Nutrition is one of the main regulators of circulating IGF-I. In humans, serum IGF-I concentrations are markedly lowered by energy and/or protein deprivation. Both energy and proteins are critical in the regulation of serum IGF-I concentrations. Indeed, after fasting, optimal intake of both energy and protein is necessary for the rapid restoration of circulating IGF-I. We believe, however, that in adult humans energy may be somewhat more important than protein in this regard. While the lowest protein intake is able to increase IGF-I in the presence of adequate energy, there is a threshold energy requirement below which optimal protein intake fails to raise IGF-I after fasting. When energy intake is severely reduced, the carbohydrate content of the diet is a major determinant of responsiveness of IGF-I to GH. The essential amino acid content of the diet is also critical for the optimal restoration of IGF-I after fasting, when protein intake is reduced. The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. For these indications, IGF-I measurement is more sensitive and more specific than measurement of the other nutrient-related serum proteins (albumin, prealbumin, transferrin, retinol-binding protein). Animal models have been developed to investigate the mechanisms responsible for the nutritional regulation of IGF-I. There is no doubt that many mechanisms are involved (Fig. 12). Decline of serum IGF-I in dietary restriction is independent of the diet-induced alterations in pituitary GH secretion. The role of the liver GH receptors is dependent on the severity of the nutritional insult. In severe dietary restriction (fasting), a marked decrease of the number of somatogenic receptors supports the role of a receptor defect in the decline of circulating IGF-I. In contrast, in less severe forms of dietary restriction (protein restriction), the decline of IGF-I results from a postreceptor defect in the GH action at the hepatic level. Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression is mainly caused by nutrient deficiency and less importantly by the nutritionally induced hormonal changes (insulin and T3). Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs.(ABSTRACT TRUNCATED AT 400 WORDS)

Nutritional Regulation of the Insulin-Like Growth Factors*

Somatostatin and Its Receptor Family

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

Since the original somatomedin hypothesis was conceived, a number of important discoveries have allowed investigators to modify the concept. Originally somatic growth was thought to be controlled by pituitary GH and mediated by circulating insulin-like growth factor-I (IGF-I, somatomedin C) expressed exclusively by the liver. With the discovery that IGF-I is produced by most, if not all, tissues, the role of autocrine/paracrine IGF-I vs. the circulating form has been hotly debated. Recent experiments using transgenic and gene-deletion technologies have attempted to answer these questions. In the liverspecific igf-1 gene-deleted mouse model, postnatal growth and development are normal despite the marked reduction in circulating IGF-I and IGF-binding protein levels; free IGF-I levels are normal. Thus, the normal postnatal growth and development in these animals may be due to normal free IGF-I levels (from as yet unidentified sources), although the role of autocrine/paracrine IGF-I has yet to be determined.

The Somatomedin Hypothesis: 2001

The neuroregulation of growth hormone (GH) secretion is mediated in part by a stimulatory, GH-releasing factor (GRF) and an inhibitory peptide, somatostatin1, both of which reach the adenohypophysis by the hypothalamic-hypophysial portal system2. Somatostatin has been shown to be a tetradecapeptide3,4, a large form of which was later also sequenced5. The existence of a GRF is supported by physiological evidence6–9 and by reports of GH-releasing activity in hypothalamic extracts10–17. Although several agents with GH-releasing activity have been identified14–16, none is of high potency and fulfils the criteria expected of a physiological GRF18,19. GH-releasing activity observed in extracts of carcinoid and pancreatic islet tumours removed from patients with GH hypersecretion, acromegaly and pituitary adenoma or hyperplasia has been partially characterized20–23. We report here the sequence of a 40 residue GH-releasing peptide purified from a pancreatic islet tumour described earlier by Thorner et al.23. A synthetic replicate of this peptide, termed human pancreatic tumour GRF [hpGRF(1–40)]-OH, co-elutes on HPLC with the native peptide and is highly potent in stimulating GH secretion in vitro and in vivo. A close structural homology with the peptides of the glucagon–secretin family, and more particularly with PHI24, is recognized. Structure–activity studies show that hpGRF(1–29)-NH2 has full intrinsic activity and potency in vitro.

Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour.

Somatomedin-C stimulates somatostatin release to a maximum of 390 percent of basal release during short-term (20-minute) incubation of rat hypothalamus. It has no effect on basal or stimulated growth hormone release from primary cultures of rat adenohypophyseal cells during a 4-hour incubation, but inhibits stimulated release by more that 90 percent after 24 hours. These findings suggest that somatomedin-C participates in the growth hormone negative feedback loop with an immediate effect on hypothalamic somatostatin and a delayed effect on the anterior pituitary.

http://science.sciencemag.org/content/sci/212/4500/1279.full.pdf

Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary

We have examined the biological effects of a partially purified ectopic GH-releasing peptide (GHRF) in primary monolayer cultures of rat adenohypophyseal cells and compared them with the GH-releasing activity in an acetic acid extract of porcine stalk median eminence (pSME) and with dibutyryl cAMP (DBcAMP). Ectopic GHRF was isolated from a pancreatic islet adenoma and two abdominal carcinoid tumors metastatic to the liver obtained from patients with clinical manifestations of GH hypersecretion. Ectopic GHRF was partially purified by gel filtration chromatography on Sephadex G- 75 or by reverse phase high performance liquid chromatography. The GH-releasing activity of pSME was partially purified by reverse phase high performance liquid chromatography; the two preparations exhibited chromatographic dissimilarities. Both crude ectopic GHRF and pSME stimulated GH release in a dose-dependent manner and exhibited parallel dose-response curves. The potency of ectopic GHRF, however, was 22 times greater than that...

Biological Effects of an Ectopic Growth Hormone-Releasing Peptide in Cultured Adenohypophyseal Cells: Comparison with Growth Hormone-Releasing Activity of Porcine Hypothalamus*

Lily Chu

Papers

Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary

Biological Effects of an Ectopic Growth Hormone-Releasing Peptide in Cultured Adenohypophyseal Cells: Comparison with Growth Hormone-Releasing Activity of Porcine Hypothalamus*

Thyrotropin increases the iodine content of rat circulating thyroglobulin as measured by equilibrium density gradient centrifugation.