Three categories of subjects will be included in this study:
- Patients with evidence for insulin resistance or a disorder associated with severe insulin resistance, including:
- Patients with various syndromes of lipodystrophy
- Patients with known or suspected mutations on the insulin receptor gene
- Patients with known or suspected autoantibodies to the insulin receptor
- Patients with other severe forms of insulin resistance
- Family members of patients, above
- Healthy control subjects without insulin resistance
Inclusion criteria for each group of subjects are given below:
- Patients with evidence for severe insulin resistance or a disorder associated with severe insulin resistance must meet all of the following criteria:
- Suspected severe insulin resistance, or a disorder associated with severe insulin resistance, as evidenced by one or more of the following:
- Hyperinsulinemia (i.e. fasting insulin >30microU/mL)
- High insulin requirement (> 2 units per kg per day or > 200 units total per day)
- Phenotypic features suggesting a defect in glucose/lipid metabolism:
- Acanthosis nigricans
- Lipodystrophy/abnormal fat distribution
- Xanthomata
- Fatty liver
- Known or suspected mutations of the insulin receptor gene
- Known or suspected autoantibodies to the insulin receptor
- Age >= 6 months
- Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
- Family members of patients, above (either affected or unaffected) must meet all of the following criteria:
- Biological relatives of patients in category (1) in whom a genetic cause of insulin resistance is known or suspected.
- Age >= 6 months
- Ability of subject (and/or legal guardian, for minor subjects) to understand and the willingness to sign a written informed assent/consent document.
- Healthy control subjects Cohort 1 must meet all of the following criteria.
- Ability of subject (and/or legal guardian, for minor subjects) to understand and the willingness to sign a written informed assent/consent document.
- In good general health with no known active medical conditions as evidenced by medical history
- Age >= 12 years
- Healthy control subjects Cohort 2. Subjects from Cohort 1 may be included in Cohort 2 if they meet the following ADDITIONAL inclusion criteria.
- Fasting glucose <100 mg/dL
- HbA1c <5.7%
- Fasting triglycerides <150 mg/dL
- Fasting insulin <30 mcU/mL
- BMI <27 kg/m\^2 or <90th percentile for age/sex (whichever is lower)
EXCLUSION CRITERIA:
- Patients with evidence for insulin resistance or a disorder associated with severe insulin resistance
--none
- Family members of patients, above
--Pregnant at the time of enrollment
- Healthy control subjects Cohort 1
- Current use of prescription or non-prescription medication. Certain exceptions are permitted, including topical medications, vitamins, and hormonal contraceptives. Other medications may be permitted at the discretion of the investigators.
- Recent (past 2 months) use of drugs or supplements that alter glucose or lipid metabolism (e.g. niacin, fish oil, red yeast rice)
- History of diabetes or abnormal glucose tolerance
- Psychiatric or cognitive disorder that will, in the opinion of the investigators, limit the subject's ability to provide informed consent/assent, or to comply with study procedures
- Pregnant or lactating
- Healthy control subjects Cohort 2. Subjects from Cohort 1 may NOT be included in Cohort 2 if they have any of the following ADDITIONAL exclusion criteria.
- Abnormal screening labs, including the following:
- ALT or AST more than 1.5 times the upper limit of normal
- Glycosuria
- Clinically significant anemia
- Low eGFR (<60 mL/min/1.73m\^2)
- Any other abnormality that, in the opinion of the investigator, will increase risk to the subject from participation, or interfere with interpretation of study data