Type 2-Diabetes Mellitus (T2DM) is a metabolic disease characterized by the hyperglycemia due to defects in the insulin secretion, insulin action, or both. The possible cause of hyperglycemia varies, but the origin lies with the molecular events arising from the peripheral insulin resistance or rupture of the glycogen homeostasis or failure in the insulin secretion response. Some people are susceptible to the condition due to their genes, but the advent of certain environmental factors plays a role. Thus, the rise of increasing cases of the T2DM is due to the collision between genes and the environment. People with greater genetic susceptibility also engage lead a lifestyle that increases the chances of getting the disease.
Due to the complications that result from insulin resistance, patients with T2DM show a cluster of abnormalities that include hypertension, increased inflammation, lowering of the levels of plasma dyslipidemia, endothelial dysfunction, among others (Marín-Peñalver et al. 2016). With the complications, patients are at a high risk of developing stroke due to hypertension, myocardial infarction (MI), and CVD. In the majority of cases, hypertension is comorbid with T2DM, which is a serious condition as it can trigger stroke. Other complications from untreated T2DM include renal failure and the death of peripheral nerves.
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The disease is chronic and progresses slowly. Currently, no treatment method can reverse the condition entirely. However, pioglitazone seeks to restore the lost function in the production of the insulin and response to insulin signalling by the liver and the associated tissues. This research aimed to understand whether pioglitazone with diet and exercise produces better outcomes compared to pioglitazone without diet and exercise. The findings indicate that while pioglitazone provides benefits independent of exercise, it also tends to increase the weight of patients (Whalen, Miller & Onge, 2015). Weight gain increases the risk of developing additional conditions, such as cardiovascular diseases. Thus, pioglitazone monotherapy is risky from that perspective.
On the other hand, pioglitazone monotherapy with exercise and diet helps address the issue of weight gain. Moreover, exercise and dietary changes are proven methods of diabetes management. Aerobic and resistant exercises increase peripheral glucose uptake, and it matched by hepatic glucose production. Moreover, a session of the aerobic exercise improves insulin action and glucose tolerance, and the benefit appears to persist for more than 24 hours but less than 72 hours (Watanabe et al. 2015). The action of both types of exercise is similar in action to the mechanism of pioglitazone. The drug works by targeting the insulin-sensitive tissues named adipose tissue, skeletal muscles, and the liver and then stimulates them. With time, the stimulation improves their ability to work as expected, and the body gradually manages to keep blood sugar under control.
Treatment options
Traditionally, the primary management method for addressing this condition has been exercise and diet. As discussed elsewhere in this paper, exercise is beneficial as it improves the ability of the body to control blood glucose. The benefits tend to persist for up to three hours after the activity. Therefore, doctors usually recommend exercise as a management strategy. For healthy people, exercise is also useful. It plays a critical role in weight management, as obesity is a risk factor for diabetes. Obesity leads to fatty liver and accumulation of the abdomen fat, which is associated with the insulin insensitivity.
Another treatment option is insulin injection for people whose conditions cannot be controlled using oral medications alone (Kashiwagi et al. 2014). The insulin injection helps the body maintain blood sugar, as well as prevent the liver from producing more sugar. Often, this treatment method is used in severe cases before the patient is transitioned into another treatment method with drugs such as pioglitazone. This treatment method does not seek to restore the impaired production of insulin in liver cells. Instead, the injection provides the insulin, which the body is unable to produce, to control the amount of blood sugar. In the end, the most practical treatment method is the use of drugs that try to restore the lost function.
However, despite the need to restore insulin sensitivity, currently, only a few drugs try to achieve that objective and do so with excellent results. Of these classes of drugs, Thiazolidinediones (TZDs) is the only anti-diabetic agent that targets to improve insulin sensitivity in the peripheral and hepatic tissues by binding and to activate the specific receptor (Kovacs et al. 2013). The food and drug administration has approved pioglitazone (Actos), the only TZDs available in the market following the withdrawal of drugs such as troglitazone (Rezulin) and rosiglitazone (Avandia).
Pharmacology of Pioglitazone
Pioglitazone targets the insulin-sensitive tissues named adipose tissue, skeletal muscles, and the liver. The drug also targets nuclear peroxisome proliferator-activated receptor-gamma (PPARγ) as well as modulating the activities of the several genes and the protein synthesis. Pioglitazone promotes adipogenesis, allowing for more lipid deposition in adipocytes. The increased parking of adipocytes reduces the availability of non-esterified fatty acids and triglycerides, which encourages the use of glucose (Rosenstock et al. 2014). As the body uses more glucose, the problem of hyperglycemia is rectified. Also, the action of the drug reduces intramyocellular FFA content as well as liver fat content; thus, improving insulin sensitivity and better utilization of glucose.
Pioglitazone also uses other mechanisms to increase insulin sensitivity. It increases the transcription of glucose transporter-4 (GLUT 4), thereby improving the levels of the adiponectin while reducing adipocyte tumor necrosis factor-alpha concentrations, effectively inhibiting resistin production. T2DM is also associated with inflammation, and the drug addresses the problem by improving lipid metabolism and slows vascular proliferation as well as atherogenesis.
The drug is effective on fasting and postprandial glycemia, which lowers the levels HbA1c by 1.3to 1.6%. For patients contraindicated for metformin, the drug is still effective as it is equipotent to metformin and sulfonylurea (Mathieu et al. 2015). As a monotherapy, pioglitazone is taken as a single daily oral dose, and it reaches peak concentrations after 2 hours. The liver metabolizes the drug through the pathway CYP2C8 and CYP3, then excreted into the bile, and then removed through the feces, although about 15-30% of the drug is recovered in urine.
Exercise and T2DM control
Fuel metabolism during exercise
Exercise has a beneficial effect on the control of T2DM as a management strategy for the condition. It increases fuel mobilization, glucose production, and muscle glycogenolysis. At rest and during exercise, the coordination and integration of the nervous system and the endocrine systems control blood sugar. When muscles contract, such as while conducting the exercise, the demand for blood sugar increases, improving the management levels of glucose in the blood. Nevertheless, processes are known as glycogenolysis and gluconeogenesis and mobilization of alternative fuels that take place in the liver help maintain glucose levels.
The fuel used during physical activity is determined by two factors, namely the intensity and the duration of the physical activity. At rest, the body relies mostly on free fatty acids, but activity makes the body shift to fat, glucose, and glucose stored in the muscle in the form of glycogen. Amino acids are also relied on to a certain extent (Irons & Minze, 2014). However, as the intensity of the exercises increases, the body almost entirely relies on carbohydrates as long as they are present in the muscles and blood in enough quantities. Initially, the body relies on glycogen, but after depletion, muscles start to take glucose and free fatty acids from adipose tissue actively. As the period of the exercise increases, the body begins to use lipids stored in the muscles, and glucose production moves from hepatic glycogenolysis to enhanced gluconeogenesis. In summary, exercise is good for sugar control as it increases the glucose uptake into active muscles balanced by hepatic glucose production.
Glucose uptake follows two pathways: insulin-dependent and insulin-independent. At rest, the body uses insulin to replenish the glycogen stores. All insulin-dependent glucose uptake is affected by T2DM. However, after exercise, the absorption of the glucose to the muscles remains high, and insulin-mediated pathways remain active even longer. GLUT proteins and insulin accomplish the transport of glucose to the muscles and contractions mediate the process. Insulin conducts complex signaling to the GLUT protein to the start of a process of uptake. Contraction, on the other hand, triggers the activities of the GLUT protein through an activation protein. The presence of the T2DM impairs the GLUT translocation. However, aerobic and resistance exercise increases GLUT abundance and the reuptake of the blood glucose even in the presence of T2DM.
Glycaemic control/BG levels after exercise
In healthy people, moderate exercise increases peripheral glucose uptake, and it matched by hepatic glucose production. Therefore, the level of glucose remains relatively stable. However, if the exercise is long, the body depletes the glycogen in the muscles. In patients with diabetes engaged in the moderate exercise, the balance noted earlier does not exist. The utilization of blood glucose by muscles is higher than hepatic glucose production, so the levels of glucose decline. The plasma insulin falls, but that does not increase the risk of the suffering from hypoglycemia for persons not taking insulin even under conditions of the prolonged exercise. A session of the aerobic exercise improves insulin action, and glucose tolerance and the benefit appears to persist for more than 24 hours but less than 72 hours. The benefits of exercise are due to the increase in the plasma catecholamine levels, which increases the production of glucose. The increase in the levels of glucose can cause hyperglycemia because blood sugar remains high for several hours even after the cessation of the activity. The cause of hyperglycemia is the levels of plasma catecholamine, and glucose production remains elevated. Resistance exercise lowers the amount of fasting glucose in the blood, and the impact remains for at least 24 hours.
A combination of the aerobic and resistance exercise appears to produce a better outcome. Resistance training increases the muscle mass, contributing to increased uptake of glucose, but that does not affect the ability of the muscle to respond to insulin. Aerobic exercise, on the other hand, enhances the uptake of glucose by improving insulin action, regardless of the changing mass of the muscle. Mild exercises tend to reduce fasting blood glucose as well as oxidative stress markers. The decline in stress markers is due to the reduction of lipid levels in the blood.
Exercise and insulin resistance
Exercise improves insulin action. The benefits tend to remain for up to three days after exercise, suggesting that regular exercise is crucial in the management of the condition. The lengthy and intensive the exercises are, the higher the benefits. However, the benefits are dependent on age and training. Some studies found that the intensive aerobic training undertaken three times a week for six months, insulin action tended to persist in the younger people compared to older ones. The onset of the impaired insulin action is linked to the increase in liver fat common in obese people and those with T2DM. The two conditions reduce hepatic and peripheral insulin action. However, while exercise is linked to a general improvement in insulin action, the gains are only found in peripheral insulin action. Another benefit of exercise is the loss of body weight, reducing hepatic lipid content, and altering fat partitioning and in the liver.
Bodyweight maintenance
The most successful programs for body weight maintenance include exercise, diet, and behavior modification. However, weight management is beneficial to glucose maintenance as well as reducing the risk of a cardiovascular event. For older people, engaging in aerobic exercise is recommended because the gains are equivalent to the caloric restriction. Sustaining exercise requires supervision and training (Jung, Jang & Park, 2014). Body weight loss is an essential ingredient in the management of T2DM. The most successful program for long-term control combines diet, exercise, and behavior modification. As discussed elsewhere in this paper, exercise improves control of blood glucose as well as reducing the risk of cardiovascular diseases. For people, especially older adults, the best method for weight loss management is the training because walking does not appear to work (Derosa et al. 2010). However, with moderate aerobic exercise, it is possible to produce greater insulin action compared to caloric restriction.
Limitations
The main limitation of the study is the reliance on the secondary data. Therefore, the reliability of the study is as accurate, depending on the data from the sources used.
SUMMARY AND CONCLUSIONS
Benefits of exercise
The result of the research indicates that exercise is beneficial for patients with T2DM. Moderate exercise increases peripheral glucose uptake, and it matched by hepatic glucose production. A session of the aerobic exercise improves insulin action, and glucose tolerance and the benefit appear to persist for more than 24 hours but less than 72 hours. A combination of the aerobic and resistance exercise seems to produce a better outcome. Exercise improves insulin action, and the benefits tend to remain for up to three days after exercise, suggesting that regular exercise is crucial in the management of the condition. However, while exercise is linked to a general improvement in insulin action, the gains are only found in peripheral insulin action. Exercise is also beneficial as it increases the loss of body weight, reducing hepatic lipid content, and altering fat partitioning and in the liver. Exercise increases fuel mobilization, glucose production, and muscle glycogenolysis. At rest and during exercise, the coordination and integration of the nervous system and the endocrine systems control blood sugar. When muscles contract, such as while conducting the exercise, the demand for blood sugar increases, improving the management levels of glucose in the blood. Nevertheless, processes are known as glycogenolysis and gluconeogenesis and mobilization of alternative fuels that take place in the liver help maintain glucose levels (Hildreth et al. 2015). Exercise is, therefore, critical in the management of diabetes, and physicians recommend it as a management strategy to control the condition.
Pioglitazone benefits independent of exercise
The use of pioglitazone appears to produce benefits independent of exercise. Pioglitazone is effective in addressing some of the problems associated with the insulin resistance because the drugs, seek to fix the problem of boosting the sensitivity of the liver cells to the insulin signaling. The drug, therefore, offers cardiovascular protective action. The possible mechanism for the protection is on the increase in plasma concentration of triglycerides (TGs) due to the rise in the accumulation of adipose tissue. That mechanism, in addition to others, makes the heart muscles more contractible, lowering the risk of a cardiac event. Pioglitazone monotherapy also reduces the risk of hypoglycemia, which increases the risk of developing heart disease or CVD (Hibuse et al. 2014). Pioglitazone targets the insulin-sensitive tissues named adipose tissue, skeletal muscles, and the liver. The drug also targets nuclear peroxisome proliferator-activated receptor-gamma (PPARγ) as well as modulating the activities of the several genes and the protein synthesis (Forst et al. 2014). Pioglitazone promotes adipogenesis, allowing for more lipid deposition in adipocytes. Pioglitazone also uses other mechanisms to increase insulin sensitivity. It increases the transcription of glucose transporter-4 (GLUT 4), thereby improving the levels of the adiponectin while reducing adipocyte tumor necrosis factor-alpha concentrations, effectively inhibiting resistin production. T2DM is also associated with inflammation, and the drug addresses the problem by improving lipid metabolism and slows vascular proliferation as well as atherogenesis.
Pioglitazone with diet and exercise
The biggest problem with pioglitazone is weight gain. The reason for the weight gain is fluid retention and fat accumulation in the body. The weight gain is a significant problem, and it limits the benefits of pioglitazone. The solution is using pioglitazone monotherapy with exercise and diet. The problem of weight gain indicates that a combination of the pioglitazone, exercise, and dietary changes improves outcomes.
Moreover, sedentary lifestyle and a long-term imbalance in the energy uptake play a critical role in the development of the T2DM. The realization has led to recommendations that include exercise for patients to augment dietary changes to address the condition. Vigorous bodily activities increase the need for fat and carbohydrates, and that improves glycemic control and dyslipidemia in diabetes patients (Alam et al. 2019). The use of pioglitazone is often recommended with diet, and lifestyle changes fail to curb the progress of the disease. The drug works by increasing sensitivity to insulin, the lack of which initially leads to diabetes. The finding of this research indicates that using pioglitazone monotherapy and the exercise and dietary changes, improves the management of the condition by reducing chances of weight gain. Therefore, patients can benefit from the pioglitazone efficacy while limiting the negative impact of the drug associated with weight gain. Moreover, weight gain leads to more complications and might lead to the development of cardiovascular condition. Thus, although pioglitazone produces benefits independent of the exercise, the most beneficial approach is to include exercise and diet control to get the most benefits.
Implications for practice
The findings indicate that the combination of pioglitazone monotherapy with exercise produces better outcomes compared to pioglitazone monotherapy without exercise. The key concern about pioglitazone is weight gain and exercise can address that issue. Therefore, patients can use exercise to fight weight gain while benefitting from the drug with proven benefits in stimulating tissues to respond to insulin and the signalling mechanism behind the critical blood sugar regulation.
Implications for research
More research is needed to understand the actual mechanism that leads to the improved outcome in pioglitazone monotherapy with exercise. Also, the real reason for the weight gain with pioglitazone is not clear. More studies are needed to understand what causes the weight gain so that future iteration of the drug can address the concern.
References
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