Mechanisms of putative IGF-I receptor resistance in active acromegaly

Acromegaly is a disease characterized by overproduction of growth hormone (GH). As a consequence of excessive GH secretion, circulating insulin-like growth factor-I (IGF-I) is elevated in active (untreated) acromegaly. IGF-I is often used as a marker of disease activity and growth hormone status in acromegaly. Although IGF-I can directly improve insulin sensitivity and glucose uptake in muscles, the excessive GH secretion in active acromegaly frequently leads to insulin resistance, glucose intolerance and even diabetes. In this review evidence will be discussed that in active acromegaly chronically elevated IGF-I, insulin and soluble Klotho (S-Klotho) levels play a pathophysiological role in the development of IGF-I receptor (IGF-IR) resistance. It is postulated that as soon as circulating IGF-I, insulin and S-Klotho rise above a certain level the IGF-IR becomes relatively resistant to actions of IGF-I. The development of a degree of IGF-IR resistance for metabolic actions may help to explain why in active acromegaly diabetogenic effects of GH predominate and are not completely counteracted and neutralized by elevated circulating levels of IGF-I. Further studies are necessary in order to support this hypothesis.