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Physical Inactivity and Insulin Resistance in Skeletal Muscle.

Primary Purpose

Metabolic Syndrome X, Insulin Resistance, Hypertension

Status

Withdrawn

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Exercise

Metformin

About this trial

This is an interventional treatment trial for Metabolic Syndrome X focused on measuring Exercise, Physical Activity, Metformin, Hyperinsulinemic-Euglycemic Clamp, Muscle Biopsy, Fatty Acid Oxidation, Peroxisome proliferator-activated receptor gamma, Detraining, Inactivity, Skeletal muscle

Eligibility Criteria

20 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Selection of inclusion for Metabolic Syndrome Subjects :

Sedentary metabolic syndrome subjects will be 20-55 y of age, overweight to Class I or II obese (BMI 25-39 kg/m2) men and women, who have a fasting glucose of 100 to 125 mg/dl, and at least 2 of 4 other characteristics of the metabolic syndrome which are the following: waist circumference greater than 102 cm in men and 88 cm in women, serum triglyceride concentration greater than 150 mg/dl, HDL-C concentration greater than 40 mg/dl in men and 50 mg/dl in women, and blood pressure greater than 130/85 mmHG.

Selection for inclusion for Endurance Athlete Subjects:

Subjects who report training (running and/or biking) greater than 30 min a day, 4 days a week for at least 1 year will be included. Final inclusion criteria will be a VO2max of greater than 55 ml/kg/min.

To take part in the study, Women must currently be taking birth control or be postmenopausal.

Exclusion Criteria:

Subjects will be excluded from the study if they have or are:

Diagnosed cardiovascular disease or diabetes or disease symptoms that could alter their ability to perform exercise, fasting blood glucose of greater than 126 mg/dl, smokers, taking any medications or supplements (e.g., statins, fibrates, metformin, thiazolidinediones, anti-hypertensives (ACE-inhibitors and angiotensin blockers) which could affect blood lipids or insulin sensitivity.

Women who are pregnant or plan to become pregnant during the duration of the study For the Metabolic Syndrome subjects only individuals exercising regularly (more than one 30 min session per week) or have a physically active lifestyle (>8,000 daily steps as measured by a pedometer) will be excluded.

Individuals with an orthopedic limitations for walking. Allergies to drugs used in the study. Past or current liver and/or kidney problems of any nature.

Sites / Locations

Harry S. Truman Memorial Veterans' Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm Description

Exercise

Metformin

Outcomes

Primary Outcome Measures

Insulin sensitivity; following 12 weeks of exercise training and 1 and 3 days of detraining and + or - Metformin.

Secondary Outcome Measures

PGC-1 alpha transcription and mitochondrial fatty acid oxidation and enzyme activity in skeletal muscle; following 12 weeks of exercise training and 1, 2, and 3 days of detraining and + or - Metformin.

Full Information

NCT ID

NCT00536211

First Posted

September 25, 2007

Last Updated

April 29, 2021

Sponsor

University of Kansas Medical Center

Collaborators

US Department of Veterans Affairs

1. Study Identification

Unique Protocol Identification Number

NCT00536211

Brief Title

Physical Inactivity and Insulin Resistance in Skeletal Muscle.

Official Title

Physical Inactivity and Insulin Resistance in Skeletal Muscle.

Study Type

Interventional

2. Study Status

Record Verification Date

August 2015

Overall Recruitment Status

Withdrawn

Why Stopped

protocol not approved by VA R&D

Study Start Date

June 2009 (undefined)

Primary Completion Date

October 2011 (Anticipated)

Study Completion Date

December 2011 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Kansas Medical Center

Collaborators

US Department of Veterans Affairs

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to determine how a decline in physical activity acutely leads to a decrease in insulin sensitivity in skeletal muscle. The hypothesis is that the loss of insulin sensitivity following physical inactivity is caused by a rapid reduction in skeletal muscle mitochondrial oxidative capacity.

Detailed Description

In this project we will study two diverse groups of subjects. Group 1 will be subjects who are sedentary, insulin resistant, and have the Metabolic Syndrome. These subjects will be tested for insulin sensitivity at the whole body level, and for key changes in skeletal muscle metabolism at baseline, following 12 weeks of exercise training, and during an acute (1-3 days) period of time following the cessation of exercise training. The design allows us to study the effects of exercise on improving insulin sensitivity and make direct comparisons to a period when insulin sensitivity quickly decreases because of the removal of exercise training. Metformin is a drug commonly prescribed to control insulin resistance and type 2 diabetes. Metformin is thought to have exercise like effects on muscle metabolism and is known to activate a molecule that is de-activated during inactivity. Thus, half of the Metabolic Syndrome subjects will cease exercise training with no treatment while another half will quite exercise training while taking the drug Metformin. Group 2 subjects will be highly trained endurance athletes. Endurance athletes display high levels of insulin sensitivity that can drop in the hours and days following the cessation of exercise. Thus we will take the same measurements in endurance athletes at baseline during their normal training regimen and in the acute (1-3 days) period following the cessation of exercise training. Again, half of the subjects will be take Metformin during the cessation of exercise in the same fashion as done in group 1. Studies in both groups seek to determine the event(s) which cause insulin resistance in skeletal muscle following a decrease in physical activity levels. Comparisons between healthy, active individuals and sedentary Metabolic Syndrome subjects may provide additional information about the underlying events that cause insulin resistance.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metabolic Syndrome X, Insulin Resistance, Hypertension, Hypercholesterolemia, Obesity

Keywords

Exercise, Physical Activity, Metformin, Hyperinsulinemic-Euglycemic Clamp, Muscle Biopsy, Fatty Acid Oxidation, Peroxisome proliferator-activated receptor gamma, Detraining, Inactivity, Skeletal muscle

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Exercise

Arm Title

Arm Type

Active Comparator

Arm Description

Metformin

Intervention Type

Behavioral

Intervention Name(s)

Exercise

Intervention Description

Exercise training will consist of walking and/or jogging on a treadmill 5 out of 7 d each week at ~60% of each subject's predetermined VO2max (75% maximal heart rate as monitored by heart rate monitors), 45 min/session, for 12 weeks. The exercise training will follow a three-stage progression: 1. wk 1 = 30 min, 3 d/wk, 60% VO2max; 2. wk 2 = 30 min, 5 d/wk, 60% VO2max; and 3. wk 3-12 = 45 min, 5 d/wk, 60% VO2max.

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

oral tablet, 1000 mg daily for 17 days

Primary Outcome Measure Information:

Title

Insulin sensitivity; following 12 weeks of exercise training and 1 and 3 days of detraining and + or - Metformin.

Time Frame

12 weeks and 3 days

Secondary Outcome Measure Information:

Title

Time Frame

12 weeks and 3 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Selection of inclusion for Metabolic Syndrome Subjects : Sedentary metabolic syndrome subjects will be 20-55 y of age, overweight to Class I or II obese (BMI 25-39 kg/m2) men and women, who have a fasting glucose of 100 to 125 mg/dl, and at least 2 of 4 other characteristics of the metabolic syndrome which are the following: waist circumference greater than 102 cm in men and 88 cm in women, serum triglyceride concentration greater than 150 mg/dl, HDL-C concentration greater than 40 mg/dl in men and 50 mg/dl in women, and blood pressure greater than 130/85 mmHG. Selection for inclusion for Endurance Athlete Subjects: Subjects who report training (running and/or biking) greater than 30 min a day, 4 days a week for at least 1 year will be included. Final inclusion criteria will be a VO2max of greater than 55 ml/kg/min. To take part in the study, Women must currently be taking birth control or be postmenopausal. Exclusion Criteria: Subjects will be excluded from the study if they have or are: Diagnosed cardiovascular disease or diabetes or disease symptoms that could alter their ability to perform exercise, fasting blood glucose of greater than 126 mg/dl, smokers, taking any medications or supplements (e.g., statins, fibrates, metformin, thiazolidinediones, anti-hypertensives (ACE-inhibitors and angiotensin blockers) which could affect blood lipids or insulin sensitivity. Women who are pregnant or plan to become pregnant during the duration of the study For the Metabolic Syndrome subjects only individuals exercising regularly (more than one 30 min session per week) or have a physically active lifestyle (>8,000 daily steps as measured by a pedometer) will be excluded. Individuals with an orthopedic limitations for walking. Allergies to drugs used in the study. Past or current liver and/or kidney problems of any nature.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John P Thyfault, PhD

Organizational Affiliation

University of Missouri-Columbia

Official's Role

Principal Investigator

Facility Information:

Facility Name

Harry S. Truman Memorial Veterans' Hospital

City

Columbia

State/Province

Missouri

ZIP/Postal Code

65201

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

10903330

Citation

Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000 Jul;106(2):171-6. doi: 10.1172/JCI10583. No abstract available.

Results Reference

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PubMed Identifier

9126003

Citation

Haapanen N, Miilunpalo S, Pasanen M, Oja P, Vuori I. Agreement between questionnaire data and medical records of chronic diseases in middle-aged and elderly Finnish men and women. Am J Epidemiol. 1997 Apr 15;145(8):762-9. doi: 10.1093/aje/145.8.762.

Results Reference

background

PubMed Identifier

16079133

Citation

Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem. 2005 Sep 30;280(39):33588-98. doi: 10.1074/jbc.M507621200. Epub 2005 Aug 3.

Results Reference

background

PubMed Identifier

14633846

Citation

Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, Deriaz O. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes. 2003 Dec;52(12):2874-81. doi: 10.2337/diabetes.52.12.2874.

Results Reference

background

PubMed Identifier

16902066

Citation

Suwa M, Egashira T, Nakano H, Sasaki H, Kumagai S. Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J Appl Physiol (1985). 2006 Dec;101(6):1685-92. doi: 10.1152/japplphysiol.00255.2006. Epub 2006 Aug 10.

Results Reference

background

PubMed Identifier

520120

Citation

Kawate R, Yamakido M, Nishimoto Y, Bennett PH, Hamman RF, Knowler WC. Diabetes mellitus and its vascular complications in Japanese migrants on the Island of Hawaii. Diabetes Care. 1979 Mar-Apr;2(2):161-70. doi: 10.2337/diacare.2.2.161.

Results Reference

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