Effect of Metreleptin Therapy in the Treatment of Severe Insulin Resistance

Study Description:

Patients with mutations of the insulin receptor have diabetes that is challenging to control with conventional therapies, leading to early morbidity and mortality. We hypothesize that recombinant leptin (metreleptin) in these patients will improve glycemia control.

Objectives:

Primary Objective: To determine if 1 year of metreleptin will improve glycemia control in patients with genetic defects of the insulin receptor. Secondary Objectives: To determine mechanisms by which metreleptin improves glycemia.

Endpoints:

Primary Endpoint: Hemoglobin A1c.

Secondary Endpoints: fasting plasma glucose, fasting insulin/C-peptide, glucose/insulin/C-peptide area under the curve during oral glucose tolerance test.

Study Population:

20 male or female patients with mutations of the insulin receptor, age (Bullet)5 years, at the NIH Clinical Center.

Description of Sites/Facilities Enrolling Participants: Description of Study Intervention:

NIH Clinical Center

Open label study of metreleptin, 0.2 mg/kg/day (max dose 0.24 mg/kg/day).

Study Description:

Patients with mutations of the insulin receptor have diabetes that is challenging to control with conventional therapies, leading to early morbidity and mortality. We hypothesize that recombinant leptin (metreleptin) in these patients will improve glycemia control.

Objectives:

Primary Objective: To determine if 1 year of metreleptin will improve glycemia control in patients with genetic defects of the insulin receptor. Secondary Objectives: To determine mechanisms by which metreleptin improves glycemia.

Endpoints:

Primary Endpoint: Hemoglobin A1c.

Secondary Endpoints: fasting plasma glucose, fasting insulin/C-peptide, glucose/insulin/C-peptide area under the curve during oral glucose tolerance test.

Study Population:

20 male or female patients with mutations of the insulin receptor, age (Bullet)5 years, at the NIH Clinical Center.

Description of Sites/Facilities Enrolling Participants: Description of Study Intervention:

NIH Clinical Center

Open label study of metreleptin, 0.2 mg/kg/day (max dose 0.24 mg/kg/day).

Eligibility Criteria:
* INCLUSION CRITERIA:
* Provision of signed and dated informed consent form
* Male or female, aged \> 5 years
* Clinically significant, severe insulin resistance caused by a known or suspected defect in the insulin receptor
* 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 American Diabetes Association (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

EXCLUSION CRITERIA:

* Pregnant at time of enrollment, 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.
* Known infectious liver disease
* Known HIV infection
* Current alcohol or substance abuse
* Active tuberculosis
* Use of anorexigenic 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.