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The metabolic role of growth hormone in humans with particular reference to fasting

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Introduction

Throughout history starvation has been a major threat to survival of the human species. Most inhabitants of the Western world are not accustomed to shortage of food but hunger remains a major global problem. Today, United Nations estimate that more than 800 million people in the world are chronically starving and malnourished and nine million men, women and children perish annually from hunger, starvation, disease and malnutrition (World Food Programme 2004).

The response to absolute deprivation of food proceeds in a number of stages, and the body can survive for around two months without any food intake as a result of coordinated regulation of metabolism [1]. During fasting, adipose tissue, muscle, liver and kidneys work in concert to supply, to convert, and to conserve fuels for the body. During the brief postabsorptive period of around 6 h, blood fuel homeostasis is maintained primarily by hepatic glycogenolysis and adipose tissue lipolysis. As fasting progresses, muscle proteolysis supplies gluconeogenic amino acids for hepatic gluconeogenesis. After a few days of starvation, the metabolic profile is set to conserve protein and to supply increased quantities of alternative fuels. In particular, free fatty acids and ketone bodies are utilized to maintain energy supplies.

During fasting and stress, growth hormone (GH) secretion is augmented [2], and these conditions may thus be viewed as the natural metabolic domain for GH action. The reciprocal association between insulin and GH (the feast–famine cycle) and its potential implications for substrate metabolism was initially recognised by Rabinowitz and Zierler [3], but surprisingly few studies of the metabolic impact of GH during fasting have been conducted. The metabolic effects of GH are complex and involve increased lipolysis, protein retention, impaired suppression of hepatic glucose production and decreased insulin-dependent glucose disposal, hyperglycemia, hyperinsulinemia, stimulation of IGF-I activity, and changes in body composition [4], [5], [6], [7], [8]. The degree to which potential secondary mediators contribute to the metabolic action of GH during fasting has not been completely investigated.

To outline the effects of GH on substrate metabolism during energy restriction the present thesis will review existing knowledge about the topic. The possible mechanisms underlying the metabolic effects of GH will be discussed.

Section snippets

The physiology of growth hormone secretion

Endogenous GH secretion rates are enhanced 5-fold by a 2-day fast in normal young men [2]. The metabolic and hormonal mechanisms by which nutritional deprivation affects the hypothalamic–somatotroph axis are not completely clarified. Until recently the regulation of GH release was believed to represent the net result of the antagonistic actions of hypothalamic growth hormone releasing hormone (GHRH) and somatostatin (SRIF) on the pituitary, as well as negative feedback via circulating IGF-I [9]

GH receptor and postreceptor signalling

Growth hormone receptors have been identified in many tissues including muscle, adipose tissue, liver, heart, kidney, brain and the pancreas [47], [48]. GH binds to a membrane receptor (GHR) which is part of the cytokine receptor superfamily [49]. The GHR exists in three forms, the full-length, long form composed of 620 amino acids, and two short forms of either 277 or 279 amino acids in length [50]. One of the short forms is membrane-bound, with a much shorter cytoplasmic domain. The soluble

Metabolic adaptation to starvation

Classic studies by Benedict [65] and Cahill [66], [67] have partly clarified the complex nature of the metabolic adaptations to starvation. More than 80 years ago Benedict [65] fasted a normal subject for 30 days, and by indirect calorimetry and measurement of excreted nitrogen found carbohydrate to provide only a small percentage of the body’s fuel, mainly for the first few days. Thereafter fat provided over 3/4 of the daily caloric consumption and protein the remainder. Benedict was unaware

Impact of GH on protein metabolism

Efforts to study the regulation of protein synthesis and degradation in vivo have been extended to include methods that examine the activity of the pathways involved (e.g., mRNA transcription and activation of translational regulatory elements). In particular the regulation of proteolysis is not fully understood, in part because of the complexity of the pathways involved in protein degradation. The bulk of all intracellular protein is degraded by the ubiquitin–proteasome pathway [106], [107].

Impact on insulin sensitivity

It is well described that prolonged fasting induces insulin resistance [70], which may be related to high circulating levels of GH [76]. Because GH promotes lipolysis in adipose tissue and elevation of GH is associated with increased plasma free fatty acid level [160], [174], [197], increased lipid availability has been suggested to be responsible for the insulin resistance observed with elevated GH levels. Neely have shown that after an overnight GH infusion in normal subjects, both GH and FFA

General conclusions

GH is traditionally considered of main importance for linear growth in childhood but the metabolic actions continue in adulthood. GH secretion is increased under conditions of fasting and stress and it is likely that GH exerts its major impact under such conditions. The mechanisms by which GH regulates metabolism are complex and include stimulation of lipolysis and increased fat utilisation, stimulation of the IGF-I system, insulin resistance and hyperinsulinemia, and protein conservation.

GH

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References (320)

  • P.I. Mansell et al.

    The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans

    Metabolism

    (1990)
  • K.S. Nair et al.

    Leucine, glucose, and energy metabolism after 3 days of fasting in healthy human subjects

    Am. J. Clin. Nutr.

    (1987)
  • K.N. Frayn

    Metabolic regulation. A human perspective

    (1996)
  • M.L. Hartman et al.

    Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men

    J. Clin. Endocrinol. Metab.

    (1992)
  • D. Rabinowitz et al.

    A metabolic regulating device based on the actions of human growth hormone and of insulin singly and together on the human forearm

    Nature

    (1963)
  • P.R. Bratusch-Marrain et al.

    The effect of growth hormone on glucose metabolism and insulin secretion in man

    J. Clin. Endocrinol. Metab.

    (1982)
  • R.A. Rizza et al.

    Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization

    Diabetes

    (1982)
  • K.C. Copeland et al.

    Acute growth hormone effects on amino acid and lipid metabolism

    J. Clin. Endocrinol. Metab.

    (1994)
  • A.A. Butler et al.

    Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles

    Annu. Rev. Physiol.

    (2001)
  • D.E. Cummings et al.

    Growth hormone therapy in adults

    Annu. Rev. Med.

    (2003)
  • M.L. Hartman

    Physiological regulators of growth hormone secretion

  • M. Kojima et al.

    Ghrelin is a growth-hormone-releasing acylated peptide from stomach

    Nature

    (1999)
  • M. Maes et al.

    Plasma somatomedin-C in fasted and refed rats: close relationship with changes in the liver somatogenic but not lactogenic binding sites

    J. Endocrinol.

    (1983)
  • C.A. Elmer et al.

    Nutritional-induced changes in hepatic insulin-like growth factor I (IGF-I) gene expression in rats

    Endocrinology

    (1987)
  • W.L. Lowe et al.

    Regulation by fasting of rat insulin-like growth factor I and its receptor. Effects on gene expression and binding

    J. Clin. Invest.

    (1989)
  • V. Beauloye et al.

    Impairment of liver GH receptor signaling by fasting

    Endocrinology

    (2002)
  • M. Berelowitz et al.

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

    Science

    (1981)
  • K.Y. Ho et al.

    Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man

    J. Clin. Invest.

    (1988)
  • M.L. Hartman et al.

    A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans

    J. Clin. Invest.

    (1993)
  • G.N. Cox et al.

    Recombinant human insulin-like growth factor (IGF)-binding protein-1 inhibits somatic growth stimulated by IGF-I and growth hormone in hypophysectomized rats

    Endocrinology

    (1994)
  • P.D. Lee et al.

    Regulation and function of insulin-like growth factor-binding protein-1

    Proc. Soc. Exp. Biol. Med.

    (1993)
  • J. Frystyk et al.

    The effect of oral glucose on serum free insulin-like growth factor-I and -II in healthy adults

    J. Clin. Endocrinol. Metab.

    (1997)
  • J. Frystyk et al.

    Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    J. Clin. Endocrinol. Metab.

    (2002)
  • H. Nørrelund et al.

    The effect of growth hormone on the insulin-like growth factor system during fasting

    J. Clin. Endocrinol. Metab.

    (2003)
  • Y. Date et al.

    Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

    Endocrinology

    (2000)
  • A.M. Wren et al.

    The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion

    Endocrinology

    (2000)
  • K. Takaya et al.

    Ghrelin strongly stimulates growth hormone release in humans

    J. Clin. Endocrinol. Metab.

    (2000)
  • N. Møller et al.

    Splanchnic release of ghrelin in humans

    J. Clin. Endocrinol. Metab.

    (2003)
  • H. Ariyasu et al.

    Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans

    J. Clin. Endocrinol. Metab.

    (2001)
  • D.E. Cummings et al.

    Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery

    N. Engl. J. Med.

    (2002)
  • D.E. Cummings et al.

    A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

    Diabetes

    (2001)
  • M. Tschop et al.

    Post-prandial decrease of circulating human ghrelin levels

    J. Endocrinol. Invest.

    (2001)
  • T. Shiiya et al.

    Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion

    J. Clin. Endocrinol. Metab.

    (2002)
  • M. Tschop et al.

    Circulating ghrelin levels are decreased in human obesity

    Diabetes

    (2001)
  • B. Otto et al.

    Weight gain decreases elevated plasma ghrelin concentrations of patients with with anorexia nervosa

    Eur. J. Endocrinol.

    (2001)
  • A.F. Muller et al.

    Ghrelin drives GH secretion during fasting in man

    Eur. J. Endocrinol.

    (2002)
  • H. Nørrelund et al.

    Ghrelin immunoreactivity in human plasma is suppressed by somatostatin

    Clin. Endocrinol.

    (2002)
  • F. Broglio et al.

    Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans

    J. Clin. Endocrinol. Metab.

    (2002)
  • A.L. Barkan et al.

    Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels

    J. Clin. Endocrinol. Metab.

    (2003)
  • A.M. Haqq et al.

    Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Praeder–Willi syndrome

    J. Clin. Endocrinol. Metab.

    (2003)
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