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.

The purpose of this protocol is to enable us to obtain adequate blood or tissue samples to study the molecular mechanisms underlying various causes of insulin resistance and diabetes mellitus. Patients with evidence for insulin resistance will be eligible to participate in this study. We particularly focus our study on the following four groups of patients:

1. Patients with various syndromes of lipoatrophy, lipodystrophy
2. Patients with mutations on the insulin receptor gene
3. Patients with autoantibodies to the insulin receptor
4. Patients with severe forms of insulin resistance

In addition, patients displaying unusual phenotypic features (i.e. presence of acanthosis nigricans) in association with hyperinsulinemia (i.e. fasting insulin levels greater than 30 microU/ml) or clinical diabetes mellitus may be eligible to be studied at NIH.

The work-up will include all or some of the following studies:

Routine biochemical profile

Fasting insulin, glucose, HbA1c, lipid profile, lipoprotein profile, IGF-1 level, leptin level

A panel of hormone levels: thyroid and sex hormones, pituitary hormones, adrenal hormones and growth hormone

Blood samples for genetic studies

Oral glucose tolerance test

In vitro insulin or IGF-1 binding

Autoantibodies to the insulin receptor if Type B insulin resistance is suspected

The total quantity of blood collected is within the approved NIH guidelines appropriate to the individual's age and size. In addition, some subjects may undergo skin biopsy for the establishment of fibroblast cell lines. Some adult patients with lipoatrophy and lipodystrophy may be asked to undergo a muscle biopsy to broaden the molecular studies. Liver biopsies may be performed if clinically indicated in patients with lipoatrophy and lipodystrophy. DEXA analyses and anthropometric measurements are performed when medically indicated during the diagnosis and evaluation to correlate markers of insulin resistance with parameters of whole body composition.

In a novel component of the study, we aim to study the biochemical and molecular changes that occur with standard therapies (such as high dose insulin, continuous insulin therapy, metformin, and TZD's) used for the treatment of insulin resistance and diabetes.

• INCLUSION/EXCLUSION CRITERIA

At least one of the following is required:

Hyperinsulinemia (i.e. greater than 30 microgramsU/mL).

Clinical presence of diabetes.

Phenotypic features suggesting a defect in glucose/lipid metabolism:

Acanthosis nigricans;

Lipoatrophy/lipodystrophy;

Lipomatosis;

Xanthomata;

Fatty liver

Family members of patients with known disease states of insulin action.