Insulin Sensitivity in Men With the Metabolic Syndrome

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Overall Status

Suspended

CT.gov ID

NCT00433173

Collaborator

American Diabetes Association (Other)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The metabolic syndrome is a medical condition defined by high levels of cholesterol in the blood, high blood pressure, central obesity (gain in fat around the region of the stomach), and insulin resistance (body responds less well to insulin). This state of impaired insulin resistance can lead to type 2 diabetes mellitus, which is one of the most common metabolic disorders in the U.S. Numerous studies have shown an inverse relationship between insulin resistance and testosterone levels in men, however, causality has not been established. This protocol investigates the role of testosterone in modulating insulin sensitivity in insulin resistant states such as the metabolic syndrome. The hypothesis is that testosterone administration will improve insulin sensitivity.

Condition or Disease	Intervention/Treatment	Phase
Metabolic Syndrome	Procedure: intravenous glucose tolerance test Drug: testosterone Drug: anastrozole Drug: goserelin acetate implant Procedure: aerobic capacity (VO2 Max) Procedure: MRI Procedure: muscle biopsy Procedure: measurement of resting metabolic rate (energy expenditure) Procedure: Dual energy x-ray absorptiometry Procedure: Fasting oral glucose tolerance test	N/A

Detailed Description

This protocol will address the impact of three months of testosterone (T) therapy on all components of the metabolic syndrome and the mechanism underlying changes in insulin sensitivity by analyzing changes in body composition, and detailed studies of fat metabolism and skeletal muscle. In addition, this protocol will address the role of estradiol (E2) in mediating the effect of testosterone on insulin sensitivity.

Seventy-two subjects will be enrolled. Study subjects will undergo a screening visit to assess eligibility after which a baseline metabolic assessment will be performed including a a fasting oral glucose tolerance test (OGTT) to measure normal glucose and insulin metabolism, an intravenous glucose tolerance test (IVGTT) to measure insulin sensitivity, MRI and DEXA scan to assess muscle and body fat distribution, VO2 max test and resting metabolic rate, and a muscle biopsy to look at how the muscle is affected by insulin and testosterone (T).

Subjects will then be randomized to one of three 12-week treatment arms, 1) Group 1 (Placebo); 2) Group 2 (Depot GnRH agonist (Zoladex) + Testosterone + placebo); or 3) Group 3 (Zoladex + Testosterone + aromatase inhibitor (anastrozole)). The rationale for this study design is as follows. Under normal physiological conditions, administration of T leads to a concomitant increase in estradiol (E2) levels due to endogenous conversion by the aromatase enzyme system. Therefore, in order to understand the relative roles of T and E2 on insulin sensitivity, one group of subjects will receive T in conjunction with the aromatase inhibitor, anastrozole.

At 13 weeks, the entire baseline evaluation including OGTT, IVGTT, resting metabolic rate and VO2 max, body composition assessment by DEXA and MRI, and muscle biopsy will be repeated. Subjects will return for a follow up visit four weeks later to measure CBC, T and PSA levels, to ensure levels are within the normal range.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

72 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Effect of Increasing Testosterone on Insulin Sensitivity in Men With the Metabolic Syndrome

Study Start Date :

May 1, 2006

Anticipated Primary Completion Date :

Feb 1, 2011

Anticipated Study Completion Date :

Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1 1) Group 1: Placebo	Procedure: intravenous glucose tolerance test The IVGTT (70) is a 4 hour study with baseline sampling for insulin and glucose, followed by the administration of 0.3 mg/kg infusion of glucose, and subsequent frequent samples through 180 minutes. At 20 minutes, subjects will receive a 0.03 U/kg infusion of regular human insulin over 45 seconds to enhance the insulin level to better help us assess the impact of insulin on glucose uptake and to facilitate minimal model analysis. The IVGTT will be administered at baseline and after 3 months. Other Names: IVGTT Procedure: aerobic capacity (VO2 Max) This test is employed to assess VO2max in all subjects. O2 and CO2 will be collected and measured from the expired air during the exercise stress test and used to calculate VO2max. This test will be administered at baseline and after 3 months. Procedure: MRI 1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months. Procedure: muscle biopsy Biopsies (20-50mg) will be obtained from the vastus lateralis muscle under local anesthesia (1% lidocaine) using a 5 mm Bergström needle (65) with suction applied. The muscle biopsy will be performed at baseline and after 3 months. Procedure: measurement of resting metabolic rate (energy expenditure) Energy expenditure in the form of resting metabolic rate (RMR) will be measured via a metabolic monitor at baseline and after 3 months. Procedure: Dual energy x-ray absorptiometry Total and regional percent body fat, fat mass, lean tissue mass and bone mineral content will be determined by DEXA (Lunar Prodigy version 8.50). DEXA provides an in vivo assessment of body composition with minimal requirements for subject cooperation and will be employed at baseline and after 3 months. Other Names: DEXA Procedure: Fasting oral glucose tolerance test To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months. Other Names: OGTT
Active Comparator: 2 2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo	Procedure: intravenous glucose tolerance test The IVGTT (70) is a 4 hour study with baseline sampling for insulin and glucose, followed by the administration of 0.3 mg/kg infusion of glucose, and subsequent frequent samples through 180 minutes. At 20 minutes, subjects will receive a 0.03 U/kg infusion of regular human insulin over 45 seconds to enhance the insulin level to better help us assess the impact of insulin on glucose uptake and to facilitate minimal model analysis. The IVGTT will be administered at baseline and after 3 months. Other Names: IVGTT Drug: testosterone transdermal 7.5 g/per day for 3 months Other Names: Androgel 1% Drug: goserelin acetate implant single depot injection 10.8 mg 3 months Other Names: Zoladex Procedure: aerobic capacity (VO2 Max) This test is employed to assess VO2max in all subjects. O2 and CO2 will be collected and measured from the expired air during the exercise stress test and used to calculate VO2max. This test will be administered at baseline and after 3 months. Procedure: MRI 1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months. Procedure: muscle biopsy Biopsies (20-50mg) will be obtained from the vastus lateralis muscle under local anesthesia (1% lidocaine) using a 5 mm Bergström needle (65) with suction applied. The muscle biopsy will be performed at baseline and after 3 months. Procedure: measurement of resting metabolic rate (energy expenditure) Energy expenditure in the form of resting metabolic rate (RMR) will be measured via a metabolic monitor at baseline and after 3 months. Procedure: Dual energy x-ray absorptiometry Total and regional percent body fat, fat mass, lean tissue mass and bone mineral content will be determined by DEXA (Lunar Prodigy version 8.50). DEXA provides an in vivo assessment of body composition with minimal requirements for subject cooperation and will be employed at baseline and after 3 months. Other Names: DEXA Procedure: Fasting oral glucose tolerance test To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months. Other Names: OGTT
Active Comparator: 3 3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)	Procedure: intravenous glucose tolerance test The IVGTT (70) is a 4 hour study with baseline sampling for insulin and glucose, followed by the administration of 0.3 mg/kg infusion of glucose, and subsequent frequent samples through 180 minutes. At 20 minutes, subjects will receive a 0.03 U/kg infusion of regular human insulin over 45 seconds to enhance the insulin level to better help us assess the impact of insulin on glucose uptake and to facilitate minimal model analysis. The IVGTT will be administered at baseline and after 3 months. Other Names: IVGTT Drug: testosterone transdermal 7.5 g/per day for 3 months Other Names: Androgel 1% Drug: anastrozole tablet (per oral) 10.0 mg/ daily 3 months Other Names: arimidex IND# 76,878 Drug: goserelin acetate implant single depot injection 10.8 mg 3 months Other Names: Zoladex Procedure: aerobic capacity (VO2 Max) This test is employed to assess VO2max in all subjects. O2 and CO2 will be collected and measured from the expired air during the exercise stress test and used to calculate VO2max. This test will be administered at baseline and after 3 months. Procedure: MRI 1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months. Procedure: muscle biopsy Biopsies (20-50mg) will be obtained from the vastus lateralis muscle under local anesthesia (1% lidocaine) using a 5 mm Bergström needle (65) with suction applied. The muscle biopsy will be performed at baseline and after 3 months. Procedure: measurement of resting metabolic rate (energy expenditure) Energy expenditure in the form of resting metabolic rate (RMR) will be measured via a metabolic monitor at baseline and after 3 months. Procedure: Dual energy x-ray absorptiometry Total and regional percent body fat, fat mass, lean tissue mass and bone mineral content will be determined by DEXA (Lunar Prodigy version 8.50). DEXA provides an in vivo assessment of body composition with minimal requirements for subject cooperation and will be employed at baseline and after 3 months. Other Names: DEXA Procedure: Fasting oral glucose tolerance test To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months. Other Names: OGTT

Arm

Intervention/Treatment

Placebo Comparator: 1

1) Group 1: Placebo

Procedure: intravenous glucose tolerance test

The IVGTT (70) is a 4 hour study with baseline sampling for insulin and glucose, followed by the administration of 0.3 mg/kg infusion of glucose, and subsequent frequent samples through 180 minutes. At 20 minutes, subjects will receive a 0.03 U/kg infusion of regular human insulin over 45 seconds to enhance the insulin level to better help us assess the impact of insulin on glucose uptake and to facilitate minimal model analysis. The IVGTT will be administered at baseline and after 3 months.

Other Names:

IVGTT

Procedure: aerobic capacity (VO2 Max)

This test is employed to assess VO2max in all subjects. O2 and CO2 will be collected and measured from the expired air during the exercise stress test and used to calculate VO2max. This test will be administered at baseline and after 3 months.

Procedure: MRI

1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months.

Procedure: muscle biopsy

Biopsies (20-50mg) will be obtained from the vastus lateralis muscle under local anesthesia (1% lidocaine) using a 5 mm Bergström needle (65) with suction applied. The muscle biopsy will be performed at baseline and after 3 months.

Procedure: measurement of resting metabolic rate (energy expenditure)

Energy expenditure in the form of resting metabolic rate (RMR) will be measured via a metabolic monitor at baseline and after 3 months.

Procedure: Dual energy x-ray absorptiometry

Total and regional percent body fat, fat mass, lean tissue mass and bone mineral content will be determined by DEXA (Lunar Prodigy version 8.50). DEXA provides an in vivo assessment of body composition with minimal requirements for subject cooperation and will be employed at baseline and after 3 months.

Other Names:

DEXA

Procedure: Fasting oral glucose tolerance test

To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months.

Other Names:

OGTT

Active Comparator: 2

2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo

Procedure: intravenous glucose tolerance test

Other Names:

IVGTT

Drug: testosterone

transdermal 7.5 g/per day for 3 months

Other Names:

Androgel 1%

Drug: goserelin acetate implant

single depot injection 10.8 mg 3 months

Other Names:

Zoladex

Procedure: aerobic capacity (VO2 Max)

Procedure: MRI

1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months.

Procedure: muscle biopsy

Procedure: measurement of resting metabolic rate (energy expenditure)

Energy expenditure in the form of resting metabolic rate (RMR) will be measured via a metabolic monitor at baseline and after 3 months.

Procedure: Dual energy x-ray absorptiometry

Other Names:

DEXA

Procedure: Fasting oral glucose tolerance test

To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months.

Other Names:

OGTT

Active Comparator: 3

3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)

Procedure: intravenous glucose tolerance test

Other Names:

IVGTT

Drug: testosterone

transdermal 7.5 g/per day for 3 months

Other Names:

Androgel 1%

Drug: anastrozole

tablet (per oral) 10.0 mg/ daily 3 months

Other Names:

arimidex

IND# 76,878

Drug: goserelin acetate implant

single depot injection 10.8 mg 3 months

Other Names:

Zoladex

Procedure: aerobic capacity (VO2 Max)

Procedure: MRI

1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months.

Procedure: muscle biopsy

Procedure: measurement of resting metabolic rate (energy expenditure)

Energy expenditure in the form of resting metabolic rate (RMR) will be measured via a metabolic monitor at baseline and after 3 months.

Procedure: Dual energy x-ray absorptiometry

Other Names:

DEXA

Procedure: Fasting oral glucose tolerance test

To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months.

Other Names:

OGTT

Outcome Measures

Primary Outcome Measures

insulin sensitivity [at baseline and after 3 months]

Secondary Outcome Measures

glucose metabolism [at baseline and after 3 months]
body composition VO2 max; resting metabolic rate; muscle biopsy analysis [at baseline and after 3 months]
VO2 max [at baseline and after 3 months]
resting metabolic rate [at baseline and after 3 months]
muscle biopsy analysis [at baseline and after 3 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years to 75 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 50-75 yr
Diagnosis of the metabolic syndrome defined by the American Heart Association/National Heart, Lung, and Blood Institute guidelines as the presence of three or more of the following:
Waist circumference > 102 cm
Serum triglycerides > 150 mg/dL
HDL cholesterol < 40 mg/dL
Blood pressure > 130 mm Hg systolic or 85 mm Hg diastolic, or treatment with anti-hypertensives
Fasting serum glucose > 100 mg/dL
Plasma total testosterone level less than 300 ng/dL (1 SD below the mean for young healthy men)
Stable weight for previous three months (no weight change greater than or equal to +/-10 lbs)
Normal TSH, prolactin and prostate specific antigen (PSA) levels (<2.5 ng/mL)

Exclusion Criteria:

New diagnosis of type 2 diabetes as defined by the ADA criteria: fasting glucose greater than 126 mg/dL or random blood glucose greater than 200 mg/dL on two occasions, or on oral hypoglycemic agents
Contraindication to stress testing
Contraindication to MRI scanning (Central nervous system aneurysm clips; Implanted neural stimulator; Implanted cardiac pacemaker or defibrillator; Cochlear implant; Ocular foreign body (e.g. metal shavings); Insulin pump; Metal shrapnel or bullet)
History of testicular disorders (i.e. cryptorchidism)
History of bleeding disorders (i.e. thrombocytopenia) or baseline hemoglobin levels less than 12g/dL
History of metabolic bone disease (osteoporosis, osteomalacia)
History of prostate cancer
History of sleep apnea (subjects will also be excluded if at their baseline assessment they admit to heavy snoring, restless sleep, and/or excessive daytime somnolence)
Symptoms of urinary outflow obstruction (i.e. benign prostatic hypertrophy)
Illicit drug use or heavy alcohol use (>4 drinks/day)
Allergic disorders
Current medications (must exclude individuals taking the following medications):
Testosterone,
Cimetidine,
Spironolactone,
Ketoconazole,
Finasteride,
DHEA,
Androstenedione,
Oral steroids,
GnRH analogs