Aging, Hypogonadism, Insulin Resistance, Obesity
Conditions
Keywords
Aging, Older men, Abdominal obesity, Central obesity, Insulin resistance, Low testosterone
Brief summary
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.
Detailed description
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.
Interventions
DRUGTopical testosterone gel 10 g/day
Testosterone gel therapy for 20 weeks
Sponsors
Solvay Pharmaceuticals
University of Southern California
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
No masking. This was an open label (un-blinded)
Eligibility
Sex/Gender
MALE
Age
60 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
* Entry Criteria: * Men \> 60 years of age * Total testosterone \< 300 ng/dL * Waist circumference \>102 cm * Fasting insulin level \> 18 U/L
Exclusion criteria
* PSA \> 4.1, symptoms of obstructive uropathy (AUA score \> 14), unexplained prostate nodule or gland firmness * Hematocrit \> 50% * Malignancy other than cutaneous cancers * Sleep apnea requiring CPAP * History of myocardial infarction, angina or stroke within the previous 6 months * Clinical diagnosis of diabetes or FPG \> 126 mg/dL * Hypothyroidism not controlled to euthyroid levels with medication for at least 3 months * LDL-C \>160 mg/dL * Transaminases \> 1.5X ULN * Systemic anticoagulation with warfarin * Active progressive resistance training * Dieting for weight loss * Active inflammatory condition (e.g. rheumatoid arthritis) * Use of any anabolic agent (e.g. growth hormone, testosterone precursor, anabolic steroid)or cytokine therapy in the proceeding 12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Mass and Regional Adipose Adiposiy | Baseline to 20 weeks | Change in total body mass, total fat mass, trunk fat, and extremity fat |
| Change in Hepatic Lipid | Baseline to week 20 | 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. |
| Intramyocellular Lipid (IMCL) | Baseline to week 20 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Lipids | Baseline to week 20 | — |
| Change in HOMA-IR | Baseline to week 20 | HOMA-IR is a measure of insulin resistance |
| Change in Percentage of Total Body Fat | Baseline and 20 weeks | Percentage of total body fat is quantified by DEXA scanning |
| Change in Plasma Free Fatty Acids During Glucose Clamp | Baseline to 20 weeks | — |
| Change in Basal FFAs in Plasma | Baseline to week 20 | FFA (plasma free fatty acids) are measure of lipid metabolism |
| 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]) | Baseline and 20 weeks | 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. |
| Change in Skeletal Muscle Mass by DEXA | Baselne to 20 weeks | Skeletal muscle mass was assesed by regional DEXA to quantify appendicular lean tissues which is primarily muscle. |
Countries
United States
Participant flow
Recruitment details
Potential subjects were primarily recruited from 2011 to 2013 and were evaluated and studied at the University of Southern California CTSI Clinical Trials Unit. 22 subjects met all eligibility requirements and begun study therapy with testosterone gel. Two did not complete treatment. Thus, 20 completed all evaluations as planned.
Pre-assignment details
Consenting subjects were evaluated for eligibility and had to be: Men 60 years-or-older, with morning testosterone \<400ng/dL, waist circumference ≥102cm, and evidence of insulin resistance; HgbA1c of 5.7-6.4% \[20\] or HOMA-IR ≥4.0. Exclusion criteria included diabetes, PSA ≥4.0μg/L, hct ≥50%, AST ≥2X ULN, concurrent inflammatory condition.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm open label treatment with testosterone gel | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Single Arm |
|---|---|
| Age, Continuous | 67.5 years |
| AM total testosterone level | 10.6 nmoles/liter |
| Basal free fatty acids | 0.35 mEq/L |
| blood panels Fasting triglycerides | 1.59 mmole/liter |
| blood panels HDL cholesterol | 1.06 mmole/liter |
| blood panels LDL cholesterol | 3.11 mmole/liter |
| blood panels total cholesterol | 4.61 mmole/liter |
| Body compotion Extremity fat mass | 12.9 kilograms |
| Body compotion Extremity lean mass | 29.1 kilograms |
| Body compotion Total body mass | 104.5 kilograms |
| Body compotion Total fat mass | 34.6 kilograms |
| Body compotion Total lean body mss | 64.3 kilograms |
| Body compotion Trunk fat mass | 19.3 kilograms |
| Change in glucose clamp free fatty acids over 0 to 4 hours | 0.30 grams |
| Hepatic lipid | 0.11 ratio |
| HOMA-IR | 3.55 microU/L) x fasting glucose (nmol/L)/22. |
| Insulin senstivity Hepatic glucose output | 2.89 dL/min per μU/mL; |
| Insulin senstivity Rate of glucose disposal | 2.93 dL/min per μU/mL; |
| Insulin senstivity Whole body insulin sensivity | 2.93 dL/min per μU/mL; |
| Intramyocellular lipid (IMCL) | 5.8 ratio |
| Patient history at enrollment Family history of diabetes | 4 Participants |
| Patient history at enrollment On Rx for hypertension | 10 Participants |
| Patient history at enrollment On Rx for lipid disorder | 12 Participants |
| Patient history at enrollment Smoking currently | 0 Participants |
| Patient history at enrollment Smoking ever | 14 Participants |
| Percentage of body fat | 31.5 percentage |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
| waist circumference | 114 centimeters |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 1 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
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
Population: Data not available for one subject
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Change in Hepatic Lipid | -36 ratio |
p-value: 0.12t-test, 2 sided
Primary
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
Population: Data for one participant was not available
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Single Arm | Change in Total Mass and Regional Adipose Adiposiy | Total body mass | 0.3 kilograms |
| Single Arm | Change in Total Mass and Regional Adipose Adiposiy | Total fat mass | -1.4 kilograms |
| Single Arm | Change in Total Mass and Regional Adipose Adiposiy | Trunk fat mass | -0.9 kilograms |
| Single Arm | Change in Total Mass and Regional Adipose Adiposiy | Extremity fat mass | -0.7 kilograms |
Comparison: Total body massp-value: 0.77t-test, 2 sided
Comparison: Total fat massp-value: 0.003t-test, 2 sided
Comparison: Statistical analysis is for change in trunk fat mass after 20 weeks of testosterone gel.p-value: 0.0007t-test, 2 sided
Comparison: Statistical analysis is for change in extremity fat mass after 20 weeks of testosterone gel.p-value: 0.01t-test, 2 sided
Primary
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
Population: data not available for 5 subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Intramyocellular Lipid (IMCL) | -30 ratio |
p-value: 0.008t-test, 2 sided
Secondary
Change in Basal FFAs in Plasma
FFA (plasma free fatty acids) are measure of lipid metabolism
Time frame: Baseline to week 20
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Change in Basal FFAs in Plasma | -0.1 mEq/L |
p-value: 0.97t-test, 2 sided
Secondary
Change in HOMA-IR
HOMA-IR is a measure of insulin resistance
Time frame: Baseline to week 20
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Change in HOMA-IR | -0.75 microU/L) x fasting glucose (nmol/L)/22 |
p-value: 0.06t-test, 2 sided
Secondary
Change in Percentage of Total Body Fat
Percentage of total body fat is quantified by DEXA scanning
Time frame: Baseline and 20 weeks
Population: Data not available for one subject
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Change in Percentage of Total Body Fat | -1.6 percentage of total body fat |
p-value: 0.0002t-test, 2 sided
Secondary
Change in Plasma Free Fatty Acids During Glucose Clamp
Time frame: Baseline to 20 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Change in Plasma Free Fatty Acids During Glucose Clamp | -0.1 grams |
p-value: 0.83t-test, 2 sided
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm | Change in Skeletal Muscle Mass by DEXA | 1.2 kilograms |
Comparison: Change in DEXA extremity (appendicular) lean tissue, a measure of extremity muscle mass after 20 weeks ot treatent with testosterone gel.p-value: 0.0006t-test, 2 sided
Secondary
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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Single Arm | 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]) | Whole body insulin sensitiity | 1.05 dL/min per μU/mL |
| Single Arm | 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]) | hepaic glucose output (HGO) | -0.16 dL/min per μU/mL |
| Single Arm | 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]) | peripheral glucose disposal (Rd) | 1.16 dL/min per μU/mL |
Comparison: Statistical analysis for change in whole body insulin sensitivity after treatment with testosterone gel for 20 weeks.p-value: 0.04t-test, 2 sided
Comparison: Statistical analysis for change in hepatic glucose output (measure of central insulin sensitivity) after treatment with testosterone gel for 20 weeksp-value: 0.59t-test, 2 sided
Comparison: Statistical analysis for change in rate of peripheral glucose disposal (test of peripheral insulin sensitivity) after treatment with testosterone gel for 20 weeksp-value: 0.03t-test, 2 sided
Secondary
Plasma Lipids
Time frame: Baseline to week 20
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Single Arm | Plasma Lipids | Fasting triglycerides | -0.33 mg/dL |
| Single Arm | Plasma Lipids | Total cholesterol | -0.52 mg/dL |
| Single Arm | Plasma Lipids | LDL cholesterol | -0.23 mg/dL |
| Single Arm | Plasma Lipids | HDL cholesterol | -0.10 mg/dL |
Comparison: A change in 20 plasma lipids (fasting triglycerides and lipid fractions) after 20 weeks of treatment with testosterone gel.p-value: 0.02t-test, 2 sided
Comparison: A change in 20 plasma lipids (fasting triglycerides and lipid fractions) after 20 weeks of treatment with testosterone gelp-value: 0.004t-test, 2 sided
Comparison: nts A change in 20 plasma lipids (fasting triglycerides and lipid fractions) after 20 weeks of treatment with testosterone gelp-value: 0.02t-test, 2 sided
Comparison: A change in 20 plasma lipids (fasting triglycerides and lipid fractions) after 20 weeks of treatment with testosterone gelp-value: 0.004t-test, 2 sided