Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in People With Insulin Receptor Mutations

Background Patients with mutations of the insulin receptor have extreme insulin resistance. This frequently results in diabetes in childhood that is extremely difficult to manage with conventional diabetes therapies, including insulin at doses 10-50 fold higher than usual. Poorly controlled diabetes, in turn, leads to microvascular complications (e.g. blindness) and early death. Hyperthyroidism, whether endogenous (e.g. Graves' disease) or exogenous, increases energy expenditure, activates brown adipose tissue, and enhances skeletal muscle perfusion, leading to enhanced glucose disposal. In a single patient with mutation of the insulin receptor and poorly controlled diabetes despite maximal therapy, iatrogenic mild hyperthyroidism for treatment of thyroid cancer resulted in normalization of glycemic control, suggesting that thyroid hormone treatment could have therapeutic benefit in this rare disease. Aim The purpose of this study is to determine if treatment with thyroid hormone will increase glucose disposal in patients with mutations of the insulin receptor, and thereby improve glycemic control. The hypotheses to be tested are: 1. Thyroid hormone will increase whole-body glucose disposal in patients with insulin receptor mutations. 2. This increased glucose disposal will be mediated via increased glucose uptake in brow adipose tissue (BAT) and muscle. 3. Increases in glucose disposal will result in improved glycemic control. Methods This study is a non-randomized pre-post design, conducted in two sequential parts. Part 1 is a short-term (2 week) proof-of-principle study to test whether thyroid hormone will increase glucose disposal in patients with insulin receptor mutations (with or without diabetes), and the mechanisms by which increased glucose disposal occurs. Part 2 is a longer term (6 month) therapeutic study to test whether thyroid hormone will result in improved glycemic control in diabetic patients with insulin receptor mutations.