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

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.

• Liothyronine (Drug): Oral supplement given every 8 hours

Primary outcomes

• Total Body Glucose Disposal in the Fasting State [2 weeks]
• Hemoglobin A1C [6 months]

Secondary outcomes

• Muscle Glucose Uptake [2 weeks]
• Muscle Glucose Uptake [6 months]

Sex: All, ages: 12 Years to 65 Years

* 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%.

Participant flow

Outcome results

• Total Body Glucose Disposal in the Fasting State (Primary), Mean, μmol/kg LBM (Lean Body Mass)/min: Patients With Insulin Receptor Mutation 21.47 +/- 6
• Hemoglobin A1C (Primary), Mean, percentage of glycosylated hemoglobin: Patients With Insulin Receptor Mutation 9.1 +/- 3
• Muscle Glucose Uptake (Secondary), Mean, μmol/min/100ml: Patients With Insulin Receptor Mutation 0.9 +/- 0.08
• Muscle Glucose Uptake (Secondary), Mean, μmol/min/100ml: Patients With Insulin Receptor Mutation 2.0 +/- 0.2

Adverse events

Time frame: 6 months

Other adverse events by term

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• 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
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• Results publication: 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
• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2018-02-15)

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