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It is also possible that in active acromegaly, chronic exposure to elevated IGF-I levels resets IGF-IR responsiveness via the induction of IGF-IR resistance (70), as it has been demonstrated that prolonged stimulation with IGF-I induces functional IGF-IR resistance in vitro through the negative feedback loop (72)

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Species-specific differences in receptor distribution further complicate extrapolation from preclinical models to humans, and the presence of these receptors in peripheral tissues raises concerns regarding off-target uptake (Zhang et al., 2020)