Metabolic Inflexibility is Related to Elevated Muscle Anaerobic Glycolysis

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.

Study Overview

• Status: Recruiting
• Conditions: Metabolic Inflexibility
• Intervention / Treatment: Procedure: Weight loss surgery

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 Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Nicholas Broskey, PhD; Phone Number: 2527374684; Email: broskeyn19@ecu.edu
• Study Contact Backup: Name: Terry Jones, PhD; Phone Number: 2527446249; Email: joneste@ecu.edu

Study Locations

• United States
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Recruiting
      • East Carolina University
      • Contact: Nicholas Broskey, PhD; Phone Number: 2527374684; Email: broskeyn19@ecu.edu
      • Contact: Terry Jones, PhD; Phone Number: 2527446249; Email: joneste@ecu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

High oxidizers Low oxidizers Obese

Description

Inclusion Criteria:

• 18-50 years old
• BMI of 25 - 30 kg/m2
• BMI > 40kg/m2
• Lactate levels in top and lower 25%

Exclusion Criteria:

• Pregnant women
• Mentally disabled
• Prisoners
• Smokers
• Subjects with heart disease
• Type 1 and 2 diabetes
• 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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Low oxidizers/high lactate; Individuals with low aerobic oxidation
High oxidizers/low lactate; Individuals with high aerobic oxidation
Obese; Severely obese scheduled for surgery	Procedure: Weight loss surgery; Severely obese women (BMI >40) undergo sleeve gastrectomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Carbohydrate/fat oxidation (RER) in the fasting condition.	RER will be measured from indirect calorimetry	Years 1-5
Muscle oxygen consumption (substrate oxidation) in the fasting condition.	Muscle oxygen consumption will be measured by near-infrared spectroscopy (NIRS)	Years 1-5
Muscle lactate release in the fasting condition.	Muscle lactate release will be measured by microdialysis	Years 1-5
Change in Carbohydrate/fat oxidation (RER) in response to glucose + insulin (metabolic flexibility)	Indirect calorimetry during glucose clamp	Years 1-5
Change in muscle fat oxidation in response to high fat feeding (metabolic flexibility).	Oxidation of fatty acid in muscle homogenate.	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)	Years 1-5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity (clamp M value).	Measured during glucose clamp.	Years 1-5
Endogenous glucose production in the fasting condition.	Measured with isotopically labeled glucose	Years 1-5

Collaborators and Investigators

• Sponsor: East Carolina University
• Collaborators: Duke University; University of Arkansas
• Investigators: Principal Investigator: Joseph Houmard, PhD, East Carolina University

Publications and helpful links

General 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.
• Camisa C, Rossana C. Variant of keratoderma hereditaria mutilans (Vohwinkel's syndrome). Treatment with orally administered isotretinoin. Arch Dermatol. 1984 Oct;120(10):1323-8.
• Craglietto T, Giarelli L, Paolini A. [Comparative study of the DNA content of human female breast adenocarcinomas and of their recurrences. (Histo-spectrophotometric findings)]. Riv Anat Patol Oncol. 1964 Nov-Dec;26(5):694-706. No abstract available. Italian.
• Ciresa M, Gabl F, Knapp E. [Acid-base equilibrium]. Wien Klin Wochenschr. 1970 Jan 2;82(1):11-2. No abstract available. German.
• Iwamasa J, Tajima C, Matsuura K, Okamura H. [Role of progesterone in the ovulatory process of PMSG/hCG treated immature female rats]. Nihon Sanka Fujinka Gakkai Zasshi. 1989 Oct;41(10):1551-6. Japanese.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2020
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: September 3, 2019
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (Actual): March 24, 2020

Study Record Updates

• Last Update Posted (Actual): August 7, 2025
• Last Update Submitted That Met QC Criteria: August 4, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Metabolic Inflexibility; Anaerobic glycolysis
• Other Study ID Numbers: UMCIRB 19-000914

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