Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in People With Insulin Receptor Mutations
Condition: Insulin Resistance; Diabetes Mellitus; Abnormal Glucose Metabolism
MeSH terms: Insulin Resistance
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Insulin receptor mutation causes high blood sugars and sometimes diabetes complications.
      Researchers want to see if thyroid hormone helps.

      Objectives:

      - To see if thyroid hormone treatment changes how the body handles sugar in people with
      insulin receptor mutation and improves blood sugar in people with diabetes.

      Eligibility:

      - People ages 12 65 with an insulin receptor mutation.

      Design:

        -  Study part 1:19-day clinic stay. Participants will be monitored for 4 days. Then for 15
           days they will take a thyroid hormone pill 3 times a day. Participants will have:

        -  Blood tests.

        -  Heart rate and skin temperature monitored.

        -  All their food provided.

        -  Two 5-hour sessions in a special room. They will wear special clothes and sometimes sit
           still.

        -  Two small tubes inserted in veins. One will deliver tiny amounts of sugar and fat with a
           non-radioactive tracer. Participants will also drink water with a tracer. The other tube
           will collect blood.

        -  A sweet drink. Participants may have finger stick blood sugar tests.

        -  Glucose-monitoring device inserted into body fat for two 24-hour periods.

        -  Adults may have samples of fat and muscle taken.

        -  Heart ultrasound.

        -  PET-CT scan in a machine. An intravenous catheter will be placed in an arm vein. A small
           amount of radioactive substance will be injected.

        -  DEXA scan of body fat and bone density.

        -  Participants with poorly controlled diabetes will then take thyroid hormone at home for
           6 months. They will have blood drawn and sent to the study team monthly.

        -  After about 3 months, they will have an overnight visit. After 6 months, they will have
           a 4-day visit.
    

Detailed description: 
      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.
    

Intervention name(s): Liothyronine
Intervention type(s): Drug
Intervention description(s): Oral supplement given every 8 hours
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Brown Adipose Tissue; Liothyronine; Insulin Receptors