Studi genetici di insulina e diabete

Subjects with severe insulin resistance disorders.

• 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