Metabolic Inflexibility is Related to Elevated Muscle Anaerobic Glycolysis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Metabolic Inflexibility is Related to Elevated Muscle Anaerobic Glycolysis

Conditions
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Metabolic Inflexibility

Intervention / Treatment
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* Procedure: Weight loss surgery


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Low oxidizers/high lactate<br>Individuals with low aerobic oxidation | |
| High oxidizers/low lactate<br>Individuals with high aerobic oxidation | |
| Obese<br>Severely obese scheduled for surgery | Procedure: Weight loss surgery<br>* Severely obese women (BMI >40) undergo sleeve gastrectomy<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic Inflexibility, Obesity, Anaerobic glycolysis