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Insulin Sensitivity in Men With the Metabolic Syndrome

Primary Purpose

Metabolic Syndrome

Status

Suspended

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

intravenous glucose tolerance test

testosterone

anastrozole

goserelin acetate implant

aerobic capacity (VO2 Max)

MRI

muscle biopsy

measurement of resting metabolic rate (energy expenditure)

Dual energy x-ray absorptiometry

Fasting oral glucose tolerance test

About this trial

This is an interventional treatment trial for Metabolic Syndrome focused on measuring testosterone, insulin sensitivity, insulin resistance, metabolic disorders

Eligibility Criteria

50 Years - 75 Years (Adult, Older Adult)MaleDoes not accept 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

Sites / Locations

Johns Hopkins Bayview Medical Center
Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Arm Description

1) Group 1: Placebo

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

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

Outcomes

Primary Outcome Measures

insulin sensitivity

Secondary Outcome Measures

glucose metabolism

body composition VO2 max; resting metabolic rate; muscle biopsy analysis

VO2 max

resting metabolic rate

muscle biopsy analysis

Full Information

NCT ID

NCT00433173

First Posted

February 8, 2007

Last Updated

March 1, 2010

Sponsor

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

Collaborators

American Diabetes Association

1. Study Identification

Unique Protocol Identification Number

NCT00433173

Brief Title

Insulin Sensitivity in Men With the Metabolic Syndrome

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2010

Overall Recruitment Status

Suspended

Why Stopped

Primary investigator is taking a leave of absence

Study Start Date

May 2006 (undefined)

Primary Completion Date

February 2011 (Anticipated)

Study Completion Date

March 2011 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

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

Collaborators

American Diabetes Association

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

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

Metabolic Syndrome

Keywords

testosterone, insulin sensitivity, insulin resistance, metabolic disorders

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Placebo Comparator

Arm Description

1) Group 1: Placebo

Arm Title

Arm Type

Active Comparator

Arm Description

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

Arm Title

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Procedure

Intervention Name(s)

intravenous glucose tolerance test

Other Intervention Name(s)

IVGTT

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

testosterone

Other Intervention Name(s)

Androgel 1%

Intervention Description

transdermal 7.5 g/per day for 3 months

Intervention Type

Drug

Intervention Name(s)

anastrozole

Other Intervention Name(s)

arimidex, IND# 76,878

Intervention Description

tablet (per oral) 10.0 mg/ daily 3 months

Intervention Type

Drug

Intervention Name(s)

goserelin acetate implant

Other Intervention Name(s)

Zoladex

Intervention Description

single depot injection 10.8 mg 3 months

Intervention Type

Procedure

Intervention Name(s)

aerobic capacity (VO2 Max)

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

MRI

Intervention Description

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

Intervention Type

Procedure

Intervention Name(s)

muscle biopsy

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

measurement of resting metabolic rate (energy expenditure)

Intervention Description

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

Intervention Type

Procedure

Intervention Name(s)

Dual energy x-ray absorptiometry

Other Intervention Name(s)

DEXA

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

Fasting oral glucose tolerance test

Other Intervention Name(s)

OGTT

Intervention Description

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

Primary Outcome Measure Information:

Title

insulin sensitivity

Time Frame