MOLECULAR REGULATION OF MUSCLE GLUCOSE METABOLISM (AIMS 2A, 2B, 3)

NCT03323827 | Unknown

• 1 other identifier: 1606632714A004
• Study Type: observational
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

The molecular nature of insulin resistance in human muscle is still incompletely defined. Our data indicate that acetylation of mitochondrial proteins in humans is regulated by muscle contraction and is dysregulated in insulin resistance. Poor function of mitochondria in skeletal muscle is a hallmark of insulin resistance in skeletal muscle. We propose to use a combination of clinical research and mass spectrometry techniques to determine how the cytosolic and mitochondrial protein acetylation is regulated by muscle contraction in insulin sensitive and resistant human volunteers. We will test the hypothesis that mitochondrial protein acetylation is decreased to a greater degree following a bout of exercise in insulin sensitive than in insulin resistant human muscle. Using these techniques we also propose to determine how acetylation of mitochondrial adenine nucleotide translocase (ANT1) at lysines 10, 23, and 92 regulates ANT1 structure and function. Finally, we propose 4) to use a combination of molecular modeling and in vitro assays together with the approach developed in Aim 3 to characterize the role of acetylation in other mitochondrial proteins. Protein targets for this aim will be prioritized based on the potential role of the protein in insulin resistance or mitochondrial function as well as dysregulation of its acetylation state in insulin resistant muscle.

Conditions

Type 2 Diabetes Mellitus; Obesity

Outcome Measures

Primary Outcomes (1)

• ANT Acetylation

  Acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle.

  2013-2017

Study Arms (3)

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.

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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.

You may qualify if:

• 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
• 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.
• 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.

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• University of Arizona: lead

Study Sites (1)

The University of Arizona

Tucson, Arizona, 85724, United States

RECRUITING

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Lawrence Mandarino, PHD

  The University of Arizona

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oscar Parra, MADM

CONTACT

520-626-6485; oscardp@email.arizona.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: October 24, 2017
• First Posted: October 27, 2017
• Study Start: November 1, 2016
• Primary Completion: August 1, 2018
• Study Completion: August 1, 2018
• Last Updated: October 27, 2017

Record last verified: 2017-10

Locations

US (1)