- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03323827
MOLECULAR REGULATION OF MUSCLE GLUCOSE METABOLISM (AIMS 2A, 2B, 3)
Study Overview
Status
Conditions
Detailed Description
The purpose of this project has been to define the molecular basis for insulin resistance in human muscle. The preceding two cycles of this project were devoted to using proteomics approaches to map and quantify serine/threonine (S/T) phosphorylation sites on insulin receptor substrate (IRS)-1 in skeletal muscle from healthy and insulin resistant humans.
Recent proteomics experiments reveal that another protein modification, lysine acetylation, is more common in non-histone proteins than has been recognized. There are no data, to our knowledge, regarding a relationship between insulin resistance in vivo in human muscle and protein acetylation. We have used proteomics techniques to discover a number of lysine acetylation sites in skeletal muscle proteins in vivo in humans, and this is prominent in mitochondrial proteins. Preliminary data show that mitochondrial protein acetylation is regulated by muscle contraction, and that this response is reduced in insulin resistance. Finally, the mitochondrial inner membrane protein adenine nucleotide translocase (ANT)1 was abundantly acetylated under resting conditions, and its deacetylation in response to contraction was reduced in insulin resistance. Because ANT1 exerts significant physiological control strength for ADP/ATP exchange, and because mitochondrial function is altered in insulin resistance, it is important to characterize this abnormality. Therefore, in order to determine how abnormalities in regulation of lysine acetylation characterize insulin resistant muscle, we propose:
2. To determine how the cytosolic and mitochondrial protein acetylomes are regulated by muscle contraction in insulin sensitive and resistant human volunteers. We will test the hypotheses that:
a. There is differential acetylation of cytosolic or mitochondrial proteins in insulin resistance.
b. Mitochondrial protein acetylation is decreased to a greater degree following a bout of exercise in insulin sensitive than in insulin resistant human muscle.
3. To determine how acetylation of the mitochondrial inner membrane adenine nucleotide translocase ANT1 regulates protein structure and function. We will use mitochondria isolated from human muscle biopsies and molecular dynamics and elastic network modeling to test the hypotheses that:
- Deacetylation of lysines 10, 23, and 92 increases ANT1 activity.
- Oxidation of the mitochondrial matrix (increasing the NAD/NADH ratio) raises deacetylation activity and decreases acetylation of ANT1.
- ANT1 molecular dynamics are altered by acetylation of lysines 10, 23, and 92.
These aims that involve clinical research will be complemented by two aims (Aims 1 and 4) performed entirely in vitro, not using human specimens or data. For context, these aims are listed on page 1 of the accompanying Research Proposal. We have retained the numbering scheme from the original proposal to avoid confusion. Please note that only Aims 2 and 3 involve clinical research.
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Locations
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Arizona
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Tucson, Arizona, United States, 85724
- Recruiting
- The University of Arizona
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Contact:
- Oscar Parra, MADM
- Phone Number: 520-626-6485
- Email: oscardp@email.arizona.edu
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Principal Investigator:
- Lawrence Mandarino, PhD
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
The study population is described here with respect to the three aims of this project.
Specific Aim 2. To determine how the cytosolic and mitochondrial protein acetylomes are regulated by muscle contraction in insulin sensitive and resistant human volunteers.
Aim 2a. Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) nondiabetics 20 subjects will be enrolled
Aim 2b (muscle contraction and acetylation). Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) 32 subjects will be enrolled
Specific Aim 3. To determine how acetylation of the mitochondrial inner membrane adenine nucleotide translocase ANT1 regulates protein structure and function.
Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) 20 subjects will be enrolled.
Description
Inclusion Criteria:
Aim 2a. Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) nondiabetics 20 subjects will be enrolled
- Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
- Subjects may be of either sex with age as described in each protocol. Female subjects must be non-lactating and will be eligible only if they have a negative pregnancy test throughout the study period.
- Subjects must range in age as described in each specific protocol.
Subjects must have the following laboratory values:
Hematocrit ≥ 35 vol% Serum creatinine ≤ 1.6 mg/dl AST (SGOT) < 2 times upper limit of normal ALT (SGPT) < 2 times upper limit of normal Alkaline phosphatase < 2 times upper limit of normal Triglycerides < 150 mg/dl. PT 11.7 -14.3 (During Liposyn/heparin infusion, PT will be determined to insure that it is < 1.5-2.0 times the normal value.) PTT 23.0-37.0.
Aim 2b (muscle contraction and acetylation). Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) 32 subjects will be enrolled
Inclusion Criteria
- Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
- Subjects may be of either sex with age as described in each protocol. Female subjects must be non-lactating and will be eligible only if they have a negative pregnancy test throughout the study period.
- Subjects must range in age as described in each specific protocol.
- Subjects must have the following laboratory values:
Hematocrit ≥ 35 vol% Serum creatinine ≤ 1.6 mg/dl AST (SGOT) < 2 times upper limit of normal ALT (SGPT) < 2 times upper limit of normal Alkaline phosphatase < 2 times upper limit of normal Triglycerides < 150 mg/dl. PT 11.7 -14.3 (During Liposyn/heparin infusion, PT will be determined to insure that it is < 1.5-2.0 times the normal value.) PTT 23.0-37.0.
Aim 3 Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) 20 subjects will be enrolled.
Inclusion Criteria
- Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
- Subjects may be of either sex with age as described in each protocol. Female subjects must be non-lactating and will be eligible only if they have a negative pregnancy test throughout the study period.
- Subjects must range in age as described in each specific protocol.
- Subjects must have the following laboratory values:
Hematocrit ≥ 35 vol% Serum creatinine ≤ 1.6 mg/dl AST (SGOT) < 2 times upper limit of normal ALT (SGPT) < 2 times upper limit of normal Alkaline phosphatase < 2 times upper limit of normal Triglycerides < 150 mg/dl. INR < 1.3
Exclusion Criteria:
Aim 2a
- Subjects must not be receiving any of the following medications: thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for the past three months before entry into the study. Subjects may be taking a stable dose of estrogens or other hormonal replacement therapy, if the subject has been on these agents for the prior three months. Subjects taking systemic glucocorticoids are excluded.
- Subjects with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
- Recent systemic or pulmonary embolus, untreated high-risk proliferative retinopathy, recent retinal hemorrhage, uncontrolled hypertension, systolic BP>180, diastolic BP>105, autonomic neuropathy, resting heart rate >100, electrolyte abnormalities.
Aim 2b Exclusion Criteria
- Subjects must not be receiving any of the following medications: thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for the past three months before entry into the study. Subjects may be taking a stable dose of estrogens or other hormonal replacement therapy, if the subject has been on these agents for the prior three months. Subjects taking systemic glucocorticoids are excluded.
- Subjects with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
- Recent systemic or pulmonary embolus, untreated high-risk proliferative retinopathy, recent retinal hemorrhage, uncontrolled hypertension, systolic BP>180, diastolic BP>105, autonomic neuropathy, resting heart rate >100, electrolyte abnormalities.
Aim 3 Exclusion Criteria
- Subjects must not be receiving any of the following medications: thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for the past three months before entry into the study. Subjects may be taking a stable dose of estrogens or other hormonal replacement therapy, if the subject has been on these agents for the prior three months. Subjects taking systemic glucocorticoids are excluded.
- Subjects with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
- Recent systemic or pulmonary embolus, untreated high-risk proliferative retinopathy, recent retinal hemorrhage, uncontrolled hypertension, systolic BP>180, diastolic BP>105, autonomic neuropathy, resting heart rate >100, electrolyte abnormalities.
- Healthy controls with BMI less than 25 who have first degree relatives with Type 2 diabetes are at high risk for insulin resistance, this is an exclusion for this study.
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
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Aim 2a
Specific Aim 2. To determine how the cytosolic and mitochondrial protein acetylomes are regulated by muscle contraction in insulin sensitive and resistant human volunteers. Protocol 2a. Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) nondiabetics 20 subjects will be enrolled |
Aim 2b
Specific Aim 2. To determine how the cytosolic and mitochondrial protein acetylomes are regulated by muscle contraction in insulin sensitive and resistant human volunteers. Protocol 2b (muscle contraction and acetylation) Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) 32 subjects will be enrolled |
Aim 3
Specific Aim 3. To determine how acetylation of the mitochondrial inner membrane adenine nucleotide translocase ANT1 regulates protein structure and function. Subjects. Two groups (aged 21-65) will be studied: lean (BMI<25), healthy insulin sensitive subjects, and obese (BMI>30) 20 subjects will be enrolled. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
ANT Acetylation
Time Frame: 2013-2017
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Acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle.
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2013-2017
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Lawrence Mandarino, PHD, The University of Arizona
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1606632714A004
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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