Genetic Studies of Insulin and Diabetes

Study Description:

Insulin is the key hormone responsible for regulating the level of glucose in plasma. In several disease states (e.g., obesity, type 2 diabetes, and acromegaly), the target cells are resistant to insulin action. Insulin resistance leads to metabolic complications including diabetes, dyslipidemia, cardiovascular disease, non-alcoholic fatty liver disease, and reproductive dysfunction. The intramural research program of the NIDDK has a long history of studying patients with rare disorders of extreme insulin resistance. We use what is learned from these rare patients both to develop therapeutics for rare diseases, and to apply what is learned to understand more common forms of insulin resistance.

Objectives:

Primary Objectives: (1) To understand the pathophysiology of insulin resistance and its relationship to diabetes, dyslipidemia, cardiovascular disease, liver disease, kidney disease, reproductive function, bone disease, and other organ dysfunction, (2) To study the molecular genetics underlying various causes of insulin resistance and diabetes mellitus, (3) To understand the natural history of insulin resistance disorders, including their response to FDA approved therapies, and (4) To conduct ex vivo studies of the physiology and pathophysiology underlying disorders of insulin resistance, and possible treatments for these disorders, using cells and tissues collected in this study.

Endpoints:

Primary Endpoint: Genetic causes of insulin resistance

Secondary Endpoints: Diabetes control (hemoglobin A1c) and complications (rates of micro- and macrovascular disease)

• 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