Genetic Studies of Insulin and Diabetes

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

- INCLUSION/EXCLUSION CRITERIA

At least one of the following is required:

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

Clinical presence of type 2 diabetes mellitus.

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;

Lipoatrophy/lipodystrophy;

Lipomatosis;

Xanthomata;

Fatty liver

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