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Thyroid hormone effects on glucose disposal in patients with insulin receptor mutations.

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
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 q8 hours for 2 weeks (n=7); additional 6 months treatment in those with 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-FDG PET/CT; 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/kgLBM/min, p=0.02), and muscle (0.7±0.1 vs 2.0±0.2 µmol/min/100ml, p<0.0001) and WAT glucose uptake (1.2±0.2 vs 2.2±0.3 µmol/min/100ml, p<0.0001). BAT glucose uptake could not be quantified due to 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.