Metabolic Inflexibility is Related to Elevated Muscle Anaerobic Glycolysis

Overview

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 Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: December 2024

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.

Interventions

  • Procedure: Weight loss surgery
    • Severely obese women (BMI >40) undergo sleeve gastrectomy

Arms, Groups and Cohorts

  • Low oxidizers/high lactate
    • Individuals with low aerobic oxidation
  • High oxidizers/low lactate
    • Individuals with high aerobic oxidation
  • Obese
    • Severely obese scheduled for surgery

Clinical Trial Outcome Measures

Primary Measures

  • 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)

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • East Carolina University
  • Collaborator
    • Duke University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Joseph Houmard, PhD, Principal Investigator, East Carolina University
  • Overall Contact(s)
    • Terry Jones, PhD, 2527446249, joneste@ecu.edu

References

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.

Fisher-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.

Chondronikola 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.

Goodpaster 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.

Galgani 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.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.