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

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02457897
• Collaborator: (none)
• Enrollment: 7
• Location: 1
• Arm: 1
• Duration (Months): 41.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Insulin Resistance; Diabetes Mellitus; Abnormal Glucose Metabolism	Drug: Liothyronine	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in Patients With Insulin Receptor Mutations
• Study Start Date: Apr 17, 2015
• Actual Primary Completion Date: Sep 18, 2018
• Actual Study Completion Date: Sep 18, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patients with insulin receptor mutation	Drug: Liothyronine; Oral supplement given every 8 hours

Outcome Measures

Primary Outcome Measures

1. Total Body Glucose Disposal in the Fasting State [2 weeks]

2. Hemoglobin A1C [6 months]

Secondary Outcome Measures

1. Muscle Glucose Uptake [2 weeks]

2. Muscle Glucose Uptake [6 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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 exclusion criteria for the short-term study, plus have poorly controlled diabetes, defined as a hemoglobin A1c greater than or equal to 7%.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Rebecca J Brown, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 15, 2018

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976 Apr 1;294(14):739-45.
• Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore). 2004 Jul;83(4):209-222. doi: 10.1097/01.md.0000133625.73570.54. Review.
• Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, Cochran C, Solomon J, Chen C, Gorden P. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab. 2010 Jan;95(1):256-62. doi: 10.1210/jc.2009-0543. Epub 2009 Nov 6.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT02457897
• Other Study ID Numbers: 150119; 15-DK-0119
• First Posted: May 29, 2015
• Last Update Posted: Dec 5, 2019
• Last Verified: Sep 18, 2018

• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Brown Adipose Tissue; Liothyronine; Insulin Receptors
• Additional relevant MeSH terms: Insulin Resistance

Study Results

Participant Flow

Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
Period Title: Part 1 Short-term (2 Weeks) Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0
Period Title: Part 1 Short-term (2 Weeks) Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
Overall Participants	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22 (5.92)
Sex: Female, Male (Count of Participants)
Female	3 42.9%
Male	4 57.1%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 42.9%
Black	2 28.6%
White	2 28.6%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	19.84 (8.33)

Outcome Measures

1. Primary Outcome

Title	Total Body Glucose Disposal in the Fasting State
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
Measure Participants	7
Mean (Standard Deviation) [μmol/kg LBM (Lean Body Mass)/min]	21.47 (6)

2. Primary Outcome

Title	Hemoglobin A1C
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
Measure Participants	5
Mean (Standard Deviation) [percentage of glycosylated hemoglobin]	9.1 (3)

3. Secondary Outcome

Title	Muscle Glucose Uptake
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
Measure Participants	5
Mean (Standard Deviation) [μmol/min/100ml]	0.9 (0.08)

4. Secondary Outcome

Title	Muscle Glucose Uptake
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
Measure Participants	2
Mean (Standard Deviation) [μmol/min/100ml]	2.0 (0.2)

Adverse Events

Time Frame	6 months
Arm/Group Title	Patients With Insulin Receptor Mutation
Arm/Group Description	Liothyronine: Oral supplement given every 8 hours
All Cause Mortality
	Patients With Insulin Receptor Mutation
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Serious Adverse Events
	Patients With Insulin Receptor Mutation
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Patients With Insulin Receptor Mutation
	Affected / at Risk (%)	# Events
Total	3/7 (42.9%)
Endocrine disorders
Hyperglycemia	1/7 (14.3%)	1
Immune system disorders
Allergic reaction (after eating Indian food)	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Upper Respiratory infection	1/7 (14.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.