Influence of the crosstalk between growth hormone and insulin signalling on the modulation of insulin sensitivity
Introduction
Growth hormone (GH) and insulin are important regulators of cellular and whole body metabolism as well as somatic growth and body composition. Studies have indicated complex feedback effects of GH on insulin action.
Almost 70 years ago, Houssay and collaborators demonstrated that GH counteracts the action of insulin on glucose homoeostasis [1]. This concept was further reinforced by studies performed in both humans and animals that demonstrated that the elevation of circulating GH levels causes hyperinsulinemia and insulin resistance [2], [3]. Acromegalic patients develop insulin resistance, which in some cases leads to overt diabetes mellitus [2], [3], [4], [5]. A significant impairment of glucose metabolism has also been observed after exogenous administration of GH in physiological or pharmacological doses in humans [6], [7], [8] and animals [2], [3], [9], [10]. The opposite condition, deficiency of GH, is associated with increased insulin sensitivity, decreased insulin secretion and decreased fasting glucose concentrations [2], [3], [11], [12], [13]. Given the growing utilization of GH in hormone-replacement therapies, the effect of the GH-insulin-like growth factor-I (IGF-I) axis on carbohydrate metabolism has become of increasing interest.
Though the metabolic consequences of altered GH levels on insulin sensitivity and action are well known, the sequence of molecular events behind these events has not been clarified yet. It has been demonstrated that at certain post-receptor levels, the signals of GH and of its main mediator, IGF-I, converge with that of insulin [14]. In this review we will examine this crosstalk between the insulin and the GH signalling systems and its physiological implications. Particularly, we will focus on the potential repercussion of this convergence in the modulation of insulin sensitivity and summarize information from recent reports that have added to the clarification of the mechanisms of GH-induced insulin resistance. Also, relevant information provided by the phenotype of various animal models of GH excess, deficiency or resistance will be examined.
In addition, we will dedicate a section to discuss recent evidence obtained from genetically engineered mice that have greatly improved our knowledge of the specific roles of GH and IGF-I on glucose metabolism.
Section snippets
Signalling by insulin
Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. The insulin receptor (IR) is a member of a subfamily of receptor tyrosine kinases that includes the IGF-I receptor (IGFR) and the insulin receptor-related receptor (IRR) [15], [16]. It is a tetrameric protein that consists of two α- and two β-subunits. Insulin binding to the α-subunit leads to activation of the kinase activity residing in the β-subunit, followed by
Signalling by GH
The GH receptor (GHR) belongs to the superfamily of cytokine/hematopoietin receptors. Like insulin, GH signalling also involves tyrosine-phosphorylation of multiple intracellular proteins. But, in contrast to the mechanism used by the IR, the GHR lacks intrinsic tyrosine kinase activity. Instead, it is constitutively associated with a tyrosine-kinase named Janus kinase (JAK) 2 [39]. Initiation of GH signalling involves binding of the hormone to two GHR molecules [40]. This dimerization event,
Shared signalling pathways between insulin and GH: relationship to the insulin-like effects of GH
Growth hormone has both acute and chronic effects on carbohydrate and lipid metabolism. The acute effects of GH are designated as insulin-like because under conditions of deficit of the hormone such as those seen in hypopituitary subjects and hypophysectomized animals, GH is able to stimulate glucose and aminoacid transport, lipogenesis and protein synthesis [2], [3]. However, these effects are short-lived, and their physiological significance is not clear. The chronic anti-insulin effects of
Relevance of the signalling crosstalk between GH and insulin
The physiological insulin antagonistic actions of GH and the development of insulin resistance and diabetes in states of GH excess may be the consequence at least in part of the ability of GH to interfere with the capacity of insulin to promote carbohydrate metabolism [2], [3]. Signalling crosstalk between GH and insulin could contribute to the diabetogenic actions of GH, although the extent and importance of this contribution is not defined yet [14]. Under fasting conditions, GH is capable of
Dissecting the relative roles of GH and IGF-I in the control of insulin sensitivity: evidence from animal models
In the past, it has been argued that IGFs were unlikely to have any direct metabolic role, especially in relation to glucose homeostasis. However, more recent data indicated that circulating IGF-I and its binding proteins are capable of modulating glucose levels and may have direct effects on glucose homeostasis [113], [114], [115]. An important contribution to the clarification of the mechanisms involved in both insulin and IGF-I action has been provided by the generation and analysis of
General conclusions
Accumulating evidence suggests that GH appears to modulate insulin sensitivity by multiple mechanisms. The utilization of rodent models of chronic GH excess, deficiency or resistance has provided relevant information to this issue. Excess of GH is associated with reduced IR levels together with increased basal phosphorylation in liver and muscle. This alteration has been demonstrated to be secondary to the resultant hyperinsulinemia than to GH itself. Chronic exposure to GH excess is associated
Acknowledgments
F.P. Dominici, A.I. Sotelo and D. Turyn, are Career Investigators from Consejo Nacional de Investigaciones Cientı́ficas y Tecnológicas (CONICET), and received grant support from the University of Buenos Aires (UBA) and CONICET. D. Turyn also received grant support from Agencia Nacional de Promoción Cientı́fica y Tecnológica (ANPCYT). D.P. Argentino and M.C. Muñoz are research fellows from CONICET. J. Miquet is a research fellow from UBA.
We apologize to all those whose work relevant to this
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