Insulin Sensitivity in Men With the Metabolic Syndrome

Condition(s) targeted: Metabolic Syndrome

Intervention: intravenous glucose tolerance test (Procedure); testosterone (Drug); anastrozole (Drug); goserelin acetate implant (Drug); 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 (Procedure)

Phase: N/A

Status: Recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Official(s) and/or principal investigator(s):
Frances J Hayes, MD, Principal Investigator, Affiliation: Massachusetts General Hospital, Boston, MA

Overall contact:
Andrew A Dwyer, RN, MSN, Phone: 617-726-8622, Email: adwyer@partners.org

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.

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

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: insulin sensitivity

Secondary outcome:

glucose metabolism

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

VO2 max

resting metabolic rate

muscle biopsy analysis

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.

Minimum age: 50 Years. Maximum age: 75 Years. Gender(s): Male.

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

Andrew A Dwyer, RN, MSN, Phone: 617-726-8622, Email: adwyer@partners.org

Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224, United States; Not yet recruiting
Dariush Elahi, PhD, Phone: 410-550-4395, Email: delahi1@jhmi.edu
Dariush Elahi, PhD, Principal Investigator

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Recruiting
Andrew Dwyer, RN, NP, Phone: 617-726-8622, Email: Adwyer@partners.org
Frances J Hayes, MD, Principal Investigator
Andrew A Dwyer, RN, NP, Sub-Investigator

Starting date: May 2006
Ending date: March 2011
Last updated: June 19, 2008