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 severeinsulin 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 withsevere insulin resistance must meet all of the following criteria:

• Suspected severe insulin resistance, or a disorder associated with severeinsulin 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 perday)

• 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 andthe willingness to sign a written informed consent document.

• Family members of patients, above (either affected or unaffected) must meet all ofthe following criteria:

• Biological relatives of patients in category (1) in whom a genetic cause ofinsulin resistance is known or suspected.

• Age >= 6 months

• Ability of subject (and/or legal guardian, for minor subjects) to understandand 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 understandand the willingness to sign a written informed assent/consent document.

• In good general health with no known active medical conditions as evidenced bymedical 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 severeinsulin 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 exceptionsare permitted, including topical medications, vitamins, and hormonalcontraceptives. Other medications may be permitted at the discretion of theinvestigators.

• Recent (past 2 months) use of drugs or supplements that alter glucose or lipidmetabolism (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 theinvestigators, 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 inCohort 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, willincrease risk to the subject from participation, or interfere withinterpretation of study data