Insulin Resistance, Diabetes Mellitus, Abnormal Glucose Metabolism
Conditions
Keywords
Brown Adipose Tissue, Liothyronine, Insulin Receptors
Brief 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.
Interventions
DRUGLiothyronine
Oral supplement given every 8 hours
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 2 WEEKS STUDY: 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: Patients must meet all inclusion and
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Total Body Glucose Disposal in the Fasting State | 2 weeks |
| Hemoglobin A1C | 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Muscle Glucose Uptake | 2 weeks |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients With Insulin Receptor Mutation Liothyronine: Oral supplement given every 8 hours | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Patients With Insulin Receptor Mutation |
|---|---|
| Age, Continuous | 22 years STANDARD_DEVIATION 5.92 |
| Body Mass Index | 19.84 kg/m^2 STANDARD_DEVIATION 8.33 |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized White | 2 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 3 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Hemoglobin A1C
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients With Insulin Receptor Mutation | Hemoglobin A1C | 9.1 percentage of glycosylated hemoglobin | Standard Deviation 3 |
Primary
Total Body Glucose Disposal in the Fasting State
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients With Insulin Receptor Mutation | Total Body Glucose Disposal in the Fasting State | 21.47 μmol/kg LBM (Lean Body Mass)/min | Standard Deviation 6 |
Secondary
Muscle Glucose Uptake
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients With Insulin Receptor Mutation | Muscle Glucose Uptake | 0.9 μmol/min/100ml | Standard Deviation 0.08 |
Secondary
Muscle Glucose Uptake
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients With Insulin Receptor Mutation | Muscle Glucose Uptake | 2.0 μmol/min/100ml | Standard Deviation 0.2 |