT-4 are normally found in oxidative slow twitch muscle fibres. Interestingly, individuals with T2DM have a distinct phenotype with a decreased amount of such fibres and reduced concentration of GLUT-4 (Rockl et al 2008).  Exercise training stimulates protein synthesis which develops lean body mass, this lean tissue burns more calories at rest than adipose tissue and helps to increase the basal metabolic rate. Training also facilitates a shift in substrate utilization, the increased mitochondrial and enzymatic activity enhances the muscles ability to extract and oxidize glucose and NEFAs from the blood, as well as increase the utilization of intramuscular triglycerides (Sigal and Kenny 2004). Moderate exercise can increase fat oxidation approximately 10 fold due to increased fatty acid mobilization and energy expenditure. Increased adipocyte catecholamine sensitivity is the proposed reason for the enhanced capability to mobilize NEFAs and reduce intramuscular triglyceride stores (Sigal and Kenny 2004).

Figure 2. Diagram representing different signaling pathways for GLUT-4 translocation to facilitate glucose transport in response to insulin and exercise (Rockl et al 2008).

Role of Exercise in Prevention of T2DM

There is a substantial body of evidence in the diabetes research literature that supports the value of exercise in the prevention of T2DM (Sigal et al 2006, Simpson et al 2003, Hansen et al 2010, Praet and Van Loon 2007). Exercise has proven to be equally as effective in preventing the progression from IGT to T2DM when compared to a combination of diet and exercise, and its beneficial effect on glycaemic control is modulated independent of weight loss (Sigal et al 2004). Current clinical recommendations declare that performing moderate intensity exercise on at least 3 days of the week for a minimum of 30 minutes per session can result in significant health benefits for patients with IFG and T2DM (Sigal et al 2006). The benefits of exercise can be greatly enhanced depending on the frequency, intensity, type, and time spent exercising.

Frequency

Following an acute bout of exercise, insulin sensitivity is enhanced for up to 72 hours. Research indicates that regular exercise has a cumulative effect on improving glycaemic control, with each successive bout of exercise further enhancing the positive responsive adaptations (Praet and Van Loon 2007). The minimum recommendations for exercise frequency is 3 days per week, with no more than 2 consecutive days between exercise bouts according to the American Diabetes Association guidelines (American Diabetes Association 2007). Greater exercise frequency as part of a long term lifestyle intervention has been shown to improve body composition in obese individuals by facilitating greater adipose tissue mass loss by creating an energy deficit, however, it has also been shown that the long term benefits of exercise on glycaemic control may be lost within 6-14 days if exercise is discontinued (Hittel et al 2005).

Intensity

Recommendations for continuous endurance training intensity varies between 40%-85% of VO_2max depending on what stage the patient is at in the lifestyle intervention (Hansen et al 2010). After exercising at intensities outlined above we get an increase in PGC-1α, this is considered as a master regulator for metabolism and increases the capability of the muscle to utilize glucose and fat (Canto and Auwerx 2009). For obese individuals, lower intensity exercise is recommended in the early stages of the intervention to assist in greater compliance to the training program. Low intensity continuous endurance-type training has shown to be as effective as high intensity continuous endurance-type training in improving glycaemic control provided that the exercise bouts are of sufficient duration (Hansen et al 2010).

Muscle glycogen plays a more important role in substrate metabolism as exercise intensity is increased. High intensity exercise depletes muscle glycogen stores to a greater degree and subsequent post-exercise glycogen synthesis is linked with improvements in glucose tolerance and insulin sensitivity (Praet and Van Loon 2007).  In theory, when the acute glucoregulatory effects of exercise are considered, high intensity exercise should be more effective than low intensity. However when both intensities have been compared, similar results were found in terms of loss of total-body adipose tissue and enhanced glycaemic control (Schjerve et al 2008). The total amount of energy expended during the exercise bout appears to be the most important factor for inducing changes in glucose homeostasis, thus low intensity exercise should be performed for longer durations than high intensity exercise (Praet and Van Loon 2007). 

Type

Current guidelines recommend the addition of resistance training alongside endurance-type regimens. The addition of resistance training results in enhanced glycaemic control for sufferers of T2DM (Hansen et al 2010). Resistance training increases energy expenditure and produces sizable gains in muscle mass, thus improving whole-body blood glucose disposal capacity (Praet and Van Loon 2007).  Resistance training improves bone density, balance, functional strength, and increases the resting basal metabolic rate which can improve long-term weight management and facilitate a more active and healthier lifestyle. Research has shown significant improvements in insulin sensitivity when resistance and endurance training is combined (77% increase) in comparison to endurance training alone (20% increase) after 16 weeks (Sigal et al 2007). One of the main factors for increased incidence of diabetes in older age is the loss of muscle mass, age-related sarcopenia can be attenuated with resistance training, thus improving the metabolic profile of older adults at risk of developing the disease (Hansen et al 2010).  The ACSM recommends 2-3 resistance training sessions per week, with 8-10 exercises that recruit the major muscle groups. 1 set of 10-15 repetitions is advised for beginners, with the aim of progressing to 3 sets of 8-10 repetitions over time (Sigal et al 2004). Although one set may be sufficient to promote strength gains, research has shown that 3 sets are optimal for producing the metabolic benefits for T2DM (Hansen et al 2010). 

Time

Currently, there is a lack of information in the scientific literature that provides guidelines on the optimal volume/duration for acute bouts of exercise (Praet and Van Loon 2007).  Rather, the intensity of exercise appears to have a greater importance. A study by Sriwijitkamol and colleagues (2007) found a greater decrease in blood plasma glucose levels in patients with T2DM after cycling for 40 minutes at 70% VO_2max, when compared to a group that exercised at 50% VO_2max. Recommendations currently focus on the energy cost of each exercise bout with energy expenditure in the region of 400-500 kcal deemed optimal regardless of the duration of the session (Praet and Van Loon 2007). 

Lifelong participation in exercise is recommended to manage and prevent T2DM. Adherence to extended exercise programs have resulted in significant improvements in glycaemic control and considerable reductions in fat mass in obesity patients with T2DM (Hansen et al 2010).  These improvements result in enhanced quality of life and life expectancy, as well as reductions in healthcare costs.

The Future Role of Exercise

Several recent studies have examined the effects of high-intensity intermittent training (HIIT) in T2DM patients. The results from these studies have so far been positive, Tjonna et al (2008) found significant increases in insulin sensitivity after a 16 week HIIT intervention in patients with IGT when compared to a continuous exercise intensity group. It has been discovered that the HIIT provides a much greater upregulation of PGC-1α, induces faster physiological adaptations in skeletal muscle, and improvements in body composition (Hansen et al 2010). This modality of training seems to provide greater benefits over traditional methods and is an area that warrants additional research in addition to future studies to provide a better understanding of the underlying mechanisms that promote the upregulation of GLUT-4 and insulin signaling features as a result of exercise. Muscle is now viewed as an endocrine hormone, not only is its contractility affecting energy expenditure during exercise but it is also releasing myokines which interact with other tissues in the body such as the liver and adipose (Pedersen 2009). Knowledge and understanding of these mechanisms can help clinicians and sports & exercise scientists to develop optimal exercise routines to enhance insulin action in patients with IGT and T2DM.

In order to combat this disease, there is a need to design strategies to address lifestyle choices on a large scale (Simpson et al 2003). A community-wide approach is recommended with special emphasis targeted at high risk groups such as pre-diabetic individuals. Education about appropriate lifestyle choices should be implemented at an early age and a structured program on lifestyle, exercise, and nutrition should form a compulsory part of the school curriculum (Simpson et al 2003). Putting these measures in place can help combat this largely preventable disease, improve quality of life, and reduce the economic burden associated with its treatment.