Genetic Studies of Insulin and Diabetes

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
• 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
• 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