FEASibility Testing a randomized controlled trial of an exercise program to improve cognition for T2DM patients (the FEAST trial): A study protocol

Abstract

While cognitive dysfunction is an important concern in persons with type 2 diabetes mellitus (T2DM), it has received little attention in the T2DM literature. Although it often remains unrecognized, cognitive dysfunction associated with T2DM can lead to severe consequences. Prior research studies have consistently shown that aerobic exercise enhances cognitive function among healthy subjects. However, very few studies have examined the effects of aerobic exercise on cognitive function in persons with T2DM. In addition, one important single nucleotide polymorphism that influences cognition in humans is the brain derived neurotrophic factor (BDNF) Val66Met variant. Despite strong evidence suggesting aerobic exercise has a beneficial effect on cognitive function, there is significant variability in individual response to exercise programs on cognitive outcomes among Val/Val vs Met carriers. However, the evidence on how the BDNF Val66Met variant influences cognitive outcomes following an aerobic exercise intervention among individuals with T2DM is currently lacking. Therefore, the purpose of this randomized controlled trial is to pilot-test a 3-month supervised exercise program to improve plasma BDNF levels and cognition, overall and according to genotypes of the BDNF Val66Met variant. A total of 81 patients with T2DM will be randomly assigned to either aerobic exercise group (n=54) or attention control group (n=27) for 3 months. Outcomes of interest include post-intervention changes in plasma BDNF levels, fasting blood glucose, hemoglobin A1c, body mass index, executive function, memory, and processing speed. This study will provide further evidence on use of exercise as a non-pharmaceutical, low-cost intervention to improve cognition in this population.

Despite declines in mortality rates from type 2 diabetes mellitus (T2DM) during the period from 2000 to 2014 (Gregg et al., 2014), complications from T2DM are now substantially increasing within the United States (Geiss et al., 2019; Gregg et al., 2019). Long-term exposure to hyperglycemia impairs brain function, leading to cognitive dysfunction (Liu, Lee, et al., 2020). Cognitive dysfunction is often unrecognized in individuals with T2DM (Liu, Lee, et al., 2020), and as a consequence of cognitive dysfunction, T2DM self-management may be interrupted/impaired (H. E. Cuevas et al., 2017). Furthermore, decreased adherence to proper management of T2DM (H. Cuevas & Stuifbergen, 2017; Feil et al., 2012; Primozic et al., 2012), reduced quality of life (Punthakee et al., 2012), and recurrent hypoglycemia (Mattishent & Loke, 2016; Punthakee et al., 2012) have also been reported. Therefore, there is an urgent need to find effective therapeutic strategies to improve cognitive function among individuals with T2DM.

Aerobic exercise, such as walking, involves continuous and rhythmic movements of large muscle groups for at least 10 minutes at a time (Sigal et al., 2018). For persons with T2DM, studies indicate aerobic exercise improves glycemic control, increases cardiorespiratory fitness, decreases insulin resistance, promotes weight loss, and improves overall health outcomes (Sigal et al., 2018). In addition, the positive effects of aerobic exercise on cognition have received abundant support (Mandolesi et al., 2018). The hippocampus has been recognized as a brain region sensitive to aerobic exercise (Thomas et al., 2012), which enhanced memory performance and ability to learn in several studies (Erickson et al., 2011; Gomez-Pinilla & Hillman, 2013; Lista & Sorrentino, 2010). However, few studies have examined the effects of aerobic exercise on cognitive function in persons with T2DM. Baker et al. (2010) found that aerobic exercise improved executive function in a small randomized controlled trial. However, evidence on the effects of aerobic exercise on other affected cognitive domains, such as processing speed and memory, is currently lacking. In a recent systematic review, the authors found that regular physical activity may improve cognition in persons with T2DM. However, the conclusion of this review was limited due to a lack of robust evidence from high-quality clinical trials, small sample sizes, and missing control groups (Podolski et al., 2017). Hence, high-quality evidence gained through clinical trials is warranted to systematically examine the effects of aerobic exercise on cognition in this growing population.

Increased levels of brain-derived neurotrophic factor (BDNF) immediately following exercise has been one the most well-documented mechanisms that underlies the exercise-induced cognitive improvements (Hamilton & Rhodes, 2015). BDNF is a moderately sized protein from the neurotrophin family responsible for promoting survival and growth of nerve cells during the cell developmental period, and it is also responsible for adult nerve cell maintenance (Kowianski et al., 2018). BDNF is highly prevalent in the central nervous system, and more specifically in the hippocampus and hypothalamus in terms of memory performance (Bathina & Das, 2015). Reduced expression of BDNF has recently been linked to neurodegenerative disorders. For example, the Framingham Heart Study examined the prospective association of serum BDNF levels with 10-year risk for incident dementia and Alzheimer’s disease. After adjusting for age and gender, each standard-deviation increase in BDNF was associated with a 33% lower risk for dementia and Alzheimer’s disease (Weinstein et al., 2014). Similarly, decreased serum BDNF levels have been associated with both memory loss (Zhen et al., 2018; Zhen et al., 2013) and cognitive dysfunction (Murillo Ortiz et al., 2016) among individuals with T2DM. Collectively, these studies suggest that decreased BDNF levels may play an important role in the development of cognitive dysfunction in individuals with T2DM. Therefore, strategies increasing BDNF levels may be especially important for improving cognitive function among persons with T2DM.

Interventions attempting to increase BDNF levels have been discouraging to date. BDNF is a moderately sized protein, and therefore only a small amount of the protein can cross the blood-brain barrier (BBB), resulting in a much lower-than-expected effect on central nervous system with several side effects, including nausea, a decreased appetite, depression, and hallucination (Eyileten et al., 2017; Tsai, 2012). Compared to pharmacologic administration of BDNF, aerobic exercise is a safe, non-pharmacologic, inexpensive, and easily accessible path to increasing endogenous BDNF levels. The majority of previous studies have focused on the effects of acute aerobic exercise on increasing BDNF levels, which has been well accepted (Dinoff et al., 2017). However, increased BDNF levels are transient and return to baseline values within 30 minutes post-exercise in serum (Walsh et al., 2016; Yarrow et al., 2010) and within 60 minutes in plasma (Yarrow et al., 2010). The effects of regular aerobic exercise on resting peripheral BDNF levels are unclear (Dinoff et al., 2016), and have not been well studied among individuals with T2DM. Of note, in persons with T2DM, integrity of the BBB is impaired, resulting in increased barrier permeability (Starr et al., 2003). Although a growing body of evidence supports the role of regular exercise in protecting BBB integrity (Malkiewicz et al., 2019), very little is known about how resting peripheral BDNF levels may change in response to regular aerobic exercise training after adjusting for BBB permeability among individuals with T2DM. Baker et al. (2010) reported that plasma BDNF levels increased in the stretching control group but decreased in the aerobic group following a six-month exercise program among older adults with T2DM. However, the difference did not reach statistical significance. Nevertheless, this study did not adjust for BBB permeability, and had a small sample size. Therefore, it may not have been adequately powered to detect significance. More clinical trials are needed to examine the effects of regular aerobic exercise on resting peripheral BDNF levels adjusting for BBB permeability in a larger sample of T2DM population.

The BDNF gene is located at locus 11p14.1, which controls expression of BDNF protein (Yates et al., 2016). The G196A (dbSNP: rs6265) is a frequent single nucleotide polymorphism (SNP) at this locus that results in an amino acid substitution at codon 66 in pro-BDNF (i.e., immature BDNF) (Val66Met), and this variant has been reported to affect cognitive function in humans (Chen et al., 2004; Egan et al., 2003). There are two different alleles: A (derived) or G (ancestral). Three different genotypes are therefore available for this particular SNP: AA, AG, and GG, corresponding to Met/Met, Val/Met or Val/Val, respectively. The Met allele has been shown to interfere with the activity-dependent secretion of mature BDNF by altering intracellular trafficking, processing, and packaging of pro-BDNF (Chen et al., 2004; Egan et al., 2003). Due to BDNF primarily being secreted in an activity-dependent manner, rs6265 may significantly decrease the availability of BDNF through reduced activity-dependent secretion and affect cognitive function in Met carriers (Brooks et al., 2014; Lim et al., 2014).

Despite the bulk of strong evidence suggesting that aerobic exercise improves cognitive function (Mandolesi et al., 2018), there is significant variability in individual response to exercise programs on cognitive outcomes among Val/Val vs Met carriers (Canivet et al., 2015; Canivet et al., 2017; Erickson et al., 2013; Hopkins et al., 2012; Kim et al., 2011; Nascimento et al., 2015; Thibeau et al., 2016; Watts et al., 2018). For example, while Val/Val carriers have benefited exclusively from cognition-enhancing effects of exercise in some studies (Canivet et al., 2015; Thibeau et al., 2016; Watts et al., 2018), other studies found that Met carriers may counterbalance lower cognitive performance associated with carrying a BDNF Met allele by engaging in higher levels of exercise (Erickson et al., 2013; Kim et al., 2011).

A recent systematic review concluded that the inconsistent findings noted above could be partly attributed to heterogeneous samples, lack of standardized exercise prescriptions, different cognitive domains examined, and more importantly, variables that were not well controlled in these studies (Liu, Li, et al., 2020). For example, the use of physical activity questionnaires in some studies (Canivet et al., 2015; Erickson et al., 2013; Kim et al., 2011; Thibeau et al., 2016; Watts et al., 2018) may have not reflected actual levels of physical activity performed. Given these limitations, further research is needed to examine the associations among aerobic exercise, cognition, and the SNP rs6265, preferably through the use of objective measurement in a rigorously designed and delivered clinical trial.

In one cross-sectional study among a representative sample of adults aged 50 years or older with diabetes, positive associations could be drawn between physical activity and all cognitive domains, including total cognition, mental status, and word recall. Furthermore, the positive associations were stronger among individuals carrying the Met alleles (Liu, Canon, et al., 2021). The study provided preliminary findings on how BDNF Val66Met variant may modulate the exercise-induced cognitive benefits in mid-age/older adults with diabetes. However, evidence is currently lacking on how the BDNF Val66Met variant influences cognitive outcomes following an aerobic exercise intervention in individuals with T2DM (Liu, Li, et al., 2020). In the absence of such knowledge, the development of an effective personalized exercise training program based on different BDNF genotypes in this high-risk patient population will likely remain elusive. The growing prevalence of T2DM and the aging of the population will likely result in an increased burden of cognitive dysfunction in persons with T2DM. It is therefore important to understand the interaction between the BDNF Val66Met polymorphism and exercise on plasma BDNF levels and cognitive outcomes in this population.

Methods

Conceptual Framework

Figure 1 demonstrates the conceptual framework of the study, which portrays the underlying biological mechanisms of BDNF expression, BBB permeability, variant Val66Met, resting peripheral BDNF levels, and cognitive performance after aerobic exercise. The framework presents the proposed pathway in this study and combines multiple pieces of evidence that have been well established in the literature along with the proposed pathway.

Figure 1. Conceptual Framework.

Note. BBB=blood-brain barrier; T2DM=type 2 diabetes mellitus; BDNF=brain derived neurotrophic factor.

Study Design

A randomized controlled trial will be conducted to test the feasibility of a supervised exercise program to improve plasma BDNF levels and cognition in persons with T2DM. Eighty-one participants will be randomly assigned to either aerobic exercise group (n=54) or attention control group (n=27) for 3 months. The anticipated attrition imbalance between the groups is reflected in the ratio between the groups (Baker et al., 2010).

Specific Aims and Hypotheses

The aims of this clinical trial are:

Aim 1: To evaluate the feasibility of a supervised exercise program.

Hypothesis: The supervised exercise program will be feasible (participation rate > 50%, drop-out rate at endpoint ⩽ 33%, exercise adherence ⩾ 80%) for adults with T2DM.

Aim 2: To evaluate preliminary efficacy of the supervised exercise program on cognitive function and plasma BDNF levels after controlling BBB permeability.

Hypothesis 1: Participants in the aerobic exercise groups will have better performance in working and episode memory, processing speed, and executive function than participants in the attention control group.

Hypothesis 2: After controlling for BBB permeability, participants in the aerobic exercise groups will have higher plasma BDNF levels than participants in the attention control group.

An exploratory aim is:

To explore the influence of the BDNF Val66Met polymorphism on cognitive outcomes and plasma BDNF levels in response to aerobic exercise intervention.

Study Setting

The Eleanor Mann School of Nursing will serve as the coordinating center for this study. Eligible participants will be recruited from Endocrinology Clinic and Senior Health Clinic of the Washington Regional Medical Center. Data will be collected in the University of Arkansas Exercise Science Research Center.

Sample

Sample Size Justification and Power

The study was powered on cognition, which is the primary outcome for this study; and G*Power 3.1.9.1 was utilized to calculate the sample size. Based on a similar intervention study, Baker et al. (2010) reported that associated effect sizes (Cohen’s f) ranged from .36 to .39 which indicated large effect sizes according to Cohen (1988) (i.e., the values of 0.10, 0.25, and 0.40 represent small, medium, and large effect sizes, respectively). To be conservative, we adopted an effect size of f = 0.36. By achieving a desired power of 80% and maintaining type I error rate at .05, we estimated a minimum sample size of 63 participants based on analysis of covariance (ANCOVA). To account for an attrition rate (21.4%) for supervised exercise interventions (Yu, 2013), a total of 81 participants will be recruited.

Inclusion and Exclusion Criteria

Adults who have low exercise levels measured by the International Physical Activity Questionnaire (Hagstromer, Oja, & Sjostrom, 2006) are eligible for this study. Participants will also need to have a medical diagnosis of T2DM, be able to speak English, and give informed consent. Participants with uncontrolled hypertension, defined as a resting blood pressure equal to or higher than 160/90mmHg, or those who have symptoms of coronary heart disease such as chest discomfort and dizziness, or have any other physical conditions that may negatively affect the ability to exercise will be excluded from the study.

Measures

After obtaining informed consent, baseline data collection will begin, and the three-month study visit will also be scheduled. The summary of variables, measures, and time of evaluation is presented in Table 1.

Table 1.

Study Measures

Study measures	Time of evaluation
Demographic measures: Age, gender, education and income level, time with T2DM, marital status, race/ethnicity, and medical history	Baseline
Biological status: Plasma BDNF levels, fasting blood glucose, HbA1c, S-100B, BMI	Baseline, 3rd month
Genotyping	Baseline
Exercise adherence (see exercise adherence in the main text)	Every exercise session
Cognitive function: Executive function, episodic memory, working memory, and processing speed	Baseline, 3rd month

Note. BDNF = Brain derived neurotrophic factor; T2DM = Type 2 diabetes mellitus; BMI = Body mass index; HbA1c = Hemoglobin A1c. S-100B is considered to be the best indicator of permeability of the blood-brain barrier.

Demographic Measures

Demographic and clinical information will be collected through standardized a self-report questionnaire designed for this study at baseline. The questionnaire will collect information on age, sex, education, and income level, time with T2DM, marital status, race/ethnicity, and medical history.

Plasma BDNF ELISA Determination

A trained research assistant (RA) will collect 3 ml of fasting blood and then distribute aliquots of approximately 200 μl of plasma into a cryotube. Any remaining red blood cells will be discarded. Aliquots are stored at −80°C until they are analyzed according to manufacturer’s instructions using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Aviva Systems Biology).

Fasting Blood Glucose

A trained RA will collect about 5 mL of venous blood after at least an 8-hour overnight fast for all participants. Then the RA will take a 20 µL amount of blood for the YSI 2900 Analyzer (Yellow Springs Instruments, Yellow Springs, Ohio) before centrifuging. The blood sample will be analyzed according to the YSI 2900 Analyzer manufacture instructions for measuring blood glucose.

Hemoglobin A1c (HbA1c)

A trained RA will collect 3 ml of fasting blood and then distribute aliquots of approximately 200 μl of serum into a cryotube. Any remaining cellular elements will be discarded. Aliquots are stored at −80°C until they are analyzed according to manufacturer’s instructions using a commercially available ELISA kit (Quantikine).

Body Mass Index (BMI)

Height will be measured without shoes to the nearest 0.1 cm using a stadiometer. Weight will be measured to the nearest 0.1 kg using a health meter, while participants are wearing lightweight clothing. BMI will be calculated by dividing body weight in kilograms by the square of body height in meters, kg/m².

BBB Permeability

The most accurate indicator of the permeability of the BBB is considered to be S-100B (Koh & Lee, 2014). A trained RA will collect 3 ml of fasting blood and then distribute aliquots of approximately 200 μl of serum into a cryotube. Any remaining cellular elements will be discarded. Aliquots are stored at −80°C until they are analyzed according to manufacturer’s instructions using a commercially available ELISA kit (Quantikine).

Genotyping by Real-Time Polymerase Chain Reaction (PCR)

Consistent with Nascimento et al. (2015), the SNP rs6265 analysis will be performed by utilizing genotyping by real-time PCR. A trained RA will collect 5 ml of fasting blood and extract the buffy coat for rs6265 genotyping after the whole blood has been centrifuged. Genomic DNA from the buffy coat will be isolated and analyzed by use of commercially made kits for DNA isolation per manufacture instructions. The SNP rs6265 will be amplified by real-time PCR and analyzed for Met allele carriers as previously described (Nascimento et al., 2015).

Cognitive Function

A series of tests evaluating cognitive function will be administered to all participants to obtain baseline levels and then performed again 3 months post-intervention. The NIH Toolbox ^® Cognition Battery (Weintraub et al., 2013) will be administered to all participants with an iPad mini 4. The Cognition Battery includes tests of episodic memory, executive function, processing speed, and working memory.

Executive function will be measured by the Dimensional Change Card Sort Test. This test involves a matching game with color and shape. Participants will first match a visual stimulus with a choice stimulus that is of the same color or shape. Those who succeed in completing the task will be required to play both games together, in which there are random shifts to shape and color is relevant within the majority of the trials (Weintraub et al., 2013). There are 40 trials in the test which require about 4 minutes to complete. Test-retest reliability is reported as 0.88. Discriminant and convergent validity are reported as 0.14 and −0.51, respectively (Weintraub et al., 2013).

Episodic memory will be measured by the Picture Sequence Memory Test. This test consists of trials with pictured objects and activities that require participants to move one picture at a time in the same order as directed by audio files. Over 3 learning trials, the test is cored based on the cumulative number of adjacent pairs of pictures remembered correctly. The test takes around 7 minutes to finish. Test-retest reliability of the test is reported as 0.77. Discriminant and convergent validity are reported as −0.08. and 0.69, respectively (Weintraub et al., 2013).

Working memory will be measured by the List Sorting Working Memory Test. Participants will be given a series of visual and oral stimuli by a computer. These stimuli are presented one at a time in a seamless fashion. Participants are asked to memorize these stimuli and present them to the examiner in order of size from smallest to largest. The final component of this test includes both a 1-list and 2-list component. In the “1-list” component, only one category of stimulus is presented (e.g., “animals” or “food”). In the ‘2-list” component, stimuli are presented in two categories (e.g., “animals” and “food”). Participants are instructed to first sort the stimuli by category and then to sequence the stimuli in size order within each category. The test takes around 7 minutes to be completed and test scores are reflected as the total correct items across all trials. Test-retest reliability is reported as 0.77. Discriminant and convergent validity are reported as 0.30 and 0.58, respectively (Weintraub et al., 2013).

Processing speed will be measured by the Pattern Comparison Processing Speed Test. Participants will be asked to identify whether two pictures presented to them are the same or not the same. If the pictures appear the same, they are to touch the YES button. Otherwise, they are to touch the NO button. The test takes around 3 minutes to compete. Test-retest reliability is reported as 0.72. Discriminant and convergent validity are reported as 0.12 and 0.49, respectively (Weintraub et al., 2013).

Procedures

Recruitment

Recruitment will take place primarily through physician referrals at routine clinic visits. In addition, a one-page flyer will be developed and posted outside of clinics, which will invite potential participants to call a research-designated phone line. We will approach interested potential participants and explain the study in detail, answer questions related to the study, screen for eligibility, and schedule an initial study visit if indicated. During participants’ first study visit, written informed consent and baseline measures will be obtained. After the baseline measures, they will be compensated each time ($15) they attend each scheduled exercise session. The flow diagram of the progress through the phases of this trial is shown in Figure 2.

Figure 2.

Flow Diagram of the Progress through the Phases of the FEAST Trial

Randomization and Blinding

Following informed consent, participants will be randomized to either the aerobic exercise group or the attention control group. Randomization is completed utilizing a randomization table generated by the SAS 9.4 and will be determined by the biostatistician. Fifty-four (n=54) participants will be assigned to the aerobic exercise group, and the remaining 28 participants will be assigned to the attention control group. Research team members and outcome assessors will be blinded to the group assignment. Finally, dummy codes will be used in the dataset so that it is not possible for data analysts to determine the randomization scheme.

Group Conditions

The intervention consists of 8 online T2DM self-management training modules and supervised exercise training sessions. The supervised exercise program consists of 36 sessions offered 3 times a week for 3 months for both groups. These sessions will be delivered at the Donna Axum Fitness Center of University of Arkansas where the study is being conducted over a 14-week period to allow make-ups for vacations or illness. Trained students will deliver the exercise sessions and one student will supervise up to three participants. Five-minute warm-ups and 5-minute cool-downs will precede and follow all exercise sessions. Weekly phone calls will be made to encourage all participants to continue participation in the exercise program. At week 15, measures on cognitive function, plasma BDNF levels, BMI, HbA1c, S-100B, and fasting blood glucose will be taken. Group assignment, schedules, and procedures are outlined in Table 2.

Table 2.

Group Assignment, Schedules, and Procedures

Group	1st – 2nd week	3rd – 14th week	15th week
Aerobic exercise	• Patient education • Online T2DM self-management training modules • Individualized instructions on use of a finger pulse oximeter	• Weekly phone calls •Structured, supervised treadmill walking	3rd month measures
Attention control	• Patient education • Online T2DM self-management training modules • Individualized instructions on use of a finger pulse oximeter • Demonstrations on stretching movements	• Weekly phone calls • Structured, supervised stretching exercise	3rd month measures

Note. T2DM = Type 2 diabetes mellitus.

Students Training

Six RAs are required to undergo standardized training through the research team to ensure the safety of participants during exercise, data quality, and intervention fidelity prior to the beginning of the study. Training of these students will include the following topics: rationale and goals of the study, informed consent process, human subject protection policies, ethics in research, establishing rapport with participants, using finger pulse oximeters to monitor heart rate, demonstrating stretching for participants, monitoring participants’ signs and symptoms of dehydration and hypoglycemia during exercise, and completing all session case reports. One of the co-investigators (Dr. Gray) has a PhD degree in exercise science and therefore has expertise in exercise prescription. She led the students training to monitor the exercise program. Training took three months and used a variety of methods including lecture-based classes, demonstrations, discussions, practice rounds, role plays, and test runs with the research team members.

Online T2DM Self-Management Training Modules.

Eight online modules have been developed by the research team. The topics of these modules were recommended by the 2017 National Standards for Diabetes Self-Management Education and Support (Beck et al., 2020). Topics to be covered and a description of these topics are presented in Table 3. Typically, these modules are approximately 5-10 minutes in length and contain animated videos that make these modules easy to understand. Language and concepts are presented at an 8^th grade level. In addition, all participants will be given printed educational materials on these topics.

Table 3.

T2DM Module Topics and Descriptions

Module topic	Description
T2DM condition process and treatment options	An overview of T2DM, including prevention, causes, symptoms, diagnosis, and treatment options, will be discussed in this module using simple terms and definitions of medical terminology.
Healthy eating	This module will focus on how different foods affect blood glucose levels and teach participants how to calculate the amount of carbohydrates they need by first determining what percentage of diet should be made up of carbohydrates. This module will also give examples of the best T2DM foods and foods/beverages to avoid by food groups (i.e., proteins, grains, fruits, vegetables, fat, and dairy).
Being physically active	This module will focus on the benefits of being physically active for people with T2DM. Tips for an active lifestyle will be covered.
Taking prescribed medications	Different categories of oral medications that can help treat T2DM and side effects of these medications will be covered in this module. Treatment with insulin, including different types of insulin (i.e., rapid-acting and long-acting insulin), when to tweak insulin routine, and signs of hypoglycemia will also be reviewed.
Monitoring your health data	The importance of monitoring blood glucose, when and how to check blood glucose will be reviewed.
Identifying, preventing, and treating acute and chronic complications	Common complications associated with T2DM, including cardiovascular disease, neuropathy, nephropathy, retinopathy, skin problems, foot damage, cognitive problems, and lung damage will be covered using simple terms and definitions of medical terminology. Possible mechanisms underlying why these organs get damaged will be discussed. The module will also focus on acute complications of T2DM, such as hypoglycemia and common triggers of hypoglycemia, and ways to identify, prevent, and treatment of these complications.
Healthy coping with psychosocial issues	Common psychological issues, such as stress, depression and other concerns will be discussed in this module, with an emphasis on how these issues may affect T2DM management and how to cope with these issues effectively.
Problem solving	Concepts of problem solving, and importance of problem solving in T2DM management, and steps and tips for problem solving will be covered in this module.

Note. T2DM = Type 2 diabetes mellitus.

Aerobic Exercise Prescription.

Aerobic exercise, including activity minutes and step count, will be measured with a treadmill. To ensure adequate exercise levels, we will monitor participants’ heart rate, which is expected to fall within the target zone during exercise sessions. For individuals with T2DM, the target training zone is between 40% to 59% of heart rate reserve, which indicates moderate-intensity exercise (Mendes et al., 2013). Heart rate reserve is the difference between a person’s maximum and resting heart rate (Cheng et al., 2002). The maximum heart rate is obtained by subtracting the person’s age from 220 (Centers for Disease Control and Prevemtion, 2020). Each participant will be provided with an individualized target heart rate zone based on his/her age and resting heart rate. For example, using the heart rate reserve method (Cheng et al., 2002), if a participant aged 50 (maximum heart rate=170 beats/min) and has a resting heart rate of 70 beats/min, the prescription will be calculated as (170-70)*40% (or 59%)+70 or 110 to129 beats/min at 40% to 59% intensity using this formula. A finger pulse oximeter will be used to determine heart rate during exercise.

Following baseline measures, participants will receive instructions on how to use a finger pulse oximeter by a student. For participants who are not physically fit or are just beginning a regular program of exercise, they will be advised to start walking on a treadmill at a comfortable pace for 5 to 10 minutes at one time (Sigal et al., 2018). Exercise duration and intensity will be progressed from week 3 to week 5, until participants are walking at 40-59% of heart rate reserve added to the resting heart rate based on their age, which will be maintained throughout the study (Table 4). Consistent with the exercise recommendations by the American Diabetes Association, starting at week 6 participants within the aerobic group will be encouraged to exercise though briskly walking for 50 minutes for 3 days a week for a total of 150 minutes per week (American Diabetes Association, 2021). In an effort to reduce attrition and improve compliance, training involves intermittent bouts of supervised treadmill walking for 10 to 15 minutes per bout, alternating with periods of rest accumulating a minimum of 50 minutes per exercise session (Linke, Gallo, & Norman, 2011). Accumulating evidence has suggested that in terms of promoting health status and fitness, aerobic exercise is as effective as traditional continuous exercise (Murphy et al., 2009).

Table 4.

Supervised Exercise Training Program Prescription and Progression

Week	% of HR reserve		Duration (Minutes)
	Aerobic exercise	Attention control
3	30 – 40%	< 40%	20 – 30
4	30 – 40%	< 40%	30 – 40
5	40 – 50%	< 40%	40 – 50
6 – 14	40 – 59%	< 40%	50

Note. HR = Heart rate. Durations do not include warm-up and cool-down.

Attention Control Prescription.

In line with Baker et al. (Baker et al., 2010), stretching exercise will be utilized as the placebo exercise in this study. Prior research has demonstrated that stretching may improve patient satisfaction, decrease attrition rate, and ensure allocation concealment (Freedland et al., 2011). After baseline measures, a trained RA will demonstrate and explain the stretching exercises as well as the use of a pulse oximeter to these participants. Beginning in week 3, participants will be instructed to perform the prescribed stretching exercises 3 times a week, while keeping their heart rate under 40% of their heart rate reserve added to the resting heart rate during the stretching exercise. Following the American College of Sports Medicine’s guidelines (American College of Sports Medicine, 2017), stretching will target all major muscle-tendon groups, including shoulder, chest, neck, truck, lower back, hips, and legs. It will also involve a slow and constant motion that accounts for any physical limitations and physician-specified precautions. Guided by a student, participants will be asked to practice each stretch up to four times in one exercise session (American College of Sports Medicine, 2017) with a minimum 3-minute rest period between different stretches. There will be a progressive increase in exercise duration in order to match with the exercise session of the aerobic exercise group (Table 4).

Validity and Reliability

Exercise Adherence

Consistent with Yu (2013), exercise adherence will be calculated as: 1) the percent of the attended sessions divided by 36 for each participant; and 2) percent of attended exercise sessions in which a participant meets both the prescribed exercise intensity and duration divided by the total number of attended sessions. The finger pulse oximeter and treadmill are used to objectively document these data. The RA who delivers the exercise session will be required to document average heart rate, exercise duration, and exercise frequency on all session case reports for each supervised participant, and the principal investigator will review these reports on a weekly basis.

Intervention Fidelity

The design of this study ensures intervention fidelity based on recommendations of the National Institutes of Health Behavioral Change Consortium (Bellg et al., 2004). Dr. Liu will meet with the students on a weekly basis to review all session case reports and randomly audit 20% of the exercise sessions using a standard form, which is used to document performance during the direct observation. The students will be re-trained as needed.

Data Analysis

Aim 1

Using descriptive statistics, the report will include a summary of the number of participants invited to the current study and the proportion who are recruited into the study and provide informed consent (participation rate). In addition, the number of people who completed the online T2DM self-management training modules and the post randomization drop-out rates will be reported for each group. Exercise adherence will be calculated as: 1) the percent of the attended sessions divided by 36 for each participant; and 2) percent of attended exercise sessions in which a participant meets both the prescribed exercise intensity and duration divided by the total number of attended sessions.

Aim 2

This study will compare the average treatment effects between the treatment and control group (i.e., aerobic and stretching exercise, respectively) across both cognitive functions and plasma BDNF using a randomized pretest posttest design. Instead of using change score analysis (Lord, 1956) due to the debate regarding the reliability in scores changing between pretest and posttest (Collins, 1996), the ANCOVA will be used for further analyses on both cognitive functions and plasma BDNF across groups. As noted by many researchers (Maxwell, Delaney, & Kelley, 2017; Petscher & Schatschineider, 2011; Porter & Raudenbush, 1987), ANCOVA can provide several advantages in terms of statistical power and precision.

In terms of evaluating cognitive functions for episodic memory, executive function, processing speed, and working memory, ANCOVA will be used to evaluate the treatment effect, with the pretest score as a covariate. In other words, the treatment effects between groups will be estimated from covariance adjustment. The data will be tested for normality by the Kolmogorov-Smirnov test. If the data violate the normality assumption, then the nonparametric ANCOVA (Knoke, 1991) will be applied to estimate conditional means. The alpha level will be set at 5% in all analyses and 95% confidence intervals with effect sizes will be reported. In addition, intention-to-treat analyses will be utilized while maintaining the integrity of the participants’ randomization to the groups. The same analysis procedure will be used for evaluating the treatment effect in plasma BDNF.

Exploratory Aim

Since this is a repeated measures design, each participant will serve as their own control. We will calculate the differences between baseline and post-intervention for all cognitive outcomes and plasma BDNF levels. Then, we plan to explore the effects of the BDNF Val66Met polymorphism on plasma BDNF levels and cognitive functioning/outcomes.

Ethical Considerations

This study has been approved by the Institutional Review Board of University of Arkansas. Participants will be informed of the purpose of the study, risks and discomforts, potential benefits of participation, costs of participation, contact information of the principal investigator, and voluntary participation at any time during the study period. Baseline data collection will begin after participants provide written informed consent.

Discussion

This rigorously designed and delivered clinical trial will provide compelling evidence as to whether aerobic exercise may improve cognitive function and plasma BDNF levels among individuals with T2DM, and if the BDNF Val66Met polymorphism has an effect on exercise-induced cognitive improvements within this specific population. Findings from this study could have important implications for nursing practice by evaluating whether individuals with T2DM with different genotypes of the BDNF Val66Met respond differently to aerobic exercise. The findings will help identify individuals who may benefit more from aerobic exercise intervention based on their genotypes. As the price for genotyping keeps dropping and genome-wide data will be widely available for most patients, the findings will also provide evidence for precision management of T2DM in the future.

Progress to Date

To date we have finished our student training, and we started enrolling participants in June, 2021. So far, we have recruited 12 participants. Due to COVID-19 pandemic and COVID-19 Delta variant, we anticipate higher-than-normal drop-out and slower-than-normal recruitment rate. To address this problem, we plan to increase our clinical recruitment sites. In addition to partnering with the Washington Reginal Medical Center, we are now collaborating with more clinical partners to enroll participants, including Rogers Adult Wellness Center, Pat Walker Health Center, and Community Clinics of Northwest Arkansas. Following university guidelines, students, staff, and all investigators working on this grant have received COVID-19 vaccine as a part of efforts to enhance the safety of the campus work and learning environment. We will be collecting some baseline data (e.g., project eligibility screener, demographics, and the International Physical Activity Questionnaire) through email. Then we will get participants scheduled for blood collection and cognitive tests on campus.

Conclusion

Cognitive dysfunction in individuals with T2DM can be an unrecognized symptom (Liu, Lee, et al., 2020), and therefore people may not actively seek treatment or advice to improve cognition. This study is a first attempt to develop a rigorously designed and delivered exercise intervention to enhance plasma BDNF levels and cognitive function of this vulnerable population. In addition, by exploring how the SNP rs6265 may influence exercise-induced cognitive outcomes, findings of the study may establish a comprehensive knowledge base for future research and development of a targeted exercise regimen for high-risk individuals who are vulnerable to negative effects on cognition based on their genomic profiles.