Insulin Sensitivity in Men With the Metabolic Syndrome

This study has suspended participant recruitment.
(Primary investigator is taking a leave of absence)
Sponsor:
Collaborator:
American Diabetes Association
Information provided by:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT00433173
First received: February 8, 2007
Last updated: March 1, 2010
Last verified: March 2010
  Purpose

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 Intervention
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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Increasing Testosterone on Insulin Sensitivity in Men With the Metabolic Syndrome

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • insulin sensitivity [ Time Frame: at baseline and after 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • glucose metabolism [ Time Frame: at baseline and after 3 months ] [ Designated as safety issue: No ]
  • body composition VO2 max; resting metabolic rate; muscle biopsy analysis [ Time Frame: at baseline and after 3 months ] [ Designated as safety issue: No ]
  • VO2 max [ Time Frame: at baseline and after 3 months ] [ Designated as safety issue: No ]
  • resting metabolic rate [ Time Frame: at baseline and after 3 months ] [ Designated as safety issue: No ]
  • muscle biopsy analysis [ Time Frame: at baseline and after 3 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 72
Study Start Date: May 2006
Estimated Study Completion Date: March 2011
Estimated Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 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 Name: IVGTT
Drug: testosterone
transdermal 7.5 g/per day for 3 months
Other Name: Androgel 1%
Drug: goserelin acetate implant
single depot injection 10.8 mg 3 months
Other Name: 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 Name: 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 Name: 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 Name: IVGTT
Drug: testosterone
transdermal 7.5 g/per day for 3 months
Other Name: 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 Name: 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 Name: 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 Name: OGTT

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.

  Eligibility

Ages Eligible for Study:   50 Years to 75 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00433173

Locations
United States, Maryland
Johns Hopkins Bayview Medical Center
Baltimore, Maryland, United States, 21224
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
American Diabetes Association
Investigators
Principal Investigator: Frances J Hayes, MD Massachusetts General Hospital
  More Information

No publications provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Frances J. Hayes, MD, Massachusetts General Hospital, Boston MA 02114
ClinicalTrials.gov Identifier: NCT00433173     History of Changes
Other Study ID Numbers: DK71168 (suspended), NIDDK # 1 RO1 DK071168-01A2
Study First Received: February 8, 2007
Last Updated: March 1, 2010
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
testosterone
insulin sensitivity
insulin resistance
metabolic disorders

Additional relevant MeSH terms:
Metabolic Syndrome X
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Methyltestosterone
Goserelin
Anastrozole
Insulin, Globin Zinc
Insulin
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Anabolic Agents
Hypoglycemic Agents
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2014