The study will be reported in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines for randomized pilot and feasibility trials [27]. This is a “proof-of-concept” 1:1 parallel-group RCT involving 34 physically inactive individuals aged 35-65 years who are overweight or obese and have i-IFG. Figure 2 presents the study’s CONSORT diagram. The Georgia Clinical Research Center (GCRC) at Emory University Hospital will serve as the site for participant recruitment and conducting study procedures. A highly trained and experienced study coordinator will recruit participants through a comprehensive 3-step screening procedure.

Potential participants will be identified using Emory’s electronic health care records system, known as “MyChart.” Queries within this database will target individuals aged 35-65 years with a BMI≥25 kg/m² (≥23 kg/m² if Asian descent) [28], who have been diagnosed with prediabetes (hemoglobin A_1c [HbA_1c] 5.7%-6.4%) [29] within the last 12 months, have no diagnosis of diabetes (FPG≥126 mg/dL or 2-hour plasma glucose ≥200 mg/dL or HbA_1c≥6.5% or currently taking antidiabetic drugs) [29], not currently taking weight-loss medications, not currently taking drugs known to influence glucose tolerance (steroids and antipsychotics), not currently taking beta-blockers and calcium channel blockers (individuals taking these drugs will not reach heart rate (HR) targets for the HIIT sessions), did not undergo bariatric surgery, no anemia (anemia may limit the exercising capacity), and have no chronic illnesses (cardiovascular disease, stroke, cancers, chronic respiratory diseases, and mental health disorders). Individuals meeting these criteria will receive an invitation through the MyChart platform to participate in the second screening step.

Those expressing interest in participating in the study through MyChart will be contacted via phone. During these calls, individuals will receive a comprehensive explanation of the study and have any questions addressed. They will then be asked to sign an electronic consent form via Emory’s REDCap (Research Electronic Data Capture; Vanderbilt University) platform [30]. Following consent, potential participants will complete a questionnaire to assess their eligibility for step 3 screening based on the following criteria.

Individuals meeting the step 2 criteria will be invited to visit the GCRC at Emory University Hospital after fasting overnight for a minimum of 8 hours [29]. During the visit, participants will complete standard questionnaires to collect sociodemographic information (education, occupation, and marital status) [34,35] and details on alcohol consumption [34,35] and dietary intake [36]. Additionally, physical measurements will be conducted using standardized instruments in accordance with the World Health Organization’s STEPwise approach to noncommunicable disease risk factor surveillance (STEPS) protocol [37]. Following these assessments, individuals will undergo an oral glucose tolerance test (OGTT) and provide blood samples for insulin. Individuals diagnosed with i-IFG, defined by the American Diabetes Association criteria as FPG between 100-125 mg/dL and 2-hour plasma glucose<140 mg/dL [29], will be deemed eligible to participate in the study. Individuals without i-IFG will be excluded from further participation in the study. They will receive a summary report of their test results and general healthy lifestyle advice and will be referred to their general practitioner if they have IGT or undiagnosed diabetes for further management.

Participants will be equally randomized into either the intervention or control group after completing baseline assessments and being found eligible, using a computer-generated randomization sequence by a statistician not involved in the trial. Given the nature of the study, only specific personnel such as nursing staff, laboratory personnel, and the data analyst will be blinded to participant allocation to the study groups. Participants, the study coordinator, the HIIT intervention instructor, and the principal investigator will not be blinded to participation allocation.

Following the recommendation of the American College of Sports Medicine [38], participants in the intervention group will be required to obtain medical clearance from their general practitioner before starting the HIIT sessions. These sessions, led by a qualified exercise physiologist (the instructor) and adhering to standard protocols [39,40], will take place in the Aerobic Exercise Laboratory at Emory University's Rehabilitation Hospital. Using “spin cycle ergometers” (Schwinn), sessions will be conducted in small groups of 5 or fewer participants at specified times on Mondays, Wednesdays, and Fridays, spanning 8 weeks. Each participant will undergo a maximum of 24 HIIT sessions. Each session will consist of a 5-minute warm-up, followed by an interval-based workout phase with steady up-tempo cadences, sprints, climbs, and interspersed recovery periods. A 5-minute cooldown will conclude each session. The workout sessions will initially last 20 minutes and will progressively increase in time based on participants’ tolerance and instructor recommendations. Each session will include “active rest” periods where resistance is reduced to lower HR, alternating with high-intensity intervals featuring sprints or climbs to elevate HR. The duration of active rest versus high-intensity intervals will be adjusted according to individual responses and target HR. To monitor and maintain intensity within the target HR range, participants will wear Polar H10 chest strap HR sensors [41]. The target HR will be calculated using the Karvonen method [42]. Exercise intensity will begin at 75% of the estimated maximum HR reserve (HRR) and will increase by 5% every week, as tolerated or deemed necessary by the instructor, over the 8-week intervention period. During the workout phase, the target HRR reserve will be maintained by averaging increases and decreases in intensity or HR with a target to maintain within a 10% offset from the HRR goal [39,40]. Participants will need to adhere to within-session HR targets at an 80% rate (or greater) for a session to be counted as attended and participants will need to attend 19 out of 24 sessions to be included as a “completer” in the final data analysis. To date, our interventions have yielded a within-session adherence rate to the prescribed intervention of 91% (as measured by HR) and a retention rate of 85% [40,43-45]. Participants’ weight and body composition will be measured weekly.

To ensure high compliance in session attendance, the instructor will hold weekly one-on-one meetings with participants to provide personalized feedback and encouragement. Participants’ HR data will also be reviewed during these meetings. Additionally, the study coordinator will remind participants of their scheduled sessions 1 day in advance through phone calls or texts. Attendance in sessions will be closely monitored, and records of attended exercise sessions will be maintained. Participants who miss sessions will be contacted via phone calls to encourage attendance.

Any adverse events occurring during or after HIIT sessions will be documented, with medical advice sought if necessary. Both intervention and control participants will receive instructions to maintain a eucaloric diet throughout the study. Dietary adherence will be monitored biweekly by a registered dietitian using the Automated Self-Administered 24-Hour Dietary Assessment Tool (National Cancer Institute) [36]. This tool will be administered via phone calls 3 times a week, covering 2 weekdays and 1 weekend day. Additionally, control participants will be instructed to refrain from engaging in intense physical activities during the study period. Physical activity adherence will be assessed biweekly using the short form of IPAQ, also administered via phone calls [32].

The details about the measurements, study tools, and timelines are outlined in Table 1.

Table 2 shows the study feasibility metrics. Continuous data collection on feasibility parameters, such as response rate, screening yield, enrollment rate, time to enrollment, intervention compliance, resource use (cost and staff time), and retention rate, will be conducted throughout the study.

The Feasibility of Intervention Measure (FIM) will evaluate the feasibility of the intervention, encompassing questions regarding its implementability, possibility, doability, and ease of use [46]. The acceptability of the intervention will be assessed through the Theoretical Framework of Acceptability (TFA) questionnaire, which explores affective attitude, burden, ethicality, perceived effectiveness, intervention coherence, self-efficacy, opportunity costs, and general acceptability [47]. The Intervention Appropriate Measure (IAM) will evaluate the appropriateness of the intervention, including questions about its fittingness, suitability, applicability, and alignment with participants’ needs [46]. Responses to the questions in all 3 questionnaires will be recorded on a Likert scale of 1 to 5. The mean total score for each of these scales will be calculated by combining the individual Likert points of each scale. Higher scores on the FIM, TFA, and IAM scales indicate greater feasibility, acceptability, and appropriateness, respectively, among participants.

By providing 288 glucose measurements per day throughout the 8-week intervention and 10-day follow-up, continuous glucose monitoring (CGM) can track the dynamic changes in fasting glucose levels induced by HIIT [48]. This can help identify when the effects of HIIT on fasting glucose levels become evident and whether these effects are sustained after the intervention, which may not be captured by a single blood glucose measurement taken after 8 weeks. All participants, regardless of their assigned treatment, will be fitted with a CGM device on their abdominal area upon enrollment. The CGM device, Dexcom G6 Pro CGM system (DexCom, Inc), will be used in blinded mode to minimize bias and ensure that it does not influence the study outcomes. Participants will be instructed to eat their last meal by 10 PM daily after the CGM fitting. They will wear CGM devices for approximately 80 days, including 10 days prior to the intervention, the 8-week intervention period, and 10 days following the intervention. Participants will be trained on how to replace the device every 10 days, using the instructions provided in the manual [49], during the first study visit. The adequacy of CGM data will be evaluated using the following criteria: a minimum of 80% of the potential 288 glucose values per day should be present for any 7 consecutive days, commencing from the day following sensor insertion [50].

Data on health behaviors, physical measurements, and biochemical measurements will be collected at both baseline and 8 weeks.

The study coordinator will enter questionnaire data, as well as physical and biochemical measurements directly into Emory University’s REDCap database [30]. This database will feature validation checks to ensure data accuracy, along with skip patterns facilitated by branching logic functions. The principal investigator (ST) will constantly review the data for any errors, promptly flagging any errors for correction by the study coordinator. Upon completion of data entry and cleaning, a master copy of the data set will be generated and securely stored within the REDCap database. CGM raw data (in CSV file format per participant) will be downloaded from the DexCom Clarity software and uploaded to REDCap. Access to these datasets will be limited to the study coordinator and the principal investigator for confidentiality and data security purposes.

Assuming a Cohen d of 0.3 to <0.7 (medium standardized effect size) [25,59] for FPG in the planned main trial, with an alpha of 5% and a power of 90%, a sample size of 15 participants per treatment group is deemed necessary for this pilot study. Factoring in a 10% loss to follow-up in each group, the total sample size was estimated to be 34 participants (17 per group).

The potential challenges that could be encountered at various stages of the study and the corresponding mitigation strategies are outlined in Table 4.

The study protocol was approved by the institutional review board of Emory University, Atlanta, USA (MOD001-STUDY00005855). All participants will provide written informed consent prior to study participation. Participant identifiers will be kept strictly confidential in a secure REDCap database, accessible only by the principal investigator and study coordinator. Data will be deidentified before analysis. Participants will receive a US $50 gift card as compensation for their participation.

This proof-of-concept study will generate data on the feasibility and acceptability of the HIIT intervention, as well as participants’ experiences and satisfaction levels. Additionally, the study will offer preliminary estimates on the efficacy of HIIT in reducing FPG levels and addressing the pathophysiology of i-IFG.

To our knowledge, this study will be the first to assess the feasibility and acceptability of a HIIT intervention exclusively among individuals with i-IFG. Additionally, we adhered to the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) statement [60] when reporting the details of this study protocol. However, there are some limitations. We will assess the pathophysiological abnormalities in i-IFG using indices derived from the OGTT and fasting insulin levels instead of gold-standard methods like the intravenous glucose tolerance test and glycemic clamps [61-63]. However, these indices have demonstrated strong correlations with estimates obtained from the gold-standard methods [61-63]. Additionally, our reliance on a single OGTT may be subject to day-to-day variability in glucose tolerance status. Nevertheless, strict adherence to standardized protocols for conducting the OGTT [52,53] should help minimize this variability to a significant extent.

The results of this study are expected to guide the design and implementation of an RCT to assess the efficacy of HIIT intervention in reducing diabetes incidence and achieving remission in individuals with i-IFG.