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Trial record 41 of 2202 for:    digestive | Open Studies | United States

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 5, 2017 by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier:
NCT02457897
First received: April 22, 2015
Last updated: May 12, 2017
Last verified: April 5, 2017
  Purpose

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 Intervention Phase
Insulin Resistance
Diabetes Mellitus
Abnormal Glucose Metabolism
Drug: Liothyronine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in Patients With Insulin Receptor Mutations

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):

Primary Outcome Measures:
  • Thyroid hormone effects on glucose disposal [ Time Frame: 2 weeks ]
  • Thyroid hormone effects on hemoglobin A1C [ Time Frame: 6 months ]

Secondary Outcome Measures:
  • Quantification of fractional gluconeogenesis and glycogenolysis using isotopic tracers [ Time Frame: 2 weeks, 6 months ]
  • Thyroid hormone effects on glucose area under the curve using 7 point daily plasma glucose measurement, continuous interstitial fluid glucose monitoring, and oral glucose tolerance testing [ Time Frame: 2 weeks, 6 months ]
  • Thyroid hormone effects on tissue-specific glucose disposal in the fasting state in brown adipose tissue, white adipose tissue, and muscle using PET/CT [ Time Frame: 2 weeks ]

Estimated Enrollment: 20
Study Start Date: April 15, 2015
Estimated Study Completion Date: November 30, 2020
Estimated Primary Completion Date: November 30, 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Liothyronine
    Oral supplement given every 8 hours
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 tum, 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 glycemia control, suggesting that thyroid hormone treatment could have therapeutic benefit in this rare disease.

Aim

The purpose ofthis study is to determine if treatment with thyroid hormone will increase glucose disposal in patients with mutations ofthe insulin receptor, and thereby improve glycemia 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 BAT and muscle.
  3. Increases in glucose disposal will result in improved glycemia 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 glycemia control in diabetic patients with insulin receptor mutations.

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 2 WEEKS STUDY:

INCLUSION CRITRIA:

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02457897

Contacts
Contact: Rebecca J Brown, M.D. (301) 594-0609 brownrebecca@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
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)
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT02457897     History of Changes
Other Study ID Numbers: 150119
15-DK-0119
Study First Received: April 22, 2015
Last Updated: May 12, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Brown Adipose Tissue
Liothyronine
Insulin Receptors

Additional relevant MeSH terms:
Diabetes Mellitus
Insulin Resistance
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperinsulinism
Insulin
Hormones
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on May 25, 2017