Leptin is a hormone produced by the fat cells that researchers have shown to play a role in
controlling appetite. Certain people with severe insulin resistance have little or no leptin.
The purpose of this study is to investigate people whose leptin levels have been found to be
lower than 85 percent of the general population. Researchers will determine whether insulin
levels in these participants improve when they are treated with genetically engineered
Study participants must be age 8 years or older and must have severe insulin resistance
syndrome and leptin deficiency. During an initial 7-day visit to the Clinical Center,
researchers will evaluate participants' metabolic parameters, such as insulin responsiveness,
lipid levels, appetite, and hormone levels. After taking these tests, participants will
self-inject doses of leptin once or twice a day and will be monitored for treatment outcomes
as well as side effects via follow-up visits. These inpatient follow-up visits will involve
both blood tests and imaging studies at the Clinical Center at 4, 8, and 12 months after the
initial visit, and every 6 months thereafter.
Since this protocol was initiated, we have observed that recombinant leptin has improved
metabolic abnormalities in subjects with lipoatrophy and leptin deficiency . The mechanism by
which leptin treatment improves insulin sensitivity in lipodystrophy patients is correlated
with the decrease in triglyceride content that occurs in the liver and muscle tissues during
leptin therapy, but it is unclear if this completely accounts for the increase in insulin
We followed two patients with mutations to their insulin receptor, who were refractory to
standard insulin resistance treatment. We administered recombinant leptin hormone for 10
months to these two patients and observed the effect on insulin sensitivity and glucose
tolerance in a pilot protocol.
Initial results from this study demonstrated that the two patients with extreme insulin
resistance responded to leptin therapy by decreasing HgbA1c, decreasing fasting serum glucose
levels, decreasing fasting serum insulin levels, and a concomitant improvement in glucose and
insulin tolerance during their treatment period on leptin therapy. Three months following
leptin withdrawal, these metabolic improvements deteriorated to the pre-treatment level.
During this 10-month period of leptin treatment, no adverse reactions to the therapy were
observed for these two patients.
The diabetes in this group is clinically very challenging to control. The new insulin
sensitizing medications are currently being tested, but clearly are not sufficient to control
diabetes in the optimal target ranges. In this study, we would like to continue to test the
safety and efficacy of leptin replacement therapy in these rare, but complex group of
patients. We would like to see whether leptin will improve insulin sensitivity, thus decrease
insulin resistance in a situation where the mechanism of insulin resistance can be attributed
to a presumed defect on the insulin receptor. This will allow us to learn if leptin can
overcome a receptor defect by activating some of the down-stream molecules in insulin
This will be an open-labeled study of 20 patients. We will include all ethnicities and all
genders of patients aged 5 and higher, with identified or presumed insulin receptor
mutations, and extreme forms of insulin resistance, manifested by fasting hyperinsulinemia,
fasting hyperglycemia, or severe glucose intolerance during a standard oral glucose tolerance
test. These patients also need to demonstrate concomitantly low fasting leptin levels (less
than 12.0 ng/mL for females and less than 8.0 ng/mL for males).
Patients will be evaluated every 6-12 months during the first two years of therapy. If no
improvements are seen after one year of therapy, then the study medication will be withdrawn.
If the patient shows improvements in his/her metabolic parameters while on leptin, the
patient will be invited to continue taking the study medication. After two years of
treatment, extending the treatment period on an annual basis will be the decision of the
patient, principal investigator and Aegerion Pharmaceuticals. Leptin is supplied by Aegerion
Pharmaceuticals, LLP and currently is only available through research studies. Neither the
NIH nor Aegerion Pharmaceuticals can guarantee that leptin will be available indefinitely
and/or after the study ends.
With leptin therapy, we hope to continue to see the improvements in metabolic control that
was demonstrated in the two pilot study patients. We hope to better assess the role leptin is
playing in regulating the glucose control and insulin sensitivity in this unique population
of patients, where the defect in insulin sensitivity is due to a known or presumed insulin
- INCLUSION CRITERIA
- Ethnicity: All ethnic groups
- Gender: Males and females
- Age >5 years. In our experience with the younger children, we find that their
participation in serial blood tests and MRI scans improves greatly when they are at
least 5 years of age. Also, in our experience with the Type A insulin resistant
patients, their initial insulin resistance is manifested as extreme hyperinsulinemia
and hypoglycemia in the younger patients. We would not want to treat a young child
experiencing chronic hypoglycemia.
- Clinically significant, severe insulin resistance. This can be documented by a known
or suspected defect in the insulin receptor that have characteristic phenotypic
identification. These include the following: Rabson Mendenhall syndrome, which usually
is associated with mutations in the insulin receptor; Type A insulin resistance, which
is usually associated with mutations in the insulin receptor; and Type B insulin
resistance, which is associated with auto-antibodies to the insulin receptor. The
inclusion criteria should include any patient with extreme insulin resistance who has
appropriately low leptin levels. Syndromes of lipodystrophy are similar, but we
already have approval to treat this group of patients.
- Circulating leptin levels < 12.0 ng/ml in females and < 8.0 ng/ml in males as measured
by Linco assay from serum samples after an overnight fast.
- Presence of at least one of the following metabolic abnormalities:
- Fasting insulin >30 (Micro)U/ml OR
- Presence of diabetes as defined by the 2006 ADA criteria:
- Fasting plasma glucose >= 126 mg/dL
- 2 hour plasma glucose >= 200 mg/dL following a 75 gram (1.75g/kg if less
than 40kg) oral glucose load, or
- Diabetic symptoms with a random plasma glucose >= 200 mg/dL
- General: Pregnant women, women in their reproductive years who do not use an effective
method of birth control, and women currently nursing or lactating within 6 weeks of
having completed nursing.
- Exclusions for underlying disease likely to increase side effects or to hinder
objective data collection:
- Known infectious liver disease
- Known HIV infection
- Current alcohol or substance abuse
- Psychiatric disorder impeding competence or compliance
- Active tuberculosis
- Use of anorexiogenic drugs
- Other conditions which in the opinion of the clinical investigators would impede
completion of the study.
- Subjects who have a known hypersensitivity to E. Coli derived proteins.