* INCLUSION CRITERIA:
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
