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

NCT02457897 | Completed Phase 2 Results

• 2 other identifiers: 15011915-DK-0119
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

Insulin Resistance; Diabetes Mellitus; Abnormal Glucose Metabolism

Keywords

Brown Adipose Tissue; Liothyronine; Insulin Receptors

Outcome Measures

Primary Outcomes (2)

• Total Body Glucose Disposal in the Fasting State

  2 weeks

• Hemoglobin A1C

  6 months

Secondary Outcomes (2)

• Muscle Glucose Uptake

  2 weeks

• Muscle Glucose Uptake

  6 months

Study Arms (1)

Patients with insulin receptor mutation

EXPERIMENTAL

Drug: Liothyronine

Interventions

Liothyronine DRUG

Oral supplement given every 8 hours

Patients with insulin receptor mutation

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.

You may not qualify if:

• Changes in doses of diabetes medications (including metformin, insulin, sulfonylureas, thiazolidinediones, leptin, GLP-1 agonists, DPP4 inhibitors, etc.) in the preceding 10 weeks.
• 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.
• 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).
• Any form of endogenous hyperthyroidism or hypothyroidism at baseline.
• Current or recent (past 8 weeks) use of thyroid hormone or anti-thyroid drugs.
• 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.
• 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).
• Current use of beta blockers
• Pregnancy or breast feeding
• 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)
• Known allergy or hypersensitivity to any form of thyroid hormone
• Known adrenal insufficiency
• Dependence on oral anticoagulant medications (adults only)
• Use of tricyclic anti-depressants, as transient cardiac arrhythmias have been observed with the concomitant use of thyroid hormone.
• Use of cholestyramine.

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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. doi: 10.1056/NEJM197604012941401.

  PMID: 176581 BACKGROUND

• 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.

  PMID: 19897683 BACKGROUND

• 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.

  PMID: 15232309 BACKGROUND

• Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, Walter PJ, Lightbourne M, Brown RJ. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest. 2020 Jul 1;130(7):3592-3602. doi: 10.1172/JCI135431.

  PMID: 32191645 DERIVED

• Kushchayeva YS, Startzell M, Cochran E, Auh S, Sekizkardes H, Soldin SJ, Kushchayev SV, Dieckmann W, Skarulis M, Abdul Sater Z, Brychta RJ, Cypess AM, Lin TC, Lightbourne M, Millo C, Brown RJ. Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations. J Clin Endocrinol Metab. 2020 Mar 1;105(3):e158-71. doi: 10.1210/clinem/dgz079.

  PMID: 31588494 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Insulin Resistance; Diabetes Mellitus

Interventions

Triiodothyronine

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Thyronines; Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Thyroxine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Rebecca Brown
• Organization: NIDDK

Rebecca.Brown@NIH.gov

301-594-0609

Study Officials

• Rebecca J Brown, M.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2015
• First Posted: May 29, 2015
• Study Start: April 17, 2015
• Primary Completion: September 18, 2018
• Study Completion: September 18, 2018
• Last Updated: December 5, 2019
• Results First Posted: December 5, 2019

Record last verified: 2018-09-18

Locations

US (1)