Insulin Sensitivity in Men With the Metabolic Syndrome

Metabolic Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT00433173
• Other study ID #: DK71168 (suspended)
• Secondary ID: NIDDK # 1 RO1 DK
• Status: Suspended
• Phase: N/A
• First received: February 8, 2007
• Last updated: March 1, 2010
• Start date: May 2006
• Est. completion date: March 2011

Study information

• Verified date: March 2010
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 72
• Est. completion date: March 2011
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 50 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Insulin Resistance
• Metabolic Syndrome
• Metabolic Syndrome X
• Syndrome

Intervention

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.

Drug:
• testosterone
transdermal 7.5 g/per day for 3 months
• anastrozole
tablet (per oral) 10.0 mg/ daily 3 months
• goserelin acetate implant
single depot injection 10.8 mg 3 months

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.
• MRI
1H-MR spectroscopy will be performed to measure IMCL at baseline and after 3 months.
• 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.
• 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.
• 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.
• Fasting oral glucose tolerance test
To examine glucose and insulin metabolism a standard 75g OGTT will be conducted at baseline and after 3 months.

Locations

Country	Name	City	State
United States	Johns Hopkins Bayview Medical Center	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	American Diabetes Association

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	insulin sensitivity		at baseline and after 3 months	No
Secondary	glucose metabolism		at baseline and after 3 months	No
Secondary	body composition VO2 max; resting metabolic rate; muscle biopsy analysis		at baseline and after 3 months	No
Secondary	VO2 max		at baseline and after 3 months	No
Secondary	resting metabolic rate		at baseline and after 3 months	No
Secondary	muscle biopsy analysis		at baseline and after 3 months	No