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

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

View full results

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

7 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-04-17

Study Completion Date

2018-09-18

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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.

Related Clinical Trials

Explore similar clinical trials based on study characteristics and research focus.

The Effect of Administration of Small Doses of Thyroxine on Glucose and Lipid Metabolism, in Type 2 Diabetes Mellitus.

NCT02509858

Diabetes Mellitus

COMPLETED NA

Effect of Metreleptin Therapy in the Treatment of Severe Insulin Resistance

NCT00085982

Severe Insulin Resistance

ACTIVE_NOT_RECRUITING PHASE2

GLP-1 and Hypoglycemia

NCT01858896

Type 2 Diabetes Mellitus

ACTIVE_NOT_RECRUITING EARLY_PHASE1

Effect of Insulin Glulisine vs Regular Human Insulin on Postprandial Endothelial Function in Type 2 Diabetes

NCT00562133

Diabetes Mellitus

COMPLETED PHASE3

Central Insulin Sensitivity in Individuals With Type 2 Diabetes (T2D) and at Risk for Developing T2D

NCT05856877

Central Insulin Resistance Diabetes Mellitus, Type 2 PreDiabetes

RECRUITING NA

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Insulin Resistance Diabetes Mellitus Abnormal Glucose Metabolism

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Patients with insulin receptor mutation

Group Type EXPERIMENTAL

Liothyronine

Intervention Type DRUG

Oral supplement given every 8 hours

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

Liothyronine

Oral supplement given every 8 hours

Intervention Type DRUG

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

Inclusion Criteria

1\. Mutation of the insulin receptor (either recessive or dominant negative). If mutation status is not known prior to enrollment, subjects will undergo genotyping at enrollment. In the unanticipated event that a patient does not have a mutation of the insulin receptor, he or she will not complete the study and his or her data will not be included in the analysis.

Exclusion Criteria

1. Changes in doses of diabetes medications (including metformin, insulin, sulfonylureas, thiazolidinediones, leptin, GLP-1 agonists, DPP4 inhibitors, etc.) in the preceding 10 weeks.
2. Any medical condition or medication that will increase risk to the subject (e.g. ischemic or structural heart disease, congestive heart failure, uncontrolled hypertension, or arrhythmia) or that will interfere with interpretation of study data.
3. Disorders that would lead to erratic gastrointestinal absorption or loss of thyroid hormone from the gut (severe diarrhea, celiac disease, use of bile acid sequestrants, excessive consumption of soybean products).
4. Any form of endogenous hyperthyroidism or hypothyroidism at baseline.
5. Current or recent (past 8 weeks) use of thyroid hormone or anti-thyroid drugs.
6. Extreme disorders of thyroid hormone binding to thyroid binding globulin (excess or deficiency) or protein loss (nephrotic range proteinuria) that would lead to difficulties achieving a consistent thyroid hormone level for study.
7. Known presence of a rare clinical disorder that leads to thyroid hormone insensitivity (known T3 receptor mutations, selenocysteine insertion sequence-binding protein 2 (SBP2) abnormalities, monocarboxylate transporter defects).
8. Current use of beta blockers
9. Pregnancy or breast feeding
10. Any EKG abnormality that could increase risk of T3 treatment (resting sinus tachycardia (age adjusted norms), atrial fibrillation, myocardial ischemia, left or right ventricular excitation block, left ventricular hypertrophy or extrasystoles)
11. Known allergy or hypersensitivity to any form of thyroid hormone
12. Known adrenal insufficiency
13. Dependence on oral anticoagulant medications (adults only)
14. Use of tricyclic anti-depressants, as transient cardiac arrhythmias have been observed with the concomitant use of thyroid hormone.
15. Use of cholestyramine.
16. History of clinically significant osteoporosis per investigator judgment (e.g. previous fragility fracture)

6 MONTHS STUDY:

Minimum Eligible Age

12 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No