Genetic Studies of Insulin and Diabetes

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.

Insulin is the key hormone responsible for regulating the level of glucose in plasma. In several disease states (e.g., obesity, non-insulin-dependent diabetes mellitus, and acromegaly), the target cells are resistant to insulin action. 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.

The purpose of this protocol is to threefold:

1. To study the molecular genetics underlying various causes of insulin resistance and diabetes mellitus.
2. To understand the natural history of insulin resistance disorders, including their response to FDA approved therapies. However, the treatment aspect of the protocol represents clinical care rather than prospective research.
3. To educate fellows in the Inter-institute Endocrinology and Pediatric Endocrinology programs of the NIH about rare and common insulin resistant disorders.

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 lipodystrophy
2. Patients with known or suspected mutations on the insulin receptor gene
3. Patients with known or suspected autoantibodies to the insulin receptor
4. Patients with other severe forms of insulin resistance

The frequency of visits and testing to be performed will vary due to the clinical heterogeneity of the patients studied as well as their worldwide geographic distribution, and will be adjusted on an individual basis. The total quantity of blood collected will be adjusted to remain within the approved NIH guidelines appropriate to the individual s age and size. The testing will include all or some of the following studies:

• Fasting blood sampling (e.g. insulin, glucose, HbA1c, lipid profile, lipoprotein profile, IGF-1 level, leptin level)
• Urine pregnancy test for applicable patients
• adrenal hormones and growth hormone
• Oral glucose tolerance test
• Stable isotope tracer studies to measure glucose and lipid turnover
• Hyperinsulinemic-euglycemic clamp studies to measure insulin sensitivity
• Analysis of body composition (anthropometric measurements, DEXA, MRI)
• Measurement of autoantibodies to the insulin receptor if Type B insulin resistance is suspected
• Biopsy of skin for the establishment of fibroblast or induced pluripotential stem cell lines
• Biopsies of subcutaneous adipose tissue and/or muscle for gene expression profiling
• Biopsies of liver or kidney if clinically indicated in patients with lipodystrophy
• Biopsies of thyroid tissue if clinically indicated