Diabetes is a very common name in today’s world. In every family, there is at least one person suffering from this disease. It is a multifactorial disease that is mainly linked to energy metabolism, predominantly involving carbohydrate and fat in the organism. More simply put, it is a chronic metabolic disorder associated with high blood glucose levels that occur due to complete or relative deficiency in a hormone called insulin. This is mainly due to dysfunction in β-cells of the pancreas which secrete insulin. Until today, it is still likely a syndrome with many pathophysiologic abnormalities involving many genetic and epigenetic factors with diverse complications, and several environmental stimuli like nutrients, infections, exercise regimens, and microbiome of gut 1,2. The communication among these factors is the main topic of concern for scientists.
Diabetes is basically characterized into Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). T1D is an early-onset autoimmune disorder, whereas T2D is a late-onset non-autoimmune form. In addition, other clinically recognized forms of diabetes are gestational diabetes, monogenic diabetes (including neonatal diabetes and maturity-onset diabetes of the young (MODY)), diseases of the exocrine pancreas (e.g. cystic fibrosis-related diabetes and pancreatogenic [or type 3c] diabetes) or drug-induced diabetes, and possibly a late-onset autoimmune form (latent autoimmune diabetes in the adult).
As mentioned above, this is an autoimmune disorder in which there is destruction of pancreatic beta cells by the body's own immune system. This basically leads to complete insulin deficiency.
Even though the age of symptomatic onset is typically childhood or adolescence, symptoms can also appear much later. Type 1 diabetes has been observed to be increased in children younger than 15 years, and predominantly in those children younger than 5 years3. This increase cannot alone be explained by genetic changes, which suggests that environmental or behavioral factors, or both play an active role. Many environmental factors that may be associated with T1D include infant and adult diets, early-life exposure to viruses associated with islet inflammation, vitamin D sufficiency, and decreased diversity of gut-microbiome. Obesity has also been observed to be associated with increasing incidence of T1D4.
The most common symptoms of T1D are polydipsia, polyuria, and weight loss with diabetic ketoacidosis5. The diagnostic criteria as defined by 2016 American Diabetes Association (ADA) for diabetes mellitus depends on signs of abnormal glucose metabolism, irrespective of the type of diabetes or the age of onset 6.
Activated B cells mainly interact with CD4+ and CD8+ T cells and dendritic cells (DCs). This antigen presentation by B cells and DCs causes the activation of β‑cell-specific T cells. Moreover, as B cells come into contact with β‑cell autoantigens, it causes production of islet-targeting autoantibodies. These autoantibodies act as biomarkers for the disease. However, the initiating factor for this whole interaction is still unknown. The probability of the role of viral infection and an environmental stimuli to act as a triggering event still needs to be studied 7.
The DCCT study has always been a prime investigation on how to manage T1D. It mainly concentrated on use of intensive insulin therapy with the aim of maintaining levels of glucose as close to normal.8 This extensive management of T1DM requires a tight teamwork among physicians, nurses, dieticians, diabetes educators and psychologists along with the patient, and their families. The basic aim is to endorse healthy living and glycemic control in order to avoid severe hypoglycemia or hyperglycemia and ketoacidosis.9
This is the most common type of diabetes (approximately 95% of patients with diabetes have T2D.
It has been predicted by the International Diabetes Federation that by 2045, approximately 783 million people will be affected by T2D worldwide 10. T2D patients are generally at increased risk of developing chronic comorbidities and secondary complications like nephropathy, neuropathy, cardiovascular disease, and retinopathy, causing a substantial economic burden of $327 billion as per estimates defined by the American Diabetes Association 11. The cause of T2D is multifaceted. One of the non-modifiable factors causing T2D are age and genetics, while other factors such as a healthy dietary pattern and physical activity are modifiable through lifestyle changes 12.
T2D is depicted by occurrence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver. It usually develops when there is failure in β-cells function to make up for the peripheral insulin resistance. Insulin resistance further causes an increase in insulin demand, which leads to β-cell compensation by aggregating both β-cell mass and insulin secretion. This causes hyper-insulinemia. In a vicious cycle, increased insulin levels intensify the metabolic dysregulations, which cause β-cell failure and hence development of T2D 13.
The treatment of patients with T2DM is quite challenging, as it is a complex disease, but glycemia can be controlled by pharmacological therapy. The four major groups of anti-diabetic agents currently being used individually or in combination are biguanides which decrease gluconeogenesis in the liver (metformin), insulin secretagogues which trigger the pancreas to secrete insulin (sulfonylureas), insulin sensitizers which enhance the sensitivity of peripheral tissues to insulin (thiazolidinediones), insulin or its analogues which deliver insulin exogenously (recombinant insulin). Metformin is usually the first-line pharmacotherapy for T2D14. However, these drugs can cause many unwanted side reactions like weight gain, fluid retention, hypoglycemia, and heart failure, which constrain their applications. Hence, nowadays natural products (NPs) have also become the important resources of bioactive agents for anti-T2DM drug discovery, as their level of toxicity is lower and they do not have any adverse effects 15 .
The rising incidence of T2D is in coincidence with the increase in obesity in most developed countries, but also in developing countries. An inactive lifestyle is the most eminent cause of this rise in T2D. However, many other reasons are also responsible for this rising epidemic, like adopting energy-dense diets and an aging population. Exercise as a consistent physical activity at a medium to vigorous intensity has been observed to be a proficient influencer for adapting to a healthier lifestyle 16.
It is a well acknowledged fact that metabolic dysfunction in T2DM is associated with chronic inflammation 17. The connection between inflammatory mediators and insulin resistance is really essential for diabetes management. Exercise has shown to induce some valuable changes in glycemic markers such as HbA1C, insulin resistance and fasting insulin, which is unquestionably a deterring step toward T2D. Decrease in visceral and abdominal fat has also been observed to be the key link between exercise and less insulin resistance 18 . Hence, the blend of physical activity with calorie constraint has been proven to not only recuperate the well-being status, but also avoid weight gain in the long term and thus overall morbidity 19.
Aerobic exercises are activities that involve larger muscles and mainly rely on energy produced by aerobic metabolism. The aerobic activity may be mild or intense. It is generally performed for a longer duration. Some of the examples of aerobic activity include jogging, running, cycling, and swimming. Resistance activity is mainly aimed to improve muscular power and strength by using machines, bodyweight, or elastic 20 . Stretching activity basically tends to increase flexibility in the body. It involves upper and lower body stretches, yoga, and calf stretches.
Various studies across different countries and among diverse sets of populations have shown that physical activity is quite effective in the prevention of T2D by promoting insulin sensitivity and changes in body mass and composition 21,22.
One study showed that a protein known as Irisin is released from skeletal muscles after physical activity. The production of Irisin is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) transcriptional coactivator. Irisin has been proposed as a possible connection between physical activity and health benefits 23. Furthermore, as we know that glucose uptake by skeletal muscles occurs through a regulated mechanism via GLUT4 in presence of insulin. However, due to insulin resistance, this pathway is disrupted. During physical activity, when muscles are in a contracted state, another pathway for glucose uptake is activated. Though the exact mechanism of how this pathway is activated is still not known, it has been observed that it does not depend on the level of insulin present. Due to physical activity, muscle contraction occurs, which further causes numerous changes in energy levels, like increase in intracellular Ca2+ level, increased AMP/ATP, increased reactive oxygen species, and Protein Kinase-C. All these lead to activation of diverse signaling pathways, some of which are probably acting as an activator of GLUT4 translocation 24 .
Retinopathy is one of the most familiar complications of diabetes. Its pathogenesis largely depends on fasting blood glucose and the daily glycemic fluctuation. Patients with good glycemic control have a decreased chance to develop retinopathy 25. One study showed that T2D patients with higher physical activity are less likely to experience diabetic retinopathy 26 . In another study, it was observed that moderate-intensity treadmill running was the main factor in reversing the development of diabetic peripheral neuropathy 27. It has also been observed that both calorie restriction and physical activity in T2D patients cause mild weight loss (6%) and improvement in kidney function (i.e. has an impact on nephropathy as well) 24 .
This type of exercise has been shown to intensely increase muscle glucose uptake by 5 times via an insulin independent mechanism. If the duration of exercise is prolonged, it leads to muscle glycogen repletion after exercise demand, which causes an increase in glucose uptake for about 2 hours by an insulin-independent pathway, and for up to 48 hours by an insulin dependent pathway 28 . Moreover, it can also interfere with diabetic complications like hypertension, dyslipidemia, nephropathy, and cardiovascular diseases 16 . In addition, studies have shown that regular exercise can improve the quality of life in diabetic patients 29 .
Recent studies have highlighted the significance and necessity of systematic resistance exercise. Studies have shown that resistance exercise is effective in managing insulin action and blood glucose levels along with other cardiovascular risk factors 30 . Combination of aerobic and resistance training have proven to create healthier adipose tissue, skeletal muscle, liver, and control insulin sensitivity which is reliant on weight loss 28 .
Combined training has been observed to be the most efficient for managing glycaemia compared to either aerobic or resistance training alone 28. Most of the studies have confirmed that if diabetes patients perform both aerobic and resistance exercise, it results in the resilient effect on increasing insulin sensitivity compared to when doing only aerobic exercise 18 . Combined exercises cause increased stability in glucose levels, and lead to less hypoglycemic experiences, both during and after the exercise session 31.
According to the American Diabetes Association, it is recommended that youngsters with type 1 or 2 diabetes should carry out moderate- or high intensity aerobic exercise for at least 60 min or more per day. It is also recommended to do resistance exercise for at least 3 days per week to strengthen bones and muscles. For T2D patients, in order to cope up with the progression of the disease morbidity, at least 210 min/week of moderate-intensity activity or 125 min/week of high-intensity exercise is required. Physical exercise intensity should always be selected depending on disease level, a patient’s individual health condition, and primary fitness 32. In relation to morbidity and common health complications of T2D patients, such as obesity or being overweight with physical disability, difficulty in visualization, or cardiovascular burdens, it is very difficult to achieve the satisfactory intensity of aerobic exercise. However, resistance exercise can be easily performed in a residential setting. Hence, these exercises are more achievable and are generally a safe choice for inactive older diabetic patients.
Even though physical exercise is full of benefits, it is highly recommended that regardless of the type of exercise, time and individual capacities should be considered. Intensity and duration of the exercise should be suitably increased and must be supervised by an exercise physiologist who has knowledge of diabetes or is a certified fitness professional. Proper exercise generally leads to increased body heat and core temperatures, which results in increased blood flow and sweating. This leads to poor glycemic control, dehydration, neuropathy, and other heat-related problems. Furthermore, in order to avoid exercise-related overuse injuries and unnecessary intensification to joint surfaces and structures, personalized exercise programs should be designed for people with diabetes, especially when they are also taking medications like statin for dyslipidemia.
Diabetes is a multifactorial disease, occurring primarily due to insulin resistance or absence. One of the various factors involved in diabetes initiation is obesity, or we can say sedentary lifestyle due to varied reasons. Hence, physical activity plays an important role in management of this lifestyle disease. Any type of activity, be it intense aerobic or just simple walking or yoga can have a deep impact on controlling the glucose levels in the body. Therefore, it is highly recommended that simple or intense activity should be part of people’s life. Physical exercise should be performed at least 2 to 3 times per week, and it is strongly advocated that special personalized exercise programs should be designed for diabetes patients by highly qualified fitness professionals.
