A. HYPOTHESES: In older men low testosterone levels, abdominal obesity and elevated fasting insulin who are at risk for the cardiovascular complications such as heart attack and stroke. 1. Supplemental testosterone will decrease abdominal adipose tissue and hepatic fat) and appendicular fat and intramyocellular lipid in peripheral muscles (IMCL). 2. Supplemental testosterone will improve insulin sensitivity by: 1. Decreasing hepatic glucose output (HGO), a measure of central insulin resistance 2. increasing peipheral glucose disposal (Rd), a measure of periperal insuln sensiivity 3. . Improving peripheral glucose disposal (Rd) by reducing IMCL 4. Increasing appendicular skeletal muscle mass B. OBJECTIVES: 1. Primary Objective: To determine the effects of supplemental testosterone to achieve testosterone levels in the upper normal physiologic range on central adipose tissue (abdominal and hepatic fat) and peripheral skeletal muscle fat (appendicular fat and IMCL). 2. Secondary Objectives: To determine the effects of supplemental testosterone to achieve testosterone levels in the upper normal physiologic range:on central insulin sensitivity ( hepatic glucose output (\[HGO\]) and peripheral insulin sensitivity (glucose disposal (Rd) Results of this study will provide greater understanding whether androgen therapy enhances insulin sensitivity by decreasing HGO, improving peripheral Rd and if these desired effects are achieved, whether they are due to reductions in abdominal fat or liver lipid, IMCL or effects of augmenting muscle mass per se. Results will generate hypotheses to investigate cellular and molecular mechanisms of androgen effects in persons at risk for the Metabolic Syndrome.
Study Design: This is an investigator-initiated open label, study to investigate the effects of supplemental testosterone (gel formulation) to increase testosterone levels to the upper normal range in 12 older hypogonadal (testosterone levels less than 300 ng/dL) men with abdominal obesity and elevated fasting insulin levels. Subjects will be assigned to receive 10 g of transdermal testosterone (Androgel) every morning to achieve levels in the upper normal physiologic range (similar to men in the 3rd and 4th decades) for 20 weeks. * For the primary objective, regional adipose tissue, namely DEXA measures of abdominal and appendicular fat mass and hepatic fat, and IMCL will be quantified by 1H-spectroscopy at baseline (study week 0) and at study week 20 (completion of study therapy). * For the secondary objective, insulin sensitivity (peripheral Rd, hepatic glucose output \[HGO\]) and hepatic gluconeogenesis will be measured directly during a two stage hyperinsulinemic euglycemic clamp at baseline and study week 20. * Indirect markers of lipid (adiponectin, ApoB 100) and carbohydrate metabolism (Fasting blood sugar, HOMA-IR) at study week 10, and study week 20. All components of the study will be conducted in the USC NIH-funded (NCRR), General Clinical Research Center.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Testosterone gel therapy for 20 weeks
LAC-USC Medical Center GCRC
Los Angeles, California, United States
Change in Total Mass and Regional Adipose Adiposiy
Change in total body mass, total fat mass, trunk fat, and extremity fat
Time frame: Baseline to 20 weeks
Change in Hepatic Lipid
Amount of liver fat is highly predictive of insulin resistance. Hepatic fat is measured by MR spectroscopy and adjusted for H2O and results are reported as ratio of these two.
Time frame: Baseline to week 20
Intramyocellular Lipid (IMCL)
IMCL is quantified by MR spectroscopy of the anterior tibialis muscle of the leg. The value is adjusted for creatine and reported as a ratio
Time frame: Baseline to week 20
Change in Percentage of Total Body Fat
Percentage of total body fat is quantified by DEXA scanning
Time frame: Baseline and 20 weeks
Change in Total and Regional Carbohydrate Metabolism During a 2-hr Hyperinsulinemic Euglycemic Clamp and [6,6-2H2] Glucose Studies (Peripheral Glucose Disposal [Rd],Hepatic Glucose Output [HGO])
In the final analysis, total and regional carbohydrate metabolism during a 2-hr hyperinsulinemic euglycemic clamp (peripheral glucose disposal \[Rd\],hepatic glucose output \[HGO\]) were analyzed by mass transfer of glucose during both stages of the clamp relative to insulin levels.
Time frame: Baseline and 20 weeks
Change in Skeletal Muscle Mass by DEXA
Skeletal muscle mass was assesed by regional DEXA to quantify appendicular lean tissues which is primarily muscle.
Time frame: Baselne to 20 weeks
Plasma Lipids
Time frame: Baseline to week 20
Change in HOMA-IR
HOMA-IR is a measure of insulin resistance
Time frame: Baseline to week 20
Change in Basal FFAs in Plasma
FFA (plasma free fatty acids) are measure of lipid metabolism
Time frame: Baseline to week 20
Change in Plasma Free Fatty Acids During Glucose Clamp
Time frame: Baseline to 20 weeks
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