Genetic Studies of Insulin and Diabetes

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT00001987

Collaborator

(none)

1,200

Enrollment

Location

Study Details

Study Description

Brief Summary

The study will allow researchers to obtain blood, plasma, DNA, and RNA for genetic studies of insulin. There will be a focus on the causes of insulin resistance and diabetes mellitus. Insulin is a hormone found in the body that controls the level of sugar in the blood. Insulin resistance refers to conditions like diabetes when insulin does not work properly. In this study researchers would like to compare patients with diabetes and other forms of insulin resistance to normal individuals. The study will investigate how insulin attaches to cells.

Researchers will take 4 to 6 ounces (100-150 ml) of blood from adult patients and may request up to 12 ounces (one unit) of blood if necessary. Skin samples may be taken for a biopsy if further genetic testing is necessary. In addition some patients may be asked not to eat for up to 72 hours prior to testing.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Severe Insulin Resistance

Detailed Description

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 cardiovascular disease, (2) To study the molecular genetics underlying various causes of insulin resistance and diabetes mellitus, and (3) To understand the natural history of insulin resistance disorders, including their response to FDA approved therapies.

Endpoints: Primary Endpoint: Genetic causes of insulin resistance

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

Study Design

Study Type:

Observational

Anticipated Enrollment :

1200 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Natural History of Disorders of Insulin Resistance

Actual Study Start Date :

Feb 1, 1976

Arms and Interventions

Arm	Intervention/Treatment
Healthy Volunteers Healthy Volunteers
Patients with severe insulin resistance patients with severe insulin resistance manifesting with acanthosis nigricans, hyperinsulinemia, type A and B insulin resistance syndromes, and patients with lipodystrophy.

Outcome Measures

Primary Outcome Measures

Genetics of insulin resistance [End of Study]
To discover the cause of the insulin resistance to better assist with treatment for it.
Diabetes control [every 6-12 months]
To help prevent additional health issues associated with poor glucose and insulin levels.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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 >30microunits/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 or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
Healthy control subjects without insulin resistance must meet all of the following criteria
In good general health with no known active medical conditions as evidenced by medical history
Age >= 12 years
Fasting glucose <100 mg/dL
HbA1c <5.7%
Fasting triglycerides <150 mg/dL
Fasting insulin <20 mcU/mL
BMI <27 kg/m^2 or <90th %ile for age/sex (whichever is lower)
Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients with evidence for insulin resistance or a disorder associated with severe insulin resistance

none

Family members of patients, above

Pregnant or lactating at the time of enrollment

Healthy control subjects without insulin resistance
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
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