Exercise, Statins, and the Metabolic Syndrome

• Mitochondrial content in skeletal muscle [ Time Frame: Baseline and after 12 weeks of treatment ] [ Designated as safety issue: No ]
  % change in mitochondrial content between baseline and after 12 weeks of treatment will be assessed in muscle from biopsies
• Metabolic Syndrome markers [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  Fasting glucose Plasma triglycerides and other blood lipids HDL-Cholesterol Waist Circumference Blood Pressure
• Metabolic Syndrome Markers [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Fasting glucose Plasma triglycerides and other blood lipids HDL-Cholesterol Waist Circumference

The metabolic syndrome (MSynd) as recently defined by Grundy et al (1) in a position statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health is "a cluster of interrelated risk factors of metabolic origin -metabolic risk factors - that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD)." Grundy et al (1) went on to describe metabolic risk factors as "atherogenic dyslipidemia, elevated blood pressure, and elevated blood glucose." These metabolic risk factors, or some may call physiological or clinical characteristics, appear to greatly increase the risk for ASCVD when they occur at the same time. Grundy et al also state the following about the MSynd "available data suggest that it is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of the cause, the syndrome identifies individuals at risk for ASCVD." Statins (St) dramatically decrease low-density lipoprotein cholesterol (LDL-C) and are the primary treatment for individuals at risk for the MSynd and CVD. Long-term studies indicating that St-treatment has reduced the incidence of CVD by only 30% have placed an emphasis on increasing high-density lipoprotein (HDL-C) levels, which are protective against CVD. Increased physical activity (i.e., exercise) is an effective treatment and may complement St-treatment. Increased physical activity or chronic exercise increases HDL-C and reverses insulin resistance, and thus may complement the effects of St-treatment. Although experts advocate St-treatment and exercise, there is a paucity of research examining their combined impact. In the proposed study, 20 sedentary individuals with the MSynd will be assigned to St-treatment (Simvastatin) (40 mg/day) for 12 weeks or to St-treatment (40 mg/day) plus a monitored exercise regimen (45 min/day @ 5 days/week) for 12 weeks. The hypothesis is that the addition of exercise to St-treatment will provide an additive benefit in lowering clinical measures which are used to diagnose the MSynd according to the AHA and NHBLI. Specifically, we will test these clinical measures: insulin resistance, blood triglycerides and HDL cholesterol, hypertension, and waist circumference. Therefore, this project's Primary Aim is to compare the effects of St-treatment (St) and St-treatment plus exercise (St+Ex) in their ability to favorably change these clinical measurements.

Elevated blood lipid levels can cause an increased storage of intramuscular triglycerides (IMTG) in skeletal muscle, a marker and possible cause of peripheral insulin resistance. Because St-treatment and exercise can lower blood lipids and improve insulin sensitivity, it is important to compare the individual and combinatory impact upon IMTG levels. Therefore, the Secondary Aim will compare the impact of St and St+Ex on IMTG content.

MSynd subjects often display an overactive sympathetic nervous system that may play a causative role in the development of insulin resistance. Previous work shows that both exercise and St-treatment can independently lower overactive sympathetic nervous drive. The final goal of this project is to determine if St + Ex will have a greater impact on lowering sympathetic drive then St treatment alone. Comparing the changes in sympathetic drive with St-treatment will also provide greater information on the associations between overactive sympathetic drive and insulin resistance.

• Metabolic Syndrome
• Obese
• Sedentary

• Drug: Statin
  Statins (40mg/day)for 12 weeks
  Other Name: simvastatin
• Other: Exercise only
  12 weeks of exercise training (5 days a week for 45-50 min a session)
  Other Name: Physical activity
• Other: Statins + Exercise
  Statins (40mg/day of simvastatin) plus exercise training (5 days/wk for 45-50 min a session) for 12 weeks
  Other Name: Statins + Physical Activity

• Experimental: Statin
  Statins (40mg/day)for an average of 12 weeks
  Intervention: Drug: Statin
• Experimental: Exercise only
  12 weeks of exercise training (5 days a week for 45-50 min a session)
  Intervention: Other: Exercise only
• Active Comparator: Statins + Exercise
  Statins (40mg/day of simvastatin) plus exercise training (5 days/wk) for 12 weeks
  Intervention: Other: Statins + Exercise

Inclusion Criteria:

• Sedentary metabolic syndrome subjects will be 25-59 y of age
• overweight to Class I or II obese (BMI 25-39 kg/m2) men and women
• 2 of 4 other characteristics of the metabolic syndrome including fasting glucose of 100 to 125 mg/dl; waist circumference greater than 102 cm in men and 88 cm in women, serum triglyceride concentration greater than 150 mg/dl, HDL-C concentrations less than 40 mg/dl in men and 50 mg/dl in women, and blood pressure greater than 130/85 mmHG
• Women must be taking birth control or be postmenopausal.

Exclusion Criteria:

• 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
• Smoking
• Taking any medications or supplements (e.g., statins, fibrates, metformin, thiazolidenediones, 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
• Individuals exercising regularly (more than one 30 min session per week)
• Individuals with an orthopedic limitations for walking.
• Report any allergies to the medications (statins, lidocaine)