This study will evaluate the safety and effectiveness of the leptin replacement therapy in
treating lipoatrophy or lipodystrophy-a condition in which there is a total or partial loss
of fat cells. Patients with lipodystrophy lack sufficient leptin, because this hormone is
produced by fat cells. The leptin deficiency usually causes high blood lipid (fat) levels
and insulin resistance that may lead to diabetes. Patients may have hormone imbalances,
fertility problems, uncontrolled appetite, and liver disease due to fat accumulation.
Patients 15 years and older with lipodystrophy are eligible for this study. Candidates are
screened with a medical history and physical examination, and fasting blood tests. Those
enrolled undergo the following additional procedures:
- Ultrasound of the liver and, if abnormalities are found, possibly a liver biopsy
- Resting metabolic rate measurement - measures the amount of oxygen breathed at rest in
order to calculate how many calories are required to maintain resting body functions
- Magnetic resonance imaging of the liver and other organs, and of muscle and fat
- Estimation of body fat - measurements of height, weight, hip size, and skin folds over
the arms and abdomen to estimate body fat content
- Insulin tolerance test - measures blood glucose levels after administration of insulin.
Insulin is given through an intravenous (IV) catheter (a thin tube placed in a vein)
and blood is drawn 5 minutes before the test begins, when the test begins, and 5, 10,
15, 20 and 30 minutes into the test
- Oral glucose tolerance test - measures blood glucose and insulin levels after drinking
a glucose (sugar) solution. Blood samples are drawn through an IV catheter 15 minutes
before the test begins, at the time the test begins, and 30, 60, 90 and 180 minutes
into the test
- Intravenous glucose tolerance test - measures tissue response to insulin and glucose
after glucose is injected into a vein. The glucose injection is followed by a short
infusion of insulin and then blood samples are taken over 3 hours to measure insulin
and glucose levels
- Appetite level and food intake - measures hunger level and caloric intake. Patients
are questioned about their hunger level, given a variety of foods they may choose to
eat and questioned again at various intervals about hunger level. On another day,
patients are given breakfast (usually a milkshake) and when they want to eat again, the
appetite level and caloric intake study is repeated.
- Hormone function tests - the function of three hormones influenced by leptin
(corticotropin-releasing hormone, thyrotropin-releasing hormone and luteinizing
hormone-releasing hormone) are assessed. The hormones are injected intravenously and
then blood samples are drawn.
When all the tests are completed, leptin therapy begins. The drug is injected under the
skin twice a day for 4 months by the patient or a caregiver (similar to self-administered
insulin injections for diabetes). Blood is drawn once a month to monitor the effects of
treatment and drug side effects. At clinic visits scheduled 1, 2 and 4 months after therapy
starts, patients have a physical examination and meet with a dietitian. Medication dosage
is also increased at these visits. At the end of 4 months, all baseline studies described
above are repeated. Throughout the study, all patients complete a form once a week, in
which they record their symptoms. Patients with diabetes also measure their blood glucose
levels at home before each meal and at bedtime.
Lipoatrophic diabetes is a syndrome characterized by insulin resistance in association with
a paucity of adipose tissue. Patients with severe lipoatrophy die prematurely, typically
from the complications of diabetes or liver disease. Experiments with lipoatrophic mice
suggest that the insulin resistance is caused by the lack of adipose tissue. Adipose tissue
normally produces leptin, a hormone that increases insulin action. To what extent does
leptin deficiency cause diabetes in lipoatrophic patients? In one mouse model of
lipoatrophy, leptin administration reversed the diabetes and liver disease. In a different,
more severely adipose-deficient mouse, the effects of leptin treatment were detectable, but
In this protocol, to be carried out at both the NIH and the University of Texas in Dallas,
we test the hypotheses that leptin can be safely administered to patients with lipoatrophic
diabetes and they will benefit from treatment with A-100 (recombinant form of human leptin
provided by Amgen). We will study patients with lipoatrophy, low leptin levels, and at
least one of the following metabolic abnormalities: severe insulin resistance, diabetes,
We will treat patients with A-100 injections for four months, with inpatient studies at
baseline, 1, 2, and 4 months of treatment. In the core protocol, we will monitor metabolic
control (e.g. glucose, insulin, free fatty acid, and triglyceride levels). Ancillary
studies will evaluate the effect of A-100 on the gonadal axis and on liver pathology.
After 8 months of treatment, we will offer a withdrawal study to the patient requiring an
inpatient admission and controlled diet. Afterwards leptin therapy will resume in a
long-term extension study with follow up visits every 6 months. Metabolic parameters will
continue to be followed, along with body fat imaging studies, gonadotropin monitoring, and
liver function analysis.
All ethnic groups
Males and females
Age greater than 14 years
Clinically-significant lipodystrophy, identified by the study physician during the
physical examination as an absence of fat outside the range of normal variation and/or
identified as a disfiguring factor by the patient.
Circulating leptin levels less than 4.0 ng/ml in females and less than 3.0 ng/ml in males
as measured by Linco assay on at least 2 occasions.
Presence of at least one of the following metabolic abnormalities:
Presence of diabetes as defined by the 1997 ADA criteria: a) fasting plasma glucose
greater than or equal to 126 mg/dL, or b) 2 hour plasma glucose greater than or equal to
200 mg/dL following a 75 gram oral glucose load, or c) diabetic symptoms with a random
plasma glucose greater than or equal to 200 mg/dL.
Fasting insulin greater than 30 micrograms/ml;
Fasting hypertriglyceridemia greater than 200 mg/dl.
General: Pregnant women, women in their reproductive years who do not use an effective
method of birth control, women currently nursing or lactating within 6 weeks of having
completed nursing, and persons who are unable to provide informed consent will be excluded
from the study.
Exclusions for underlying disease likely to increase side effects or to hinder objective
Known liver disease due to causes other than non-alcoholic steatohepatitis
Current alcohol or substance abuse
Psychiatric disorder impeding competence or compliance
Use of anorexiogenic drugs
Other condition 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