Testosterone Replacement in Men With Diabetes and Obesity

Hypogonadotropic hypogonadism (HH) occurs in approximately one-third of obese and type 2
diabetic men. Considering that there are 24 million diabetic and 100 million obese people,
of which half are males, obesity and type 2 diabetes potentially constitute the major cause
of hypogonadism in the population. We hypothesize that 1) HH in obese and type 2 diabetic
men is associated with decreased insulin sensitivity, increased fat tissue mass, decreased
lean body mass, increased inflammatory and oxidative stress, impaired sexual function and
depressed mood as compared to diabetic and obese men with normal testosterone
concentrations; and that 2) testosterone replacement for 24 weeks in men with HH leads to an
improvement in these parameters. Our proposed study would be the first prospective,
randomized trial to comprehensively evaluate the effect of HH on insulin sensitivity, body
composition, inflammatory and oxidative indices in obese and type 2 diabetic subjects and
the effect of six months of T replacement on these parameters. The study will have 2 arms
(obese and type 2 diabetic arm) with 120 subjects in Diabetes arm and 80 subjects in obese
arm. Half of men in each arm will have HH and half men will have normal testosterone
concentrations(eugonadal men). Insulin sensitivity will be assessed by
hyperinsulinemic-euglycemic clamps. Subcutaneous fat mass and lean body mass will be
measured by DEXA and intra-abdominal (visceral) fat mass by MRI. All subjects will undergo
hyperinsulinemic-euglycemic clamp, MRI, DEXA and give blood and urine samples (for
measurement of inflammatory and oxidative stress) at baseline. Men with HH will then be
randomized to receive testosterone or placebo gel for a total of 24 weeks. These men will
undergo hyperinsulinemic-euglycemic clamps and give blood and urine samples for inflammation
and oxidative stress at 4 weeks and 24 weeks. MRI and DEXA examinations will be carried out
at 24 weeks again in men with HH. The primary endpoint of the study is to define a
difference in whole body glucose uptake during hyperinsulinemic-euglycemic clamps between
hypogonadal and eugonadal diabetes patients at baseline and an increase in glucose uptake in
HH subjects after treatment with testosterone for 24 weeks. 30 subjects per
group(testosterone and placebo gel each) will provide adequate power (0.8) to detect a
significant difference of 10% in whole body glucose uptake. Therefore there will be 60 men
with HH in each arm in diabetes group. For baseline comparisons, 60 men with normal
testosterone concentrations will also be needed in each arm. We will recruit 40 obese
patients in each arm. Thus there will be 120 diabetic men and 80 obese men in the study.

Inclusion Criteria:

- T2D arm: Males with age 30-65 years

- Obese non-diabetic arm: Obese non-diabetic males with age 30-65 years

Exclusion Criteria:

1)Coronary event or procedure(myocardial infarction, unstable angina, coronary artery
bypass, surgery or coronary angioplasty) in the previous twelve weeks; 2) PSA > 4ng/ml;
3)Hemoglobin A1c > 8%; 4)h/o prostate carcinoma; 5)Hepatic disease (transaminase > 3 times
normal) or cirrhosis; 6)Renal impairment (defined as GFR<30); 7)HIV or Hepatitis C
positive status; 9)Participation in any other concurrent clinical trial; 10)Any other
life-threatening, non-cardiac disease; 11)Use of over the counter health supplements which
contain androgens; 12)Use of an investigational agent or therapeutic regimen within 30
days of study; 13)prostate nodule or severe enlargement on digital rectal examination;
14)Use of testosterone currently or in the past 4 months; 15)Hematocrit > 50%; 16)History
of untreated severe obstructive sleep apnea(defined as apnea-hypopnea index ≥30);
17)symptoms suggestive of severe BPH; 18)Congestive heart failure, class III or IV;
20)Known to have anemia secondary to iron, B12 or folic acid deficiency; 21)bone marrow
disorder such as myelodysplasia or aplastic anemia; 22) currently suffering from
symptomatic depression, with or without treatment; 23) history of severe depression in the
past which needed hospitalization; 24)currently suffering from foot ulcer, significant
periodontal disease or any other chronic infectious condition; 25)planning to have
children. 26) Subjects on testosterone or with testosterone replacement in the past 4
months will be excluded.