Understanding Insulin Resistance Pathophysiology and Natural History in Relation to Various Health Conditions

Study start date: February 1, 1976

* 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