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Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

Primary Purpose

Insulin Resistance, Obesity

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Resistance Exercise
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Insulin Resistance focused on measuring Resistance Exercise

Eligibility Criteria

50 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria

  • age 50-75yrs
  • BMI 30-38kg/m2
  • hip to waist ratio of >0.85 in women and 1.0 in men
  • fasting glucose ≥100-140mg/dl

Lean Group

  • age 50-75 years
  • hip to waist ratio of <0.76 in women and 0.90 in men
  • fasting glucose of <100mg/dl.

Exclusion criteria for the study are as follows:

  • Coronary artery disease or heart failure.
  • Participation in a structured exercise program >2 days per week
  • A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:

    • Inpatient psychiatric treatment in the past 6 months
    • Presence of a known adrenal disorder
    • Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
    • Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty
    • Active gastroparesis
    • If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study
    • Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L); testing required within three months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise
    • Abuse of alcohol or recreational drugs
    • Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis).
    • Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or systolic blood pressure >160 mmHg) at the time of screening.
    • Oral steroids
    • A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol
    • Restrictions on Use of Other Drugs or Treatments:
    • Medications that may impact study end points such as mitochondrial biology eg. beta blockers
    • Anti-hyperglycemic drugs including metformin
    • Any other medication that the investigator believes is a contraindication to the subject's participation.

Sites / Locations

  • Mayo Clinic in Arizona
  • Mayo Clinic in Florida
  • Mayo Clinic in RochesterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

No Intervention

No Intervention

Arm Label

Insulin Resistant Exercise Group

Insulin Resistant Control Group

Insulin Sensitive Lean Group

Arm Description

Resistance (RE) training will be performed 4 days per week using a combination of upper and lower body exercises at 8-12 repetitions per set. Resistance training will be performed using a combination of upper and lower body exercises using machine and free weights. Upper body exercises are chest press, incline press, seated row, lat pull down, triceps extension, biceps curl and lateral raises. Major muscle groups for upper body exercises will include chest (pectoralis major and minor), arm (biceps and triceps), shoulder (deltoids) and back (latissimus dorsi and rhomboids). Lower body exercises are leg press, lunge (with body weight progressing to dumbbells), seated leg extension, seated leg curl, calf raises and abdominal crunches. Major muscle groups for the lower body exercises will be thighs (quadriceps and hamstrings), calves (gastrocnemius and soleus) and core (rectus abdominus and obliques).

Participants in this group will perform no exercise for the 3 month study period.

Participants in this group will have a baseline study for comparison to the insulin resistant groups.

Outcomes

Primary Outcome Measures

Change in PGC1a Expression
Measures of PGC1a4 mRNA at baseline and after 3 months in IR people - in both randomization arms. Specifically, this analysis will be a linear regression of change in PGC1a4 from baseline to 3 months, with randomization group (binary) and baseline PGC1a4 as explanatory variables. Prior to analysis, PGC1a4 mRNA measures will be log transformed so that estimated effect sizes from the analysis can be exponentiated and interpreted as relative levels or 'fold changes'; in addition to testing we shall obtain a 95% confidence interval (CI) for these estimated effects.
Change in PPARb Expression
Measures of PPARb mRNA at baseline and after 3 months in IR people - in both randomization arms. Specifically, this analysis will be a linear regression of change in PPARb from baseline to 3 months, with randomization group (binary) and baseline PPARb as explanatory variables. Prior to analysis, PPARb mRNA measures will be log transformed so that estimated effect sizes from the analysis can be exponentiated and interpreted as relative levels or 'fold changes'; in addition to testing we shall obtain a 95% confidence interval (CI) for these estimated effects.
Change in Protein degradation
The primary analysis for outcome 3 will involve measures of protein degradation as fragment counts from multiple proteins. As there are counts for multiple proteins, some with high variability for which power will be relatively low to detect modest changes, we shall focus on the subset of proteins for which the estimated coefficient in variation (CV) of changes is less than 1.0 and we will perform this analysis in the RE-trained arm only. We will perform a simple paired t-test to assess changes; or possibly a test based on a negative binomial regression as the data are counts. These tests will be performed on each protein separately. To take account of multiple testing we shall estimate the false discovery rate (FDR) among those proteins with significance at the unadjusted 5% level and use global permutation-based tests to assess overall significance. We shall also perform informal comparison with protein degradation measures in the control arm.

Secondary Outcome Measures

Change in Glycogen Content
We will assess whether there are changes in glycogen content in muscle, and whether such changes are associated with changes in PGC1a4.
Change in Glycogen Synthase
We will assess whether there are changes in glycogen synthase in muscle, and whether such changes are associated with changes in PGC1a4.

Full Information

First Posted
November 5, 2019
Last Updated
April 17, 2023
Sponsor
Mayo Clinic
Collaborators
National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT04158375
Brief Title
Molecular Mechanisms of Exercise Benefits to Insulin Resistant People
Official Title
Molecular Mechanisms of Exercise Benefits to Insulin Resistant People
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 2, 2020 (Actual)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mayo Clinic
Collaborators
National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This proposal will investigate the underlying mechanisms of enhanced insulin sensitivity and improvement of muscle loss and performance in insulin resistant people by resistance exercise training. Based on the investigator's preliminary data, they hypothesize that the key regulators of health benefits of resistance training are two genes: PGC-1a4 and PPARB;, and that the increased expression of these genes following resistance training facilitates storage of glucose in muscle and enhances its utilization for the energy need of muscle for contraction as well as enhancing muscle mass and performance. The investigators will also determine whether resistance training can reduce the higher oxidative stress in insulin resistant humans and improve their muscle protein quality.
Detailed Description
Identification of the molecular regulatory points of exercise benefits is of high national priority because of the opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in the older population associated with sarcopenia. The investigators propose a novel metabolic regulatory role of PGC-1α4 (α4), a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, the investigators hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as well as increasing muscle mass and performance. Based on their novel preliminary data, they will also investigate whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data indicates that RE reduces protein degradation which will be investigated in the current proposal. The investigators will determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein degradation and enhancing synthesis and ameliorating oxidative stress. They will study 48 IR people 50-75 yrs before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with lean IS people. They will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase, glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. They will also measure markers of oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent muscle protein degradation, which they hypothesize is reduced by increased anti-oxidant effect of Rβ with RE training. They also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by enhancing contractile protein synthesis. These studies will render the necessary mechanistic explanation on how RE enhances IS, glycolysis, reduces oxidative stress and promote muscle performance and mass in IR people, thus substantially contributing to health and life span.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Resistance, Obesity
Keywords
Resistance Exercise

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
64 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Insulin Resistant Exercise Group
Arm Type
Experimental
Arm Description
Resistance (RE) training will be performed 4 days per week using a combination of upper and lower body exercises at 8-12 repetitions per set. Resistance training will be performed using a combination of upper and lower body exercises using machine and free weights. Upper body exercises are chest press, incline press, seated row, lat pull down, triceps extension, biceps curl and lateral raises. Major muscle groups for upper body exercises will include chest (pectoralis major and minor), arm (biceps and triceps), shoulder (deltoids) and back (latissimus dorsi and rhomboids). Lower body exercises are leg press, lunge (with body weight progressing to dumbbells), seated leg extension, seated leg curl, calf raises and abdominal crunches. Major muscle groups for the lower body exercises will be thighs (quadriceps and hamstrings), calves (gastrocnemius and soleus) and core (rectus abdominus and obliques).
Arm Title
Insulin Resistant Control Group
Arm Type
No Intervention
Arm Description
Participants in this group will perform no exercise for the 3 month study period.
Arm Title
Insulin Sensitive Lean Group
Arm Type
No Intervention
Arm Description
Participants in this group will have a baseline study for comparison to the insulin resistant groups.
Intervention Type
Behavioral
Intervention Name(s)
Resistance Exercise
Intervention Description
Resistance (RE) training will be performed 4 days per week using a combination of upper and lower body exercises at 8-12 repetitions per set. Participants will complete 2 progressing to 4 sets of 8 to 12 repetitions per exercise, with 1 minute rest between sets. Participants will warmup for 5 minutes on a treadmill, cycle ergometer or elliptical at ~50% VO2 peak then begin resistance training. Resistance will be performed 4 days per week with lower body exercise on Monday and Thursday, and upper body on Tuesday and Friday. Wednesdays are a rest day. Participants will begin at 2 sets per exercise on weeks 1 and 2, then 3 sets for week 3, and 4 sets for weeks 4 to 12.
Primary Outcome Measure Information:
Title
Change in PGC1a Expression
Description
Measures of PGC1a4 mRNA at baseline and after 3 months in IR people - in both randomization arms. Specifically, this analysis will be a linear regression of change in PGC1a4 from baseline to 3 months, with randomization group (binary) and baseline PGC1a4 as explanatory variables. Prior to analysis, PGC1a4 mRNA measures will be log transformed so that estimated effect sizes from the analysis can be exponentiated and interpreted as relative levels or 'fold changes'; in addition to testing we shall obtain a 95% confidence interval (CI) for these estimated effects.
Time Frame
Baseline and after 3 months
Title
Change in PPARb Expression
Description
Measures of PPARb mRNA at baseline and after 3 months in IR people - in both randomization arms. Specifically, this analysis will be a linear regression of change in PPARb from baseline to 3 months, with randomization group (binary) and baseline PPARb as explanatory variables. Prior to analysis, PPARb mRNA measures will be log transformed so that estimated effect sizes from the analysis can be exponentiated and interpreted as relative levels or 'fold changes'; in addition to testing we shall obtain a 95% confidence interval (CI) for these estimated effects.
Time Frame
Baseline and after 3 months
Title
Change in Protein degradation
Description
The primary analysis for outcome 3 will involve measures of protein degradation as fragment counts from multiple proteins. As there are counts for multiple proteins, some with high variability for which power will be relatively low to detect modest changes, we shall focus on the subset of proteins for which the estimated coefficient in variation (CV) of changes is less than 1.0 and we will perform this analysis in the RE-trained arm only. We will perform a simple paired t-test to assess changes; or possibly a test based on a negative binomial regression as the data are counts. These tests will be performed on each protein separately. To take account of multiple testing we shall estimate the false discovery rate (FDR) among those proteins with significance at the unadjusted 5% level and use global permutation-based tests to assess overall significance. We shall also perform informal comparison with protein degradation measures in the control arm.
Time Frame
Baseline and after 3 months
Secondary Outcome Measure Information:
Title
Change in Glycogen Content
Description
We will assess whether there are changes in glycogen content in muscle, and whether such changes are associated with changes in PGC1a4.
Time Frame
Baseline and after 3 months
Title
Change in Glycogen Synthase
Description
We will assess whether there are changes in glycogen synthase in muscle, and whether such changes are associated with changes in PGC1a4.
Time Frame
Baseline and after 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria age 50-75yrs BMI 30-38kg/m2 hip to waist ratio of >0.85 in women and 1.0 in men fasting glucose ≥100-140mg/dl Lean Group age 50-75 years hip to waist ratio of <0.76 in women and 0.90 in men fasting glucose of <100mg/dl. Exclusion criteria for the study are as follows: Coronary artery disease or heart failure. Participation in a structured exercise program >2 days per week A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples: Inpatient psychiatric treatment in the past 6 months Presence of a known adrenal disorder Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty Active gastroparesis If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L); testing required within three months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise Abuse of alcohol or recreational drugs Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis). Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or systolic blood pressure >160 mmHg) at the time of screening. Oral steroids A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol Restrictions on Use of Other Drugs or Treatments: Medications that may impact study end points such as mitochondrial biology eg. beta blockers Anti-hyperglycemic drugs including metformin Any other medication that the investigator believes is a contraindication to the subject's participation.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rose A McCain
Phone
507-255-6770
Email
bilderback.rose@mayo.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
K Sreekumaran Nair
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Individual Site Status
Not yet recruiting
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Individual Site Status
Not yet recruiting
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sreekumaran Nair, MD/PhD
Phone
507-255-2949
Email
nair@mayo.edu

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://www.mayo.edu/research/clinical-trials
Description
Mayo Clinic Clinical Trials

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Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

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