Personalised Exercise Training in Adolescents With Type 2 Diabetes for the Early Prevention of Beta Cell Dysfunction

Exercise training is a key component in the prevention and treatment of various chronic diseases such as Type 2 diabetes (T2DM). Adaptations and effects that occur with exercise training differ according to exercise protocols. Most exercise interventions in T2DM base their results on HbA1c. Since the molecular and epigenetic effects of exercise training on β-cell function have not been fully revealed, the importance and effect of exercise training have not been fully understood.

The patients included in the study will be divided into six groups; the control group (20 adolescents), the moderate continuous aerobic exercise training group (20 adolescents), the high-intensity interval training group (20 adolescents), the resistance exercise training group (20 adolescents), combination of moderate continuous aerobic exercise training with resistance exercise training group (20) and combination of high-intensity interval training with resistance exercise training (20 adolescents). At the beginning of the study, demographic and physical characteristics of the patients will be recorded, and anthropometric and laboratory evaluations, pulmonary function test, measurement of respiratory muscle strength and endurance, measurement of peripheral muscle strength, evaluation of functional and aerobic capacity, measurement of physical activity levels and energy consumption, evaluation of the quality of life, epigenetic analysis, evaluation of β-cell function and biochemical structure of insulin will be done.

All patients will receive exercise training 3 days a week for 16 weeks. All measurements and evaluations will be made before starting exercise training and after 16 weeks of exercise training. As a result of the data obtained, it will be tried to objectively present which type of exercise intervention, at which doses and frequencies, will be more effective for patients with T2DM, with its effect on epigenetic factors.

Diabetes Mellitus (DM) is a metabolic disease characterized by hyperglycemia due to insulin secretion or insufficiency in insulin function. In Type 2 diabetes (T2DM), the most common type of DM, high body mass index, unhealthy diet, reduced physical activity, an unfavorable intrauterine environment, and adverse genetic predisposition is among the risk factors. Over the past 20 years, the prevalence of T2DM among adolescents has increased several folds in the World.

Compared to adults with T2DM who develop secondary complications at a later age despite being insulin resistant for years, adolescents develop clinical T2DM and complications more rapidly and aggressively. Adolescents with T2DM have very poor treatment outcomes and a rapid decline in their glycemic control with the current treatment protocols. Early onset of T2DM and prolonged exposure to these metabolic abnormalities amplifies the long-term micro and macrovascular complications of these children. Also, according to the T2DM atlas of the International Diabetes Federation, T2DM will reach an epidemic level in the 2045 projection in adolescents and young people. Therefore, preventing the development of T2DM, slowing down the progression of the disease, stopping and treatment gaining great importance.

The core metabolic factors in the development of T2DM in adolescents include IR in the liver, muscle, adipose tissue, and eventual β-cell failure. However, the detailed molecular mechanisms related to the pathological process are not yet clear. Oxidative stress, which is expressed as disruption of oxidative balance, attacks healthy cells in the body and causes deterioration in their functions and structures. It has been reported that oxidative stress plays an important role both in the pathogenesis of T2DM and in the development of disease-related complications. Also another important factor for the development of T2DM is IR. IR is more pronounced by obesity and a sedentary lifestyle. Unlike their adult counterparts, children tend to overproduce insulin disproportionately in response to IR. Studies have shown that peripheral IR plays a significant role in the initiation of type 2 DM. Considering the role of oxidative stress and IR in the pathogenesis of T2DM and its effect on the development of disease-related complications, it is thought that exercise training may be beneficial in the prevention and/or treatment of T2DM. Therefore, it is very important to define the adaptation mechanisms that explain the oxidative stress preventive and therapeutic potential of exercise training.

Epigenetic processes have been associated with predisposition and progression to T2DM in response to various lifestyle factors or environmental exposures, including malnutrition, obesity, physical inactivity, stress, and toxins. Increasing evidence indicates that dynamic changes in the epigenome can occur within an individual's lifetime and that these changes can affect metabolic health. The molecular mechanisms governing the protective effects of exercise in T2DM are not yet fully understood. Several recent studies have shown that there are epigenetic modifications with exercise. Although there are in-vitro studies investigating the protective effects of different exercise protocols at the molecular level, no human studies are showing their epigenetic modifications.

Exercise training is a key component in the prevention and treatment of various chronic diseases such as T2DM. Adaptations and effects that occur with exercise training differ according to exercise protocols. Most exercise interventions in T2DM base their results on HbA1c. Since the molecular and epigenetic effects of exercise training on β-cell function have not been fully revealed, the importance and effect of exercise training have not been fully understood.

Considering the role of oxidative stress and inflammation, epigenetic changes in the pathogenesis of T2DM, and the development of disease-related complications, exercise training will be effective in the prevention and/or treatment of T2DM in young people. For this reason, with this project, the optimal exercise protocol will be determined to improve β-cell dysfunction, which will ensure the formation and protection of oxidative balance and reduce IR.

Personalised medicine aims to predict therapeutic response according to a personal profile that includes clinical, physiological and genetic data. So with this project, the development of epigenetic marker panels that will predict an individual's response to a particular exercise training protocol will contribute to revealing personalised epigenetic memory. Better knowledge of these connections will allow for the development of personalised exercise training regimens that will allow a person to achieve their training goals with maximum efficiency. Also this project aims to establish an artificial intelligence platform that brings together data from clinical research on the effects of different exercise training protocols with the purpose of identifying predictors. All results will be combined into a single data platform to develop predictive models for the treatment response. This data platform help to develop a decision support system for personalised exercise training in adolescents with T2DM.

The patients included in the study will be divided into six groups; the control group (20 adolescents), the moderate continuous aerobic exercise training group (20 adolescents), the high-intensity interval training group (20 adolescents), the resistance exercise training group (20 adolescents), combination of moderate continuous aerobic exercise training with resistance exercise training group (20) and combination of high-intensity interval training with resistance exercise training (20 adolescents). At the beginning of the study, demographic and physical characteristics of the patients will be recorded, and anthropometric and laboratory evaluations, pulmonary function test, measurement of respiratory muscle strength and endurance, measurement of peripheral muscle strength, evaluation of functional and aerobic capacity, measurement of physical activity levels and energy consumption, evaluation of the quality of life, epigenetic analysis, evaluation of β-cell function and biochemical structure of insulin will be done.

All patients will receive exercise training 3 days a week for 16 weeks. All measurements and evaluations will be made before starting exercise training and after 16 weeks of exercise training.

As a result of the data obtained, it will be tried to objectively present which type of exercise intervention, at which doses and frequencies, will be more effective for patients with T2DM, with its effect on epigenetic factors. In addition, determining an optimal non-pharmacological treatment method for a disease defined as an epidemic in the 2045 projection will contribute to the prevention of mortality and morbidity and the reduction of health expenditures.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosed with T2DM,
* Being between the ages of 10-19,
* Body mass index (BMI) below 40 kg/m2,
* Being able to cooperate and walk for the exercise training and evaluation methods.

Exclusion Criteria:

* Having type 1 diabetes,
* Known lung disease,
* Have had any cardiac event or surgery in the last six months,
* Diabetes complications such as nephropathy, retinopathy and severe neuropathy,
* Being on insulin therapy,
* Having a known cancer disease,
* Having a known autoimmune, rheumatological disease,
* Having any known neuromuscular disease,
* Having other known endocrine disease other than T2DM,
* Existence of limitations and diseases that may affect exercise training.