Metabolic InflexibilityNCT04320264
Metabolic Inflexibility is Related to Elevated Muscle Anaerobic Glycolysis
An observational study of Metabolic Inflexibility, run by East Carolina University at 1 site in United States.
Trial summary
The focus of this proposal is on overweight (25>BMI<30 kg/m2) subjects, as these individuals exhibit a high risk of becoming obese and/or developing metabolic diseases. We hypothesize that in some overweight individuals there is a "metabolic program" in skeletal muscle which predisposes them to the development of… Read more about this study
- Who is it for?
- Ages 18 to 50 years
- Conditions the study is for
- Metabolic Inflexibility
- What is being tested?
- Weight loss surgery
- Type of treatment
- Surgery or procedure
- How many people
- 100 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Mar 2020to Dec 2025
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- No healthy volunteers
- Adult
Study population: High oxidizers Low oxidizers Obese
Who may be able to join
- 18-50 years old
- BMI of 25 - 30 kg/m2
- BMI > 40kg/m2
- Lactate levels in top and lower 25%
Who cannot join
- Pregnant women
- Mentally disabled
- Prisoners
- Smokers
- Subjects with heart disease
- Type 1 and 2 diabetes
Show all 13Show fewer
- Endocrine disease
- Hypertension
- Musculoskeletal disease
- Peripheral occlusion
- Hepatic disease
- Have had weight fluctuations exceeding + 3% in the previous 12 months
- On medications which alter carbohydrate metabolism will not be studied
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
East Carolina University
Greenville, North Carolina, 27834
Terry Jones, PhD, 2527446249, joneste@ecu.edu
Nicholas Broskey, PhD, 2527374684, broskeyn19@ecu.edu
About this study
The focus of this proposal is on overweight (25>BMI<30 kg/m2) subjects, as these individuals exhibit a high risk of becoming obese and/or developing metabolic diseases. We hypothesize that in some overweight individuals there is a "metabolic program" in skeletal muscle which predisposes them to the development of obesity. Findings may lead to clinical screening tools for determining risk for obesity in non-obese individuals and targeting this group for prevention.
Read the detailed description
Our overall hypothesis is that increased reliance on anaerobic glycolysis in muscle shifts fasting metabolism from fat towards carbohydrate utilization, which results in metabolic inflexibility and subsequent metabolic disease (i.e. obesity). To test our hypothesis, overweight subjects (BMI 25 to 30 kg/m2) will be recruited and screened for reliance on anaerobic glycolysis (resting/fasting plasma lactate concentrations). Subjects with high (top quartile) and low (bottom quartile) resting/fasting plasma lactate will be chosen. The premise of this screening is that subjects with low lactate will have high muscle aerobic substrate oxidation, while those with elevated lactate will have low muscle oxidative metabolism. Severely obese subjects will be studied as a comparator group. In aim 1 in vivo muscle lactate release and respiratory exchange ratio (RER) will be determined to investigate if subjects with high reliance on anaerobic glycolysis exhibit a shift towards carbohydrate utilization at the whole-body level. Aim 2 will test whether subjects with elevated reliance on anaerobic glycolysis in muscle are metabolically inflexible. To establish causality, aim 3 is designed to follow subjects after an intervention that shifts skeletal muscle metabolism from carbohydrate to fat utilization. Our preliminary findings indicate that bariatric surgery normalizes muscle lactate production; therefore, severely obese subjects will be studied before and after gastric bypass surgery (aim 3).
The study (MetFlex) will enroll 74 adults; (Group 1) 60 overweight (BMI 25 to 30 kg/m2) males and females ages 18-50 years old and (Group 2) 14 severely obese (BMI 40 to 50 kg/m2) adult females who are scheduled for bariatric surgery.
Endpoints to be investigated in the 3 specific aims.
Carbohydrate/fat oxidation (RER) in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Muscle oxygen consumption (substrate oxidation) in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Muscle lactate release in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Endogenous glucose production in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Insulin sensitivity (clamp M value). High lactate vs low lactate groups (aim 1)
Change in Carbohydrate/fat oxidation (RER) in response to glucose + insulin (metabolic flexibility). High lactate vs low lactate groups (aim 2)
Change in muscle fat oxidation in response to high fat feeding (metabolic flexibility). High lactate vs low lactate groups (aim 2)
Change in muscle oxygen consumption (substrate oxidation) in response to high fat feeding (metabolic flexibility). High lactate vs low lactate groups (aim 2)
Our basic premise is that elevated fasting plasma lactate causes glucose production to be increased and that a "Vicious Cori cycle" is the underlying cause of the metabolic syndrome.
- Conditions
- Metabolic Inflexibility
- Being tested
- Weight loss surgery
- Keywords
- Metabolic Inflexibility, Obesity, Anaerobic glycolysis
- Medical subject headings
- Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Weight loss surgeryProcedure or surgery
Severely obese women (BMI >40) undergo sleeve gastrectomy
| Study group | Role | What they receive |
|---|---|---|
| Low oxidizers/high lactate | Individuals with low aerobic oxidation | |
| High oxidizers/low lactate | Individuals with high aerobic oxidation | |
| Obese | Severely obese scheduled for surgery Receives: Procedure: Weight loss surgery |
What is being measured
The primary outcome is the main question the study is designed to answer.
Carbohydrate/fat oxidation (RER) in the fasting condition.
RER will be measured from indirect calorimetry
Measured: Years 1-5
Muscle oxygen consumption (substrate oxidation) in the fasting condition.
Muscle oxygen consumption will be measured by near-infrared spectroscopy (NIRS)
Measured: Years 1-5
Muscle lactate release in the fasting condition.
Muscle lactate release will be measured by microdialysis
Measured: Years 1-5
Change in Carbohydrate/fat oxidation (RER) in response to glucose + insulin (metabolic flexibility)
Indirect calorimetry during glucose clamp
Measured: Years 1-5
Change in muscle fat oxidation in response to high fat feeding (metabolic flexibility).
Oxidation of fatty acid in muscle homogenate.
Measured: Years 1-5
Change in muscle oxygen consumption (substrate oxidation) in response to high fat feeding (metabolic flexibility).
Oxygen consumption measured by near-infrared spectroscopy (NIRS)
Measured: Years 1-5
Secondary outcomes (2)
Insulin sensitivity (clamp M value).
Measured during glucose clamp.
Measured: Years 1-5
Endogenous glucose production in the fasting condition.
Measured with isotopically labeled glucose
Measured: Years 1-5
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Mar 2020
- Study start3 Mar 2020
- Primary completionDec 2025 (estimated)
- Study completionDec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Metabolic InflexibilityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- East Carolina University
- Sponsor type
- University, hospital or other
- Collaborators
- Duke University, University of Arkansas
- Responsible party
- Sponsor
- Investigators
- Joseph Houmard, PhD, Principal investigator, East Carolina University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04320264
- Sponsor's protocol ID
- UMCIRB 19-000914
- Status last verified
- Aug 2025
- First submitted
- 3 Sep 2019
- Last updated
- 7 Aug 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ryan TE, Brophy P, Lin CT, Hickner RC, Neufer PD. Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements. J Physiol. 2014 Aug 1;592(15):3231-41. doi: 10.1113/jphysiol.2014.274456. Epub 2014 Jun 20.
PubMed 24951618Fisher-Wellman KH, Davidson MT, Narowski TM, Lin CT, Koves TR, Muoio DM. Mitochondrial Diagnostics: A Multiplexed Assay Platform for Comprehensive Assessment of Mitochondrial Energy Fluxes. Cell Rep. 2018 Sep 25;24(13):3593-3606.e10. doi: 10.1016/j.celrep.2018.08.091.
PubMed 30257218Chondronikola M, Magkos F, Yoshino J, Okunade AL, Patterson BW, Muehlbauer MJ, Newgard CB, Klein S. Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial. Obesity (Silver Spring). 2018 Apr;26(4):683-688. doi: 10.1002/oby.22129. Epub 2018 Feb 24.
PubMed 29476613Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 2;25(5):1027-1036. doi: 10.1016/j.cmet.2017.04.015.
PubMed 28467922Galgani JE, Moro C, Ravussin E. Metabolic flexibility and insulin resistance. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1009-17. doi: 10.1152/ajpendo.90558.2008. Epub 2008 Sep 2.
PubMed 18765680
Study at a glance
From the registry record, last updated by the sponsor on 7 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metabolic Inflexibility is Related to Elevated Muscle Anaerobic Glycolysis
- ClinicalTrials.gov ID
- NCT04320264
- Acronym / sponsor ID
- UMCIRB 19-000914
- Conditions
- Metabolic Inflexibility
- Keywords
- Metabolic Inflexibility, Obesity, Anaerobic glycolysis
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- East Carolina UniversityUniversity, hospital or other
- Collaborators
- Duke University, University of Arkansas
- Study start
- 3 Mar 2020 (actual)
- Primary completion
- Dec 2025 (estimated)
- Study completion
- Dec 2025 (estimated)
- First posted
- 24 Mar 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The focus of this proposal is on overweight (25>BMI<30 kg/m2) subjects, as these individuals exhibit a high risk of becoming obese and/or developing metabolic diseases. We hypothesize that in some overweight individuals there is a "metabolic program" in skeletal muscle which predisposes them to the development of obesity. Findings may lead to clinical screening tools for determining risk for obesity in non-obese individuals and targeting this group for prevention.
Detailed description
Our overall hypothesis is that increased reliance on anaerobic glycolysis in muscle shifts fasting metabolism from fat towards carbohydrate utilization, which results in metabolic inflexibility and subsequent metabolic disease (i.e. obesity). To test our hypothesis, overweight subjects (BMI 25 to 30 kg/m2) will be recruited and screened for reliance on anaerobic glycolysis (resting/fasting plasma lactate concentrations). Subjects with high (top quartile) and low (bottom quartile) resting/fasting plasma lactate will be chosen. The premise of this screening is that subjects with low lactate will have high muscle aerobic substrate oxidation, while those with elevated lactate will have low muscle oxidative metabolism. Severely obese subjects will be studied as a comparator group. In aim 1 in vivo muscle lactate release and respiratory exchange ratio (RER) will be determined to investigate if subjects with high reliance on anaerobic glycolysis exhibit a shift towards carbohydrate utilization at the whole-body level. Aim 2 will test whether subjects with elevated reliance on anaerobic glycolysis in muscle are metabolically inflexible. To establish causality, aim 3 is designed to follow subjects after an intervention that shifts skeletal muscle metabolism from carbohydrate to fat utilization. Our preliminary findings indicate that bariatric surgery normalizes muscle lactate production; therefore, severely obese subjects will be studied before and after gastric bypass surgery (aim 3).
The study (MetFlex) will enroll 74 adults; (Group 1) 60 overweight (BMI 25 to 30 kg/m2) males and females ages 18-50 years old and (Group 2) 14 severely obese (BMI 40 to 50 kg/m2) adult females who are scheduled for bariatric surgery.
Endpoints to be investigated in the 3 specific aims.
Carbohydrate/fat oxidation (RER) in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Muscle oxygen consumption (substrate oxidation) in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Muscle lactate release in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Endogenous glucose production in the fasting condition. High lactate vs low lactate groups (aim 1). Pre-surgery vs post-surgery (aim 3)
Insulin sensitivity (clamp M value). High lactate vs low lactate groups (aim 1)
Change in Carbohydrate/fat oxidation (RER) in response to glucose + insulin (metabolic flexibility). High lactate vs low lactate groups (aim 2)
Change in muscle fat oxidation in response to high fat feeding (metabolic flexibility). High lactate vs low lactate groups (aim 2)
Change in muscle oxygen consumption (substrate oxidation) in response to high fat feeding (metabolic flexibility). High lactate vs low lactate groups (aim 2)
Our basic premise is that elevated fasting plasma lactate causes glucose production to be increased and that a "Vicious Cori cycle" is the underlying cause of the metabolic syndrome.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Low oxidizers/high lactate | – | –Individuals with low aerobic oxidation |
| High oxidizers/low lactate | – | –Individuals with high aerobic oxidation |
| Obese | – | Procedure: Weight loss surgerySeverely obese scheduled for surgery |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- Study population
- High oxidizers Low oxidizers Obese
Key inclusion criteria (4 listed)
- 18-50 years old
- BMI of 25 - 30 kg/m2
- BMI > 40kg/m2
- Lactate levels in top and lower 25%
Key exclusion criteria (13 listed)
- Pregnant women
- Mentally disabled
- Prisoners
- Smokers
- Subjects with heart disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Weight loss surgerySeverely obese women (BMI >40) undergo sleeve gastrectomy | Procedure or surgery | Obese |
Primary outcome
Carbohydrate/fat oxidation (RER) in the fasting condition.
Time frame: Years 1-5
RER will be measured from indirect calorimetry
Muscle oxygen consumption (substrate oxidation) in the fasting condition.
Time frame: Years 1-5
Muscle oxygen consumption will be measured by near-infrared spectroscopy (NIRS)
Muscle lactate release in the fasting condition.
Time frame: Years 1-5
Muscle lactate release will be measured by microdialysis
Change in Carbohydrate/fat oxidation (RER) in response to glucose + insulin (metabolic flexibility)
Time frame: Years 1-5
Indirect calorimetry during glucose clamp
Change in muscle fat oxidation in response to high fat feeding (metabolic flexibility).
Time frame: Years 1-5
Oxidation of fatty acid in muscle homogenate.
Change in muscle oxygen consumption (substrate oxidation) in response to high fat feeding (metabolic flexibility).
Time frame: Years 1-5
Oxygen consumption measured by near-infrared spectroscopy (NIRS)
2 secondary outcomes
Insulin sensitivity (clamp M value).
Time frame: Years 1-5
Endogenous glucose production in the fasting condition.
Time frame: Years 1-5
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Aug 2025.
- Background: PubMed 24951618Ryan TE, Brophy P, Lin CT, Hickner RC, Neufer PD. Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements. J Physiol. 2014 Aug 1;592(15):3231-41. doi: 10.1113/jphysiol.2014.274456. Epub 2014 Jun 20.
- Background: PubMed 30257218Fisher-Wellman KH, Davidson MT, Narowski TM, Lin CT, Koves TR, Muoio DM. Mitochondrial Diagnostics: A Multiplexed Assay Platform for Comprehensive Assessment of Mitochondrial Energy Fluxes. Cell Rep. 2018 Sep 25;24(13):3593-3606.e10. doi: 10.1016/j.celrep.2018.08.091.
- Background: PubMed 29476613Chondronikola M, Magkos F, Yoshino J, Okunade AL, Patterson BW, Muehlbauer MJ, Newgard CB, Klein S. Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial. Obesity (Silver Spring). 2018 Apr;26(4):683-688. doi: 10.1002/oby.22129. Epub 2018 Feb 24.
- Background: PubMed 28467922Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 2;25(5):1027-1036. doi: 10.1016/j.cmet.2017.04.015.
- Background: PubMed 18765680Galgani JE, Moro C, Ravussin E. Metabolic flexibility and insulin resistance. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1009-17. doi: 10.1152/ajpendo.90558.2008. Epub 2008 Sep 2.
- Individual participant dataSharing planned: No
Related trials for Metabolic Inflexibility
Not yet recruitingObservational study
PeriOperative Medicine - Metabolic Inflexibility as a Mechanism for Myocardial Injury After Non-Cardiac Surgery
MINS
Not yet recruiting
Effect of High Protein Diet on Hepatic Steatosis in Patients With MAFLD
Metabolic Dysfunction Associated Fatty Liver Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Joseph Houmard, PhD principal investigator
East Carolina University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Metabolic Inflexibility, run by East Carolina University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 7 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Terry Jones, PhD (2527446249, joneste@ecu.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Carbohydrate/fat oxidation (RER) in the fasting condition. (time frame: Years 1-5). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04320264, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Aug 2025.