Protocol Number: 02-DK-0022

Title:

Long-Term Efficacy of Leptin Replacement in Treatment of Lipodystrophy

Number:

02-DK-0022

Summary:

This study will evaluate the safety and effectiveness of leptin replacement therapy in patients with lipodystrophy (also called lipoatrophy). Patients have a total or partial loss of fat cells. They also lack the hormone leptin, which 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, large appetite, and liver disease due to fat accumulation.

Patients age 5 and older with significant lipodystrophy may be eligible for this study. Candidates will be screened with a physical examination and blood tests. Participants will be admitted to the NIH Clinical Center for 10 days for the following studies before beginning 12 months of leptin therapy:

- Insulin tolerance test -measures blood sugar levels after intravenous (IV) administration of insulin. Blood samples are collected through the IV tube at various intervals during the 1-hour test.

- Ultrasound of the liver and, if abnormalities are found, possibly liver biopsies.

- Fasting blood tests - to measure blood count, blood lipids and various hormones and assess liver function.

- Resting metabolic rate - to measure 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.

- Pelvic ultrasound in women - to detect ovarian cysts.

- Estimation of body fat - measurements of height, weight, waist, hip size, and skin folds over the arms and abdomen to estimate body fat content.

- Oral glucose tolerance test -measures blood sugar and insulin levels. The patient drinks a very sweet drink containing glucose (sugar), after which blood samples are collected through an IV tube in an arm vein at various intervals during the 3-hour test.

- Intravenous glucose tolerance test -measures tissue response to insulin and glucose after glucose injection and insulin infusion. Blood is collected over 3 hours to measure insulin and glucose levels.

- Appetite level and food intake - to measure 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.

- Questionnaire - patients complete a questionnaire about their activities and how they feel.

- 24-hour urine collections - to measure specific hormones, proteins and sugars excreted in the urine.

Additional studies may include blood tests for genetic studies of lipodystrophy, a muscle biopsy to study muscle proteins involved in regulating energy expenditure before and after leptin replacement, and examination of a surgical specimen (if available) to study molecules that may be involved in energy storage and use.

When the above tests are completed, leptin therapy begins. The drug is injected under the skin twice a day for 4 months and then once a day, if feasible. The dose is increased at the 1- and 2-month visits. Follow-up visits at 1, 2, 4, 6, 8 and 12 months after therapy starts include a physical examination, blood tests and a meeting with a dietitian. At the end of 12 months, all baseline studies described above are repeated. Patients record their symptoms weekly throughout the study. Those with diabetes measure their blood glucose levels daily before each meal and at bedtime.

Sponsoring Institute:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

All ethnic groups.

Males and females.

-Age greater than 5 years old.

-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 6.0 ng/ml in females and less than 3.0 ng/ml in males as measured by Linco assay on at least 2 occasions (specify when) obtained from pooled samples collected fasting at 6 AM, 6:30 AM and 7 AM.

Presence of diabetes as defined by the 1997 ADA criteria

a. Fasting plasma glucose 126 mg/ml, or

b. 2 hour plasma glucose 200 mg/dl following a 75 gram oral glucose load, or

c. Diabetic symptoms with a random plasma glucose 200 mg/dl

Fasting insulin greater than 30 micro units/ml.

Fasting hypertriglyceridermia greater 200 mg/dl

EXCLUSION CRITERIA:

Pregnant women, women in their reproductive years who do not use an effective method of birth control, 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 diseases likely to increase side effects or hinder objective data collection:

- Known infectious liver disease

- Current alcohol or substance abuse

- Psychiatric disorder impeding competence or compliance

- Active tuberculosis

- Use of anorexiogenic drugs

- Other condition which in the opinion of the clinical investigators would impede completion of the study

-Subjects who have known hypersensitivity to E. Coli derived proteins.

Special Instructions: Currently Not Provided

Keywords:

Lipoatrophic Diabetes

Leptin

Diabetes Mellitus

Hypertriglyceridemia

NASH

Recruitment Keywords:

Lipodystrophy

Leptin

Lipoatrophic Diabetes

Diabetes

Conditions:

Lipodystrophy

Investigational Drug(s):

Recombinant Methionyl Human Leptin A-100

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Troglitazone action is independent of adipose tissue

Life without white fat: a transgenic mouse

Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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