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.