Low Dose Growth Hormone Treatment in Subjects With Metabolic Syndrome.

The study will be a double-blinded randomized placebo-controlled cross-over study. Thirty
subjects will be screened for eligibility initially, and the first 12 eligible subjects will
be enrolled. Six subjects will be randomized to receive the low GH dose (0.1 mg/day)
treatment and 6 subjects to receive Placebo treatment for 12 weeks, exchanging their
treatment for a further 12 weeks after a 4-week washout period. The study drugs will be
stored at the Oregon Health and Science University (OHSU) Research Pharmacy and following
randomization, the subjects will be taught by either the Principal Investigator or one of
our Endocrine Nurses to self-administer the injections using Norditropin/Placebo vials and
insulin syringes into the abdomen at 2200h. Randomization for treatment assignment will be
performed by an investigator not directly involved in the patients' recruitment, treatment
and follow-up care. The randomization process will be performed by computerized pre-assigned
random codes by blocks, stratified by age and examined for possible differences in body mass
index. During their in-patient stay at the Oregon Clinical and Translational Research
Institute (OCTRI) at OHSU, subjects will only be allowed to eat the food provided to them by
the OCTRI.

Initial Screening Assessment (outpatient)

The following assessments will be performed:

- Written informed consent

- Demographics (demographic information including the subject's birth date, and race)

- Physical exam and medical history

- Previous/significant medical history

- Concomitant medication review

- Vital signs, e.g., pulse and blood pressure measurements

- Height, weight and waist circumference

- Laboratory findings, e.g. CBC, electrolytes, and fasting glucose levels

Visit 1, Baseline Assessment for the First Treatment Phase (in-patient)

The following is a description of the assessments that will be performed after consent is
obtained:

- Physical exam and medical history

- Vital signs, e.g., pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Urine pregnancy test for female child-bearing subjects

- Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, non-esterified fatty acids (NEFAs),
adiponectin, and ghrelin

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

- Randomization to GH or Placebo

- Teach GH or Placebo self-administration

Visit 2, Final Assessment for the First Treatment Phase (Week 12 +/- 1 week) (outpatient)

The following is a description of the assessments that will be performed at the end of the
first treatment phase with either GH or Placebo. Subjects will also be monitored for safety
with the collection of the following:

- Physical exam and medical history

- Vital signs, e.g. pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Adverse event recording

- Urine pregnancy test for female child-bearing subjects

- Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, non-esterified fatty acids (NEFAs),
adiponectin, and ghrelin

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

Washout Period and Crossover after the first treatment phase with GH or Placebo, the
subjects will have a 4-week washout period and the treatment will be crossed over for
another 12-week treatment phase with either GH or Placebo. During this time, the subjects
will be advised to maintain a stable diet and weight.

Visit 3, Baseline Assessment for the Second Treatment Phase (Week 16 +/- 1 week) (as
outpatient)

The following is a description of the assessments that will be performed:

- Physical exam and medical history

- Vital signs, e.g., pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Urine pregnancy test for female child-bearing subjects

- Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, non-esterified fatty acids (NEFAs),
adiponectin, and ghrelin

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

- Treatment exchanged to Placebo or GH

Visit 4, Final Assessment for the Second Treatment Phase (Week 28 +/- 1 week) (as inpatient)

The following is a description of the assessments that will be performed at the end of the
second treatment phase with either GH or Placebo. Subjects will also be monitored for safety
with the collection of the following:

- Physical exam and medical history

- Vital signs, e.g., pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Urine pregnancy test for female child-bearing subjects

- Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, non-esterified fatty acids (NEFAs),
adiponectin, and ghrelin

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

Because of the potentially long duration of Visits 1, 2 and 4, the studies can either be
divided into two separate admissions upon prior arrangement or can be done all at once with
one admission, depending on the subject's wishes and schedule.

Inclusion Criteria:

- Ability to provide written informed consent and comply with study assessments for the
full duration of the study.

- Age 21 to 65 years

- Body mass index between 25 to 40 kg/m2

- Diagnosis of MBS based on the consensus statement by the International Diabetes
Federation i.e., central obesity defined by waist circumference in men of ≥ 94 cm and
in women of ≥ 80 cm plus two other components from the following: 1) dyslipidemia
(triglyceride levels ≥ 150 mg/dl or on therapy and/or HDL in men of < 40 mg/dl and in
women of < 50 mg/dl or on therapy); 2) hypertension (blood pressure ≥ 130/85 mmHg or
on therapy and 3) hyperglycemia (fasting plasma glucose ≥ 100 mg/dl or on therapy)

- Stable weight and diet for at least 6 months prior to study entry

- Normal thyroid function

- Normal renal and hepatic function

- Able to self administer GH/Placebo injections

Exclusion Criteria:

- Inability to comply with study requirements

- Body mass index < 30 kg/m2 and > 40 kg/m2 (patients with body mass index > 40 kg/m2
are excluded because they will not fit into the MRS scanner)

- Untreated hypothyroidism or hyperthyroidism

- Anemia from any cause

- Known diabetes mellitus

- Patients with an increased risk of venous thrombosis or previous history of recurrent
venous thrombosis

- Patient on any insulin-sensitizers (e.g., Metformin, Rosiglitazone, Pioglitazone)
within 30 days of screening assessment

- Patient on any anti-androgens (e.g., Spironolactone, Cyproterone acetate, Flutamide,
Finasteride) within 30 days of screening assessment

- Patient with other concurrent illnesses

- Pregnant (positive pregnancy test) prior enrollment in the study or planning to
conceive whilst participating in the study

- Emotional/social instability likely to prejudice study completion

- Previous history of known malignancy

- Recurrent or severe unexplained hypoglycemia

- Known or suspected drug/alcohol abuse

- Patient with any metals in the body

- Any other condition/s that the investigator believes would pose a significant hazard
to the subject if the investigational therapy were initiated

- Participation in another simultaneous medical investigation or trial