Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

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.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Insulin Resistance
• Intervention / Treatment: Behavioral: Resistance Exercise

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.

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rose A McCain; Phone Number: 507-255-6770; Email: bilderback.rose@mayo.edu

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Not yet recruiting
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Not yet recruiting
      • Mayo Clinic in Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic in Rochester
      • Contact: Sreekumaran Nair, MD/PhD; Phone Number: 507-255-2949; Email: nair@mayo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Insulin Resistant Exercise Group; 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).	Behavioral: Resistance Exercise; 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.
No Intervention: Insulin Resistant Control Group; Participants in this group will perform no exercise for the 3 month study period.
No Intervention: Insulin Sensitive Lean Group; Participants in this group will have a baseline study for comparison to the insulin resistant groups.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and after 3 months
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.	Baseline and after 3 months
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.	Baseline and after 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and after 3 months
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.	Baseline and after 3 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: K Sreekumaran Nair, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2020
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: November 5, 2019
• First Submitted That Met QC Criteria: November 7, 2019
• First Posted (Actual): November 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Resistance Exercise
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: 19-006273; 1R01AG062859-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No