Abstract
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.
Highlights
Is a disease characterized by overproduction of growth hormone (GH)
GH produced by the pituitary is the main regulator of circulating insulin-like growth factor-I (IGF-I), which is produced by the liver [36,56]
Whereas GH leads to a decreased glucose uptake, elevated insulin secretion, reduced insulin sensitivity and an increased lipolysis, IGF-I leads to an increased glucose uptake, a reduced insulin secretion, enhanced insulin sensitivity and neutral effects on lipolysis (Table 1)
Summary
In healthy subjects GH is released from somatotroph cells of the anterior pituitary in a pulsatile fashion and activates the growth hormone receptor (GHR) which is present at the cellular surface of target tissues such as liver, muscle, adipose tissue, bone and kidney [36]. It has been found that IGF-I itself might exert negative feedback on GH secretion at the level of the hypothalamus and at anterior pituitary [5,7] (Fig. 1). IGF-I inhibits basal and GHRH-stimulated GH release from cultured pituitary cells after 24 h of incubation [5]. Other important mechanisms whereby GH signaling is thought to be negatively regulated is through protein tyrosine phosphatases (PTPs) and ubiquitin-dependent GHR endocytosis [33]. Precise regulation of GH signaling is important for the proper maintenance of body growth and metabolism
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