Original ResearchEffect of Acute Aerobic Exercise and Rapamycin Treatment on Autophagy in Peripheral Blood Mononuclear Cells of Adults With Prediabetes
Introduction
Type 2 diabetes is a disease with increasing prevalence that has become a global health problem that affects people of all socioeconomic classes. According to the International Diabetes Federation Atlas (1), the estimated diabetes prevalence in 2017 was 425 million, with >641 million people predicted to be living with type 2 diabetes worldwide by the year 2040. It is well established that type 2 diabetes is associated with increased risk of developing microvascular disorders, including nephropathy, neuropathy and retinopathy (2). Furthermore, individuals with type 2 diabetes have increased morbidity and mortality because of increased risk of cardiovascular disorders, such as coronary artery disease, hypertension and stroke 3, 4. However, prior to the development of type 2 diabetes, a period of prediabetic state occurs, which may be characterized by impaired glucose and insulin tolerance, mild to moderate obesity and fluctuations in normoglycemic and hyperglycemic states (5).
Exercise is known to play a fundamental role in the prevention and treatment of type 2 diabetes, in part because of improvements in insulin sensitivity and increased maximal oxygen consumption (Vo2max) (6). Additionally, exercise-induced adaptations include an increased abundance of proteins involved with insulin signalling (e.g. insulin receptor substrate 1) and glucose metabolism important in cellular homeostasis 7, 8. However, these metabolic adaptations have been reported to be impaired in patients with type 2 diabetes and patients with prediabetes, indicating a potential resistance to the beneficial effects of exercise (9).
Macroautophagy (herein referred to as autophagy) is a catabolic cellular process, which involves the degradation of protein aggregates and damaged organelles, and is crucial in maintaining cellular homeostasis (10). Autophagic flux refers to the complete process of autophagy, including the amount and rate of cargo sequestered and degraded (11). Stimulation of autophagic flux has been shown to be crucial in the development of cellular adaptations to exercise (12). However, disruption of autophagy in mice has been shown to impair endurance exercise performance and glucose metabolism during an acute exercise bout (13). Furthermore, impaired autophagic functioning may contribute to the development of prediabetes and type 2 diabetes through the development of insulin resistance (14) and other comorbidities including neurodegenerative disorders 15, 16, cardiomyopathy (17) and cancer (18). Although the beneficial effects of exercise in prediabetes and type 2 diabetes have been well established (19), little is known about the effect of exercise on autophagy in people with prediabetes and people with type 2 diabetes. It has recently been demonstrated that an acute bout of endurance exercise (1 to 2 h) is sufficient to stimulate autophagic signalling in skeletal muscle of young healthy adult men 20, 21. Recent evidence suggests that the acute autophagic response may be intact in human skeletal muscle of people with type 2 diabetes in response to 60 min of cycling exercise at 70% of Vo2max (22). This may be because of an autophagic adaptation to chronic hyperglycemic conditions; however, it is unknown if people with prediabetes exhibit this adaptive response (23). Therefore, the autophagic response to exercise in individuals with prediabetes remains to be established.
The aim of this study was to investigate the response of autophagy in response to an acute bout of exercise and subsequent recovery in peripheral blood mononuclear cells (PBMCs) of individuals with prediabetes compared with age- and sex-matched control subjects. Because PBMCs come into contact with every cell in the human body and are sensitive to various physiological, pathologic and environmental changes, they were chosen as a representation of the whole body autophagy response (24). To further elucidate the mechanism of autophagic modulation, we treated PBMCs from people with prediabetes with the known autophagy inducer, rapamycin (RAPA).
Section snippets
Human participants
The study was approved by the University of New Mexico's Human Research Review Committee (HRPO-14-200), and all participants provided written informed consent. Twelve adult participants (6 men and 6 women) between the ages of 27 and 61 years and who were free of known illness or disease were recruited. This sample size was determined via an a priori power analysis (G*Power; Universität Düsseldorf, Düsseldorf, Germany) which estimated 12 participants were required based on the variable
Clinical and metabolic characteristics
Participants with prediabetes had significantly higher A1C levels (p=0.001) than control participants but showed a similar Vo2max (p=0.36), indicating minimal differences in cardiorespiratory fitness between groups. Furthermore, no differences were observed in body mass index (p=0.47), body fat percentage (p=0.56) or waist circumference (p=0.49) between participants with prediabetes and control participants (Table 1).
Effect of aerobic exercise on markers of autophagy
The protein abundance of important autophagy markers was examined between
Discussion
In this study, we examined the impact of an acute bout of moderate intensity (50% Vo2max) endurance exercise on markers of autophagy response in PBMCs of individuals with prediabetes and age- and sex-matched control subjects. To further understand differences in autophagy between people with prediabetes and control subjects, we treated PBMCs from the same participants with prediabetes and control subjects with RAPA. Our findings suggest a minor impairment of the autophagic response in people
Acknowledgments
This research was supported in part by the University of New Mexico College of Education and the University of New Mexico Research Allocation Committee. We thank Trisha VanDusseldorp, Elizabeth Harding and Hung-Sheng Hsu for their assistance with conducting the exercise trials. We also thank Len Kravitz and Fabiano Amorim for their careful review of the manuscript.
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