Due to COVID-19 restrictions.

This proposal's objective is to investigate the effects of a high-intensity intermittent stair climbing program on insulin resistance in individuals with obesity and at risk of type 2 diabetes (T2D).

Obesity (defined as body mass index ≥ 30kg/m2) is a major risk factor for T2D. The connection between obesity and T2D involves the development of insulin resistance (IR). Exercise training is an effective non-pharmacological approach to prevent and treat IR. Despite the efficacy of exercise training on ameliorating IR, most individuals do not achieve the minimum recommended levels of physical activity and cite "lack of time" and difficulty in accessing exercise facilities as barriers to exercise. Proposed as a time-efficient alternative, high-intensity interval training (HIIT), which consists of short periods of high-intensity efforts alternated with brief periods of recovery, is an efficient strategy to improve IR. However, most HIIT protocols have been studied in laboratory-based settings requiring access to specialized equipment (i.e. treadmills, cycle ergometers) and are not practical for the general population. The use of high-intensity intermittent stair climbing may be a suitable exercise strategy from an accessibility perspective. With evidence to suggest improvements in IR following HIIT in individuals with obesity or T2D, the application of a similar approach using high-intensity intermittent stair climbing to directly assess changes in IR in a population at risk of T2D populations is warranted. Completion of this study will help elucidate if an easy to implement, time-efficient and low-cost exercise training program improves insulin resistance in individuals at risk of T2D.

Significance The obesity epidemic is a worldwide public health problem. Recent data indicate that over 650 million adults around the world (~13%) are considered obese. Obesity is one of the major risk factors for type 2 diabetes mellitus (T2D) and 90% of T2D cases are attributable to excess fat mass. The connection between obesity and T2D is believed to be intrinsically related to insulin resistance (IR). IR is characterized by a blunted effect of insulin on decreasing circulating blood glucose at the whole-body level and/or a lower response of certain tissues to the action of insulin. For example, skeletal muscle is responsible for ~70% of insulin-stimulated postprandial glucose uptake and plays a key role in the maintenance of whole-body insulin sensitivity and glycemic homeostasis. Additionally, IR is one of the earliest detectable defects preceding hyperglycemia, present up to 10 years before diabetes is diagnosed.

Although the cause of obesity-induced IR is complex and multifactorial, the beneficial effects of exercise training in preventing and treating IR are well established. In individuals with IR, an improvement in insulin action on skeletal muscle glucose metabolism is one of the main effects induced by exercise training. For example, previous research demonstrated that a single session of exercise reduced cellular stress, which may contribute to exercise-induced increases in insulin sensitivity. Despite the efficacy of exercise training on IR, the majority of individuals do not achieve the minimum recommended levels of physical activity: 30 minutes or more of moderate intensity physical activity at least 5 days a week, or 20 minutes of vigorous physical activity at least 3 days a week, or a combination thereof, in addition to activities of daily living. Of note, lack of time and difficulty in accessing facilities for exercise are commonly cited as barriers to physical activity.

In this context, the high-intensity interval training (HIIT), which consists of short periods of intense exercise (≥ 80% of maximal heart rate) alternated with periods of active recovery or rest, is a relatively time-efficient training strategy to improve metabolic health and has been considered more enjoyable than moderate-to-vigorous intensity continuous training. HIIT increases skeletal muscle oxidative capacity and induces physiological remodeling like the changes promoted by continuous moderate-intensity aerobic training. HIIT appears effective in improving insulin sensitivity, particularly in those at risk of, or with, T2D. A previous study using 10 x of 60-seconds of cycling intervals (∼90% of maximal heart rate) interspersed with 60-seconds of active recovery, three times per week over a period of two weeks, reduced hyperglycemia and increased skeletal muscle oxidative capacity in patients with T2D. Recently published data has shown that an 8-week HIIT program resulted in lower IR in individuals with obesity and also promoted greater expression of proteins related to oxidative metabolism in skeletal muscle. Although HIIT may be an efficient option to improve insulin sensitivity and glycemic control in individuals at risk of T2D, most HIIT studies have been conducted primarily in traditional laboratory setting and may not be practical for the general population.

Innovation The common approach to study the effects of exercise are either using treadmills or cycle ergometers. These approaches have limited translation to a "real word" scenario. Among the barriers generally reported for a regular physical activity program are lack of time, difficulty in accessing facilities for exercise, and low motivation. The goal of the proposed study is to investigate the effects of a HIIT program using a suitable exercise alternative (stair climbing) on IR in individuals with obesity and at risk of T2D. Stair climbing can be considered an activity of daily living and is easily accessible. Previous studies have shown that one short bout of stair climbing (<6 min) acutely increased postprandial glucose uptake in middle-aged men with impaired glucose tolerance and older T2D subjects. Another study showed 6 weeks of a brief high intense intermittent stair climbing program was effective improving cardiorespiratory fitness in healthy individuals but did not improve IR. More recently, a preliminary study examined the effect of 6 weeks of brief intermittent stair climbing exercise on glycemic control in people with T2D. The authors reported that the protocol (3 x 1-minute bouts of repeatedly ascending and descending a single flight of stairs) was insufficient to induce improvements in glucose control. In this context, the volume was too low (approximately 50 stairs) and there was no progression of training volume over time. Additionally, the authors counted for the time descending the stairs as part of the 1-minute bout which may have reduced even more the time spent ascending the stairs. To address these limitations, the proposed study will implement a more prolonged protocol with progressive increase in exercise volume and will only count the time spent ascending the stairs. To the best of the author's knowledge, no study has tested this approach using HIIT in individuals with obesity and a risk of T2D. Findings from this study will help to translate research-based evidence to clinical practice and contribute to prevent or treat individuals at risk of T2D with a nonpharmacological and low-cost approach. This topic is within the "Cell and Organism" New Mexico - Idea Network of Biomedical Research Excellence (NM-INBRE) focus area to advance the understanding of human health.

Approach The study is an 8-wk within-subject intervention design where participants will be tested pre and post intervention. 20 participants (10 males and 10 females) will be recruited from the local community through poster advertisement and one-to-one interaction. Before agreeing to participate in the study, the participants will given written informed consent, which will be approved by the institutional review board of the local institution. Inclusion criteria include body mass index (BMI) ≥ 30 kg/m2; homeostasis model assessment for insulin resistance (HOMA-IR) ≥ 2.71; no fear of being totally submerged underwater; freedom from orthopedic injuries, diagnoses of T2D or glucose intolerance, known acute or chronic diseases, and current use of anti-inflammatory, hypoglycemic or other drugs known to affect metabolism. Subjects that meet the initial requirements will have a fasting blood draw. Individuals with altered glucose metabolism (fasting plasma glucose >126 mg/dL) will be excluded. The researchers will ensure the inclusion of males and females from differing ethnic background. The required sample size was calculated a priori based on changes in the HOMA-IR using an alpha level of 0.05 and power of 80%. Prior to exercise training, participants undergo: a fasting blood draw for blood glucose and insulin measurements, anthropometrics and body composition analysis, and a maximal graded exercise test.

The exercise training protocol consist of 8 weeks of HIIT using stair climbing with a frequency of 3 times a week, totaling 24 training sessions. For the first week of the stair training exercise program subjects will meet at UNM's Teaching Education Building (Stair Case 2). The following 7 weeks subjects can perform the exercise program at a staircase most convenient to them and approved by the research team. The warm-up will consist of 2 minutes of ascending and descending the stairs at a comfortable pace. The high-intensity intermittent exercise will be comprised of 6-12 x 30-seconds bout of ascending at an all-effort at a moderate pace. A 30- seconds walking recovery will occur between the exercise bouts. After the exercise session the subject will walk during a 2-minute cool down. Every session will last between 10 to 15 minutes. The number of bouts (6-12) will be increased progressively over the weeks. During the first (week 1) and final week (week 8) of the exercise program subjects will be monitored by a trained exercise physiologist. During these supervised visits, heart rate and rating of perceived exertion (OMNI scale) will be measured at the end of each stair climbing bout and after active recovery. Subjects will have the option to request further monitoring if desired. Weeks 2 through 7 OMNI will be self-recorded by the subjects.

Measurements Insulin resistance - After a 10-hour fast and at least 72 hours before and after the training, venous blood samples will be collected for the measurement of blood glucose and insulin. HOMA-IR (calculated by [glucose (mmol)] x [insulin (µU/ml)] ÷ 22.5) will be determined from the fasting glucose and insulin concentrations.

Anthropometric and body composition measurements - Height and body mass will be measured using an analog scale with coupled stadiometer. BMI will be calculated using height in m and body mass in kg. Relative body fat (%BF) values will be determined through underwater weighing (UWW) at measured residual lung volume. The highest 3 UWW trials ± 100 g will be averaged and used for computation of body volume. Body volume will be corrected for residual lung volume using the dry-land oxygen dilution technique so that body density can be computed and converted into %BF formula.

Maximal Oxygen Consumption - Maximal oxygen consumption will be measured using a maximal ramp graded test protocol conducted on a treadmill. The speed will be increased every 60s at an individual rate, which will be based on the participant's exercise history questionnaire (Veterans Specific Activity Questionnaire), to induce fatigue within 8 to 12 minutes. Expired gases will be analyzed using a metabolic cart. Heart rate (HR) will be recorded continuously using a HR transmitter strap (S810i series, Polar, USA).

Calculations and Statistical Analyses Data will be presented as mean ± standard deviation. A statistical software will be used for statistical analysis. The Shapiro-Wilk test will be used to analyze the data normality. Area under the curve (AUC) for insulin and glucose will be calculated using the Trapezoidal method. For study 1, a Student t test will be used to analyze the effects of training (pre vs post). For study 2, a two-way analyses of variance (ANOVA) will be used to test the effect of the two exercise protocols (factor 1 = pre and post 8 weeks of training and factor 2 = single session vs multiple sessions). If statistically significant F values are observed, a Tukey post hoc test will be performed. The alpha level is set at P ≤ 0.05 for statistical significance.

Potential problems and strategies: Dropout and compliance are limitations in exercise training interventions. The researchers will provide training session on three different times a day (early morning, afternoon and evenings) to accommodate people with different schedules. Also, participants will be compensated for time.

Inclusion Criteria:

• 18-45 years,
• body mass index (BMI) equal or superior than 30 kg/m²;
• homeostasis model assessment for insulin resistance (HOMA-IR) ≥ 2.71,
• no fear of being totally submerged underwater for 2 to 10 seconds
• comfortable having blood taken from a forearm vein.

Exclusion Criteria:

• smokers,
• currently taking any medications known to impact their metabolism or immune system,
• bleeding or blood clotting disorder,
• physical injury,
• physical limitations,
• diagnostic of T2D,
• currently under the active care of a physician for any condition that may interfere with their safety.
• cardiovascular conditions (cardiac, peripheral vascular, or cerebrovascular disease),
• diseases that prevent participation in a maximal effort test without physician clearance per the American College of Sports Medicine (ACSM) guidelines (2017).
• signs and symptoms of cardiovascular disease, at rest or during physical activity, which includes pain, discomfort in the chest, neck, jaw, arms, or other areas that may result from ischemia; shortness of breath at rest or with mild exertion; dizziness or syncope; orthopnea or paroxysmal nocturnal dyspnea; ankle edema; palpitations or tachycardia; intermittent claudication; known heart murmur; or unusual fatigue or shortness of breath with usual activities.