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 leptin.

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.

Condition	Treatment or Intervention	Phase
Insulin Resistance	Drug: hu Leptin (A-100)	Phase II

Over the course of the past three years, 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 sensitivity.

We followed two children with presumed 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 children 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 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 signaling cascade.

This will be an open-labeled study of 20 patients. We will include all ethnicities and all genders of patients aged 8 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 6.0 ng/mL for females and less than 4.0 ng/mL for males).

Patients will be evaluated every 4 months during the first year 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 the first year of treatment, the patient will be evaluated every 6 months, until the second year of treatment, and then the study period will end. After two years of treatment, extending the treatment period on an annual basis will be the decision of the patient, principal investigator and Amgen, Inc. Leptin is supplied by Amgen, Inc., and currently is only available through research studies. Neither the NIH nor AMGEN, Inc 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 receptor mutation.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Ethnicity: All ethnic groups.
Gender: Males and females.
Ages greater than 8 years.
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 less than 6.0 ng/ml in females and less than 4.0 ng/ml in males as measured by Linco assay obtained from pooled samples collected fasting at 6 AM, 6:30 AM and 7 AM.
Presence of at least one of the following metabolic abnormalities:
a) Fasting insulin greater than 30 micro U/ml, or
b) Presence of diabetes as defined by the 1997 ADA criteria:
-Fasting plasma glucose greater than or equal to 126 mg/dL
-2 hour plasma glucose greater than or equal to 200 mg/dL following a 75 gram (1.75mg/kg if less than 40 kg) oral glucose load, or
-Diabetic symptoms with a random plasma glucose greater than or equal to 200 mg/dL.
EXCLUSION CRITERIA:
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 data collection:
-Known infectious liver disease
-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

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  030257; 03-DK-0257
Record last reviewed:  May 17, 2004
Last Updated:  May 17, 2004
Record first received:  June 18, 2004
ClinicalTrials.gov Identifier:  NCT00085982
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-08