The Impact of Physical Exercise on the Presence of Micronuclei in Buccal Mucosa Cells in Individuals with Different Glycemic States

Abstract

Diabetes Mellitus (DM) is a group of metabolic disorders characterized by elevated blood glucose levels, with a worldwide increasing prevalence attributed to socioeconomic, demographic, environmental, and genetic factors. Type 2 Diabetes Mellitus (T2DM) is closely linked to obesity, unhealthy diets, and physical inactivity, resulting in oxidative stress and DNA damage due to insulin resistance and mitochondrial dysfunction. Additionally, T2DM leads to hyposalivation, elevated salivary glucose, and periodontal disease. This study aimed to evaluate DNA damage in the oral mucosa of 78 individuals (ages 30-76) with T2DM, pre-diabetes, or healthy controls, who reported engaging in physical exercise or not. Micronuclei were assessed in 100 oral epithelial cells per individual. Statistical analysis included descriptive and normality tests, as well as Kruskal-Wallis. Our results showed an increased number of micronuclei in T2DM patients, regardless of physical exercise. This suggests that T2DM can induce DNA damage, an effect not prevented by self-reported physical exercise. These DNA damages are involved in the comorbidities associated with T2DM, leading to cellular dysfunction. Moreover, the micronuclei assay proved to be a reliable, effective, minimally invasive, and low-cost biomarker for the prevention, screening, and monitoring of T2DM.

Key words
Micronucleus; DNA damage; Exfoliative Cytology; Physical Activity; Glycemia

INTRODUCTION

Diabetes is one of the fastest-growing global health emergencies of the 21st century. In 2021, it was estimated that 537 million people had diabetes, number expected to grow to 643 million by 2030. Brazil presents the highest number of individuals with diabetes in Latin America, and the 6th largest in terms of diagnoses in the world (International Diabetes Federation 2021). Diabetes prevalence is driven by a complex interaction of socioeconomic, demographic, environmental and genetic factors (Bertolucci et al. 2020). Type 2 Diabetes Mellitus (T2DM) accounts for 90%–95% of all diabetes cases and is associated with an inadequate lifestyle and obesity, which induces insulin resistance along with partial deficiency on insulin secretion by pancreatic β-cells. (Rodacki et al. 2022, Sociedade Brasileira de Diabetes 2019, Cattin 2016).

The inadequate lifestyle characterized by lower physical activity and increased food consumption induces an obesity state, characterized by a low-grade inflammatory state. This inflammation induces insulin resistance and alterations on glucose metabolism, resulting in intermediate hyperglycemia, the pre-diabetic state. With the continuous lifestyle, pancreatic beta cells suffer from overload due to insulin resistance, resulting in beta cell apoptosis, hyperglycemia and T2DM installation (American Diabetes Association 2020, Galicia-Garcia et al. 2020).

In Brazil, less than 30% of people with diabetes maintain regular glycemic levels. Adherence to pharmacological treatment alone is insufficient; it requires consistent physical activity and adequate nutrition, which are often neglected (Maeyama et al. 2020, Mendes 2012, Panarotto et al. 2009). Besides that, physical exercise is fundamental in glucose control once stimulates glucose uptake in skeletal muscle using an insulin dependent/independent pathway. Regular exercise has been shown to improve insulin resistance and glucose levels (Hawley & Lessard 2008) by, at least in part, myokines secretion, an important crosstalk between muscle and other organs as endocrine pancreas (Chen et al. 2024).

Metabolic disorders in T2DM are associated with genomic instability, which could be analyzed by the frequencies of micronuclei and other biomarkers of DNA damage in cells. Micronucleus (MN) assays are validated indicators of genotoxicity, evaluating numerical and structural chromosomal alterations. The exfoliated buccal cell micronucleus assay (EMN-CBE) is frequently used because it is a non-invasive and effective method for measuring micronuclei frequency in epithelial tissue (Deo et al. 2021, Thomas et al. 2009, 2011). Oral mucosal cells are significant as they represent the first barrier in ingestion or inhalation routes and are capable of metabolizing reactive species (Toneline et al. 2014, Holland et al. 2008, Sommer et al. 2020).

Individuals with diabetes exhibit hyposalivation, high salivary glucose concentrations, and increased susceptibility to periodontal disease. Research applying the micronucleus test to the oral mucosa of diabetic patients indicates that Diabetes Mellitus results in high rates of micronucleation and nuclear budding, which may be related to elevated oxidative stress and, consequently, genomic damage (Uchôa & Magalhães 2019, Blasiak et al. 2004). Considering these factors, this study aimed to assess whether T2DM is able to induce DNA damage in oral mucosa cells in individuals with T2DM, pre-diabetics and healthy, submitted or not to a self-declared physical exercise. Moreover, highlighted the MN assay as a tool as a complementary strategy in the prevention, screening, monitoring, and progression of T2DM.

MATERIALS AND METHODS

The study was approved (CAAE: 59991422.7.0000.9727, opinion number 5.753.402) by the Human Experimentation Ethics Committee of Centro Universitário de Pato Branco - UNIDEP. Convenience sampling was conducted at three basic health units (PROFILURB 2, Porto Belo, AKLP) and at the Foz do Iguaçu Diabetics Association (ADIFI) in the city of Foz do Iguaçu, PR. Individuals who expressed interest in participating signed an Informed Consent Form and completed a questionnaire on biological information, habits, lifestyle, and clinical profile. The inclusion criteria for all sample groups (T2DM, pre-diabetics, and controls) were a medical diagnosis and age between 30 and 76 years. The control group had no underlying pathology.

Exclusion criteria included pregnant women and individuals who had undergone bariatric surgery. Participants were randomly selected, with inclusion based on profiles most similar in terms of anti-diabetic drug class (enhancers of insulin secretion and sensibility). Regarding physical activity, individuals were grouped according to self-declaration into: regular physical activity or no physical activity. All volunteers, from both the control and sample groups, were identified anonymously by a numerical code.

To collect of oral mucosa samples, at least 24 hours after the last physical exercise training, a preliminary rinse with water was performed to ensure asepsis of the oral region and prevent bacterial contamination or other interferences with the readings. Cells from the oral mucosa (cheek) were then collected using a small-headed cytology brush.

The material obtained from the oral mucosa using the cytology brush was transferred to a clean slide immediately after collection. After 24 hours, the slides were fixed with absolute ethanol for 10 minutes, stained with 5% Giemsa for 15 minutes, and then washed in running water. The slides were analyzed under an optical microscope. A total of 100 cells from the oral mucosa epithelium of each individual were analyzed to determine the frequency of micronuclei, following the methods of Thomas et al. (2009) and the criteria of Bolognesi et al. (2013).

Criteria for defining a micronucleus (MN) included: intensity of chromatin and staining pattern similar to the main nucleus; absence of refringency; clearly identifiable edges indicating a nuclear membrane; circular or oval shape, separated from the main nucleus without overlapping the nuclear border; presence in the same optical plane as the main nucleus; within the same cytoplasm as the main nucleus; and diameter between 1/16 and, at most, 1/3 of the main nucleus (or between 1/256 and 1/9 of the area of one of the main nuclei).

Statistical analyses were performed using IBM SPSS Statistics software version 22.0. For data that did not follow a normal distribution, the Kruskal-Wallis test was used to compare groups, with a significance level set at p < 0.05.

RESULTS

Characterization and Biochemical Parameters of the study group

The study comprised 78 individuals, including 51 women (65.3%) and 27 men (34.6%) (χ²(1) = 7.384; p = 0.007). Of these, 28 (35.90%) were non-diabetic (control group), 15 (19.23%) were pre-diabetic, and 35 (44.87%) were diabetic (χ²(2) = 7.923; p = 0.01902). Physical activity was reported by 43 participants (55.1%), while 35 (44.9%) did not engage in physical activity (χ²(1) = 0.82051; p = 0.36516) (Table I).

Table I
Percentage Distribution of Individuals by Group and Demographic and Type 2 Diabetes Risk Characteristics.

	Total			Control		pre-DM		T2DM
	N = 78	Yes	No	Yes	No	Yes	No	Yes	No
Sex	Female (51)	27 (62.79%)	24 (68.57%)	11 (73.33%)	10 (76.92%)	5 (71.43%)	8 (100%)	11 (52.38%)	6 (42.86%)
	Male (27)	16 (37.21%)	11 (31.43%)	4 (26.67%)	3 (23.07%)	2 (28.57%)	0 (0.00%)	10 (47.62%)	8 (57.14%)

• Legend: Groups: Control : Individuals without a diagnosis of diabetes or pre-diabetes. T2DM : Individuals diagnosed with type 2 diabetes. Pre-DM : Individuals diagnosed with pre-diabetes. N (Number of Individuals): Total number of individuals in each group. Male : Percentage of men in each group. Female : Percentage of women in each group. Physical activity group: No: individuals who do not practice physical activity. Yes: individuals who practice physical activity.

Among the 35 diabetic individuals, 13 engaged in more than 30 minutes of physical activity per day or more than 4 hours per week, 8 engaged in less than 30 minutes per day or less than 4 hours per week, and 14 did not participate in any physical activity. Of the 15 pre-diabetic participants, 2 engaged in more than 30 minutes per day or more than 4 hours per week, 5 engaged in less than 30 minutes per day or less than 4 hours per week, and 8 did not participate in any physical activity. Among the control group (non-diabetics), 12 engaged in more than 30 minutes per day or more than 4 hours per week, 3 engaged in less than 30 minutes per day or less than 4 hours per week, and 13 did not participate in any physical activity. The mean fasting blood glucose levels of participants in each group are presented in Table II.

Table II
Mean fasting blood glucose levels (mg/dL) of participants according to glycemic condition and physical activity status.

Group	Mean Fasting Blood Glucose (mg/dL)
Non-diabetic without physical activity	91.00
Non-diabetic with physical activity	94.93
Pre-diabetic without physical activity	104.25
Pre-diabetic with physical activity	105.57
Diabetic without physical activity	132.93
Diabetic with physical activity	139.26

A significant difference was observed among the groups in terms of mucosal micronuclei (MNM) counts (KW = 25.21, p = 0.0001). Individuals with Type 2 Diabetes Mellitus (T2DM) exhibited a higher MNM count in oral mucosa cells compared to the other groups (Figure 1). Moreover, this increased MNM count was also observed in T2DM individuals who reported engaging in physical exercise (Figure 2), suggesting that self-reported exercise did not mitigate DNA damage in this context. No differences were observed between pre-diabetic and non-diabetic individuals, regardless of whether they reported engaging in physical activity or not.

Figure 1
Giemsa-stained exfoliated cell from the oral mucosa of a diabetic individual, exhibiting: a) a cell with a nucleus (arrowhead); b) a cell with a nucleus (arrowhead) and two micronuclei (indicated by arrows) and a nucleus (N). The cellular and micronuclei pattern exhibits similarities across groups, with differences observed solely in the frequency of micronucleated cells. Scale bar: 10 μm.

Figure 2
Graphical presentation of the mean MNM and standard error for the participant groups (T2DM, pre-diabetic, and control), stratified by the presence (yes) or absence (no) of physical activity. The categories are described as follows: MNM: Mucosal Micronuclei. T2DM-no: Participants with type 2 diabetes who do not engage in physical activity. T2DM-yes: Participants with type 2 diabetes who engage in physical activity. Pre-DM-no: Pre-diabetic participants who do not engage in physical activity. Pre-DM-yes: Pre-diabetic participants who engage in physical activity. Control-no: Control participants who do not engage in physical activity. Control-yes: Control participants who engage in physical activity. Significance level: p < 0.05. *A significant difference was found between diabetic individuals and the other groups. However, no significant difference was observed between diabetic individuals who reported engaging in physical activity and those who did not. The measurements represent the mean and median of the micronucleus (MN) presence percentage in individuals from each group.

DISCUSSION

Diabetes Mellitus (DM) is a complex group of metabolic disorders characterized by persistently elevated blood glucose levels, resulting from a multifaceted interplay of genetic, environmental, and lifestyle factors. Chronic hyperglycemia associated with diabetes can cause long-term damage, leading to degeneration and potentially failure of organs such as the heart, kidneys, eyes, nerves, and blood vessels (American Diabetes Association 2021). This disease was the direct cause of 1.5 million deaths in 2019, with 48% occurring in individuals under the age of 70 (World Health Organization 2021).

In this study, the analysis of micronucleus levels in buccal mucosa cells (MNM) revealed significant differences between the groups (T2DM, Pre-DM, control). This suggests that glycemic status, is associated with substantial variations in DNA damage, as measured by micronuclei. Other studies have also demonstrated that diabetes increases oral MNM frequency when compared to healthy individuals, effect also observed in type 1 and type 2 diabetes (Grindel et al. 2017, Quintero Odeja et al. 2018, Parsadanyan et al. 2024). In our study, besides we demonstrate that T2DM increases MNM frequency, we have also explored this field in pre-diabetic condition and self-reported exercise.

Evaluation of the groups showed that the T2DM group had the highest MNM averages, indicating a greater degree of DNA damage compared to the Pre-DM and control groups. This difference may reflect the relationship between glycemic control and DNA integrity. Metabolic dysregulation causes an increase in blood glucose levels (hyperglycemia), which, along with other factors, promotes the formation of advanced glycation end products (AGEs). These AGEs bind to specific receptors (RAGE), activating NADPH oxidase, which results in a high production of reactive oxygen species (ROS) (Merecz et al. 2015, Deo et al. 2020, Franzke et al. 2020). Furthermore, analysis of MNN frequency in pre-DM individuals revealed no significant differences compared to the control group, suggesting that DNA damage had not yet occurred in this population.

Given that regulating blood glucose is essential due to the cascade of damage it can cause, studies show that regular exercise, by inducing skeletal muscle contraction, helps extract glucose from the blood and use it as an energy source. This positively impacts the regulation of blood glucose levels, a crucial factor in managing T2DM. Physical exercise improves insulin sensitivity and helps control blood glucose levels, reducing the risk of progression to T2DM and its associated complications (Sylow et al. 2017, Evans et al. 2019, Ghafouri-Fard et al. 2022, Maulida et al. 2022, Michielsen et al. 2022, Sousa et al. 2014). However, we did not observe any differences in MNM frequency in the self-reported exercise group. This data points to the importance of physical exercises intensity, one variable that we did not control in self-reported exercise.

The frequency of micronuclei (MN) in humans provides valuable insights into genomic integrity and its relationship with metabolic and health conditions. Micronuclei form over time due to the cumulative effects of chronic or repeated exposures and are characterized by persistent genetic alterations, making them potentially predictive. Additionally, MNM have been shown to be more sensitive (Kirsch-Volders et al. 2020, Fenech et al. 2020).

When analyzing MNM frequency in diabetic and non-diabetic individuals, primary prevention involves identifying individuals who are still in a normoglycemic state but are at risk of progressing to pre-diabetes, and promoting lifestyle changes (Lindström 2003, Song 2022). The oral mucosal micronucleus technique can be utilized as a preventive measure for type 2 diabetes mellitus. Therefore, the micronucleus assay is a reliable, effective, minimally invasive, and low-cost biomarker and can be considered a valuable tool in the prevention, screening, monitoring, and progression of type 2 diabetes mellitus.

In the long term, individuals with greater glucose dysregulation are more likely to have accumulated DNA damage over time (Donath & Shoelson 2011, Evans et al. 2019). Studies indicate that even a simple walk can help flatten the glucose curve. The skeletal muscles contract and absorb glucose without the need for insulin, reducing blood glucose, easing the burden on the pancreas to produce insulin to manage the remaining glucose (Gill et al. 2002).

It is important to note that although the control group showed lower levels of MNM, T2DM patients who engaged in physical activity still exhibited significantly higher levels of MNM (0.307 ± 0.17) compared to active controls (p < 0.0002). This indicates the presence of DNA damage, even among those who are self-reported physically active. Studies suggest that many people experience sudden changes in blood glucose throughout their lives without being aware of it, which can lead to long-term damage and increase the risk of progression to pre-diabetes, complicating its classification. Avoiding glucose spikes is both feasible and crucial, as the variability caused by these spikes presents a major problem (Ohara et al. 2016, Acciaroli et al. 2018).

Therefore, besides self-reported physical exercise did not modulates MNM frequency, pre-diabetic condition is not able to induce DNA damage yet. In this sense, is important to detect these individuals, avoiding T2DM development and glucose associated DNA damage.

CONCLUSIONS

The results of this study show that individuals with T2DM have high levels of micronuclei in oral mucosa cells (MNM) compared to controls. Although self-reported physical exercise is associated with a reduction in DNA damage, the condition of T2DM continues to significantly impact MNM levels, even among those who exercise regularly. This finding reinforces the need for stricter glycemic control and highlights the importance of integrated management strategies. Moreover, our data shows that pre-diabetic condition is not able to induce oral mucosa cell’s DNA damage, highlighting the importance of detecting pre-diabetes condition in order to avoid DNA damage and T2DM development.

In addition to self-reported physical activity, strict glycemic control is essential to minimizing long-term damage, suggesting the need for integrated strategies that include exercise and continuous monitoring of glycemic levels for effective T2DM management. In this context, the micronucleus assay is a reliable, effective, minimally invasive, and low-cost biomarker that can be considered a valuable tool in the prevention, screening, monitoring, and management of type 2 Diabetes Mellitus.

Acknowledgements

This work was funded by UNILA and PPG-Biocience UNILA. TA receives support from "Programa de Bolsa Institucional da UNILA" (PROBIU, Brazil).

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Publication Dates

• Publication in this collection
  19 Sept 2025
• Date of issue
  2025

History

• Received
  13 Sept 2024
• Accepted
  4 Apr 2025