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. 2019 Jun 1;104(6):2216-2228.
doi: 10.1210/jc.2018-02289.

Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes

Yevgeniya S Kushchayeva  1 , Sergiy V Kushchayev  2 , Megan Startzell  1 , Elaine Cochran  1 , Sungyoung Auh  1 , Yuhai Dai  3 , Marissa Lightbourne  4 , Monica Skarulis  1 , Rebecca J Brown  1
Affiliations

Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes

Yevgeniya S Kushchayeva et al. J Clin Endocrinol Metab. .

Abstract

Context: Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia.

Objective: The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population.

Design: Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin.

Results: The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin.

Conclusion: Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.

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Figures

Figure 1.
Figure 1.
Thyroid ultrasonography in patients with homozygous (−/−) (A) vs heterozygous (+/−) (B) INSR mutations. Patients with INSR−/− mutations had significantly larger thyroid volume adjusted for BSA (10.4 ± 5.1 vs 3.8 ± 1.5 mL, P = 0.017). One patient with INSR−/− mutation was diagnosed with PTC at age 18 [in (A); thyroid US with white arrow at the location of PTC]. Solid red lines show thyroid gland borders; dashed red lines indicate that a portion of the thyroid tissue was not captured by the US probe.
Figure 2.
Figure 2.
Proposed mechanism of thyroid enlargement in patients with homozygous INSR mutation. Solid blue arrows indicate intact signaling pathways. Dashed black arrows indicate inhibited signaling pathways. Red Xs indicate blocked receptors and downstream signaling. In patients with homozygous INSR mutation the proliferative effect on thyroid tissue might be mediated via the direct stimulation of IGF-1R by a high concentration of circulating insulin and/or hyperinsulinemia-mediated upregulation of hybrid receptors (+). A low level of IGF-1 can upregulate the number of IGFR1 receptors (++) and/or increase IGF-1R activity, resulting in increased insulin binding to IGF-1Rs with further stimulation of the MAPK pathway. MAPK-mediated proliferative signaling will lead to thyroid enlargement.
See this image and copyright information in PMC

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