Effects of Pioglitazone on Exogenous Carbohydrate Oxidation During Steady-State Exercise at High Altitude

Apparent hypoxia-induced insulin insensitivity along with alterations in glucose kinetics suggests reduction in glucose uptake by the peripheral tissue is a primary factor contributing to reductions in exogenous glucose oxidation at HA. As such, the primary objective of this study is to determine the ability of an insulin sensitizer (Pioglitazone, PIO) to enhance exogenous glucose oxidation and metabolic clearance rate during metabolically-matched, steady-state exercise during acute HA exposure compared to placebo (PLA) in native lowlanders. Secondary objective of this study will be to assess the impact of PIO on markers of inflammation and iron status compared to PLA. This randomized crossover placebo control double blinded study will examine substrate oxidation and glucose kinetic responses to ingesting supplemental carbohydrate (glucose) during metabolically-matched, steady-state exercise with acute (~5 h) exposure to HA (460 mmHg, or 4300m, barometric pressure similar to Pike's Peak) after receiving PIO (HA+PIO), or after receiving a matched placebo (HA+PLA). Eight healthy, recreationally active males between the ages of 18-39 yrs will be required to complete this study. Following a 4 day glycogen normalization period receiving PIO or PLA daily, volunteers will complete two 80-min trials, performing metabolically-matched, steady-state aerobic (same absolute workload corresponding to ~55 ± 5% of V̇O2peak at HA) exercise on a treadmill, and consuming 145 g of glucose (1.8 g/min); one trial with HA+PIO and the other with HA+PLA. A dual glucose tracer (13C-glucose oral ingestion and [6,6-2H2]-glucose primed, continuous infusion) technique and indirect calorimetry will be used to selectively analyze endogenous and exogenous glucose oxidation, as well as glucose rate of appearance (Ra), disappearance (Rd) and metabolic clearance rate (MCR). Serial blood samples will be collected during each trial to assess endocrine and circulating substrate responses to exercise, carbohydrate, and hypoxia with or without PIO. All trials will occur at the same time of day in the USARIEM hypobaric/hypoxic chamber and be separated by a minimum 10-d washout period. The primary risks associated with this study include those associated with acute hypobaric hypoxia, exercise, and blood sampling.

Study Overview

• Status: Completed
• Conditions: High Altitude
• Intervention / Treatment: Drug: Pioglitazone 15mg; Other: Placebo

Detailed Description

This randomized crossover placebo controlled double blinded study will examine substrate oxidation and glucose kinetic responses to ingesting supplemental carbohydrate (glucose) during metabolically-matched, steady-state exercise with acute (~5 h) exposure to HA (460 mmHg) after short-term (5 days) use of Pioglitazone (HA+PIO), or matched placebo (HA+PLA). Eight healthy, recreationally active males between the ages of 18-39 yrs will be enrolled. Following a 48-hr muscle glycogen normalization period, volunteers will complete 80-min of metabolically-matched, steady-state (same absolute workload corresponding to ~55 ± 5% of V̇O2peak at HA) exercise on a treadmill, and consume 145 g of glucose (1.8 g/min) with HA+PIO and HA+PLA. A dual glucose tracer (13C-glucose oral ingestion and [6,6-2H2]-glucose primed, continuous infusion) technique and indirect calorimetry will be used to analyze endogenous and exogenous glucose oxidation, as well as glucose rate of appearance (Ra), disappearance (Rd), and MCR. Serial blood samples will be collected during each trial to assess endocrine and circulating substrate responses to exercise, carbohydrate, and hypoxia, with or without PIO. Isotope methodology and aerobic exercise protocols will be identical to our previous work (3, 4), allowing comparison of outcomes across studies. All trials will be conducted in the USARIEM hypobaric/hypoxic chamber and be separated by a minimum 10-d washout period.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Natick, Massachusetts, United States, 01760
      • US Army Research Institute of Environmental Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Men aged 18 - 39 years
• Born at altitudes less than 2,100 m
• Physically active (exercise minimum 2 days per week)
• Have supervisor approval (permanent party military and civilians)
• Willing to refrain from alcohol, smokeless nicotine products and dietary supplement use during study periods
• Fully vaccinated against COVID-19

Exclusion Criteria:

• Born at altitudes greater than 2,100 m
• Musculoskeletal injuries that compromise exercise capability
• Metabolic or cardiovascular abnormalities, or gastrointestinal disorders
• Taking medication that affects macronutrient metabolism and/or the ability to participate in strenuous exercise
• Living in areas that are more than 1,200 m, or traveled to areas that are more than 1,200 m for five days or more within 2 months of data collection
• Evidence of apnea or other sleeping disorders
• Prior diagnosis of high altitude pulmonary edema or high altitude cerebral edema
• Presence of asthma or respiratory tract infections
• Smoking or vaping
• Taking medications that interfere with oxygen delivery and transport
• Anemia (HCT <38% and HBG <12.5 g/dL) and Sickle Cell Anemia/Trait
• Blood donation within 8 weeks of beginning the study
• Unwilling or unable to consume study diets or foods provided due to personal preference, dietary restrictions, and/or food allergies
• Unwilling or unable to adhere to study physical restrictions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pioglitazone; Pioglitazone administered as a 15 mg oral dose per day for 5 days	Drug: Pioglitazone 15mg; Pioglitazone (PIO) will be administered as a 15 mg oral dose per day for 5 days; Other Names: Actos
Placebo Comparator: Placebo; Microcrystalline cellulose pill administered as an oral dose per day for 5 days	Other: Placebo; 100% microcrystalline cellulos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Exogenous Glucose Oxidation	Determine the effects of PIO on exogenous glucose oxidation and glucose turnover during exercise under acute HA exposure compared to PLA	8 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Interleukin-6	Determine the effects of PIO on inflammation during acute HA exposure compared to PLA.	8 hours
Concentration of Serum Iron	Determine the effects of PIO on markers of iron status during acute HA exposure compared to PLA	8 hours

Collaborators and Investigators

• Sponsor: United States Army Research Institute of Environmental Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Actual): July 1, 2023
• Study Completion (Actual): July 1, 2023

Study Registration Dates

• First Submitted: September 19, 2023
• First Submitted That Met QC Criteria: December 1, 2023
• First Posted (Estimated): December 11, 2023

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Altitude Sickness; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 22-07H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes