Physical Inactivity and Insulin Resistance in Skeletal Muscle.

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Metabolic Syndrome X; Insulin Resistance; Hypertension; Hypercholesterolemia; Obesity	Behavioral: Exercise; Drug: Metformin	Not Applicable

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	0 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Physical Inactivity and Insulin Resistance in Skeletal Muscle.
Study Start Date :	June 2009
Estimated Primary Completion Date :	October 2011
Estimated Study Completion Date :	December 2011

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1; Exercise	Behavioral: Exercise; 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.
Active Comparator: 2; Metformin	Drug: Metformin; oral tablet, 1000 mg daily for 17 days

Outcome Measures

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Primary Outcome Measures :

1. 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 Measures :

1. 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. [ Time Frame: 12 weeks and 3 days ]

Eligibility Criteria

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Ages Eligible for Study:	20 Years to 55 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

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.

Contacts and Locations

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Locations

United States, Missouri
Harry S. Truman Memorial Veterans' Hospital
Columbia, Missouri, United States, 65201

Sponsors and Collaborators

University of Kansas

VA Office of Research and Development

Investigators

Principal Investigator:	John P Thyfault, PhD	University of Missouri-Columbia

More Information

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Publications:

Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000 Jul;106(2):171-6. Review.

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.

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. Epub 2005 Aug 3.

Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, Dériaz 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.

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. Epub 2006 Aug 10.

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.

Responsible Party:	John Thyfault, University of Missouri-Columbia
ClinicalTrials.gov Identifier:	NCT00536211 History of Changes
Other Study ID Numbers:	1095378
First Posted:	September 27, 2007
Last Update Posted:	August 11, 2015
Last Verified:	August 2015

Keywords provided by University of Kansas Medical Center:

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

Additional relevant MeSH terms:

Metabolic Syndrome X; Insulin Resistance; Hypercholesterolemia; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases	Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs