Effect of Leptin Therapy in the Treatment of Severe Insulin Resistance

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.

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 sensitivity .

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 signaling cascade.

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 receptor mutation.