Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations

Abstract

Context: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume.

Objective: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation.

Design: Single-arm, open-label study of liothyronine.

Setting: National Institutes of Health.

Participants: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation.

Intervention: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4).

Outcomes: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c.

Results: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism.

Conclusion: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

Keywords: INSR mutation; extreme insulin resistance; liothyronine.

Figure 1.

Study design. Abbreviations: DEXA, dual energy x-ray absorptiometry; EKG, electrocardiogram; FDG PET, fluorodeoxyglucose positron emission tomography; T3, triiodothyronine. ¹TSH, free thyroxine, total thyroxine, free triiodothyronine, total triiodothyronine, reverse triiodothyronine. ²Free fatty acids, lipid panel, osteocalcin, sex hormone–binding globulin.

Figure 2.

CONSORT flow chart. F18-FDG PET, [¹⁸F] fluorodeoxyglucose positron emission tomography; HbA1c, hemoglobin A1c.

Figure 3.

Thyroid panel before and during liothyronine administration. All measurements are trough values (before liothyronine dosing) except for peak TT3 (measured 3 hours after dosing). Dotted lines indicate upper (fT3, TT3) or lower (TSH, fT4, TT3) normal reference ranges. Data shown as mean ± SEM. Liothyronine was initiated after the day 1 trough measurement (indicated by black arrows). (A) A decrease in TSH consistent with mild hyperthyroidism was seen beginning on day 4 of liothyronine. (B) Increases in fT3 above the upper limit of normal, and (C, D) TT3 trough and TT3 peak above the target levels were seen on days 3, 2, and 3, respectively, of liothyronine. (E) fT4 and (F) rT3 were below the lower limit of normal on day 8. TT3 peak and rT3 were not measured at the 180-day time point. Abbreviations: fT3, free triiodothyronine; fT4, free thyroxine; rT3, reverse triiodothyronine; TT3, total triiodothyronine; TT4, total thyroxine.

Figure 4.

Effects of liothyronine on glycemia. (A) Glucose disposal (R_d) did not change after 2 weeks but increased after 6 months of liothyronine. (B) Hemoglobin A1c (HbA1c) did not change after 2 weeks or 6 months of liothyronine. (C) Fructosamine significantly decreased after 2 weeks, but this was not maintained after 6 months. One patient (open square on graphs) had increased hemoglobin A1c and fructosamine at the 6-month visit in the context of an accidental >50% decrease in insulin dose. (D) Glucose levels before meals (pre) and 2 hours after meals (post) at baseline (closed circles) and after 2 weeks of liothyronine (open squares). Area under the curve for glucose did not change with liothyronine administration.

Figure 5.

Tissue glucose uptake based on fluorodeoxyglucose positron emission tomography studies. (A) Glucose uptake by muscle did not change after 2 weeks of liothyronine, but significantly increased after 6 months. (B) Glucose uptake by WAT significantly decreased after 2 weeks but increased after 6 months of liothyronine. Data are presented in mean ± standard error of the mean of within-subject replicates. (C) Small amounts of BAT were detectable at baseline and during liothyronine treatment with no visually apparent increase in BAT after 2 weeks or 6 months of liothyronine. Red color pointed to by black arrows represents the areas that met criteria for BAT (computed tomography voxel values consistent with adipose tissue -300 to -10 Hounsfield units) and positron emission tomography standardized uptake value values ≥1.0 in the positron emission tomography image registered to the computed tomography). Glucose uptake in regions meeting criteria for BAT was not quantified because of the small volume of tissue. Abbreviations: BAT, brown adipose tissue; WAT, white adipose tissue.

Figure 6.

Relative expression of mRNA in muscle (n = 2) and WAT (n = 1) after 2 weeks of liothyronine compared with baseline. No statistical comparisons were performed because of small sample size. The most marked changes were a 4-fold increase in expression of the glucose transporter GLUT4 in muscle (but not WAT), and a 12-fold increase in the brown adipose tissue marker ZIC1 in WAT after liothyronine. Abbreviations: CD137 – cluster of differentiation 137; GLUT 1 and 4, glucose transporters 1 and 4; HOXC8, homeobox C8; LEP, leptin; TBX1, T-box 1; TMEM26, transmembrane protein 26; UCP1 and 3, uncoupling proteins 1 and 3; ZIC1, Zinc finger protein 1; WAT, white adipose tissue.