Metabolic Actions of Insulin-Like Growth Factor-I in Normal Physiology and Diabetes

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Introduction

Insulin-like growth factor-I (IGF-I) has significant structural homology with proinsulin. IGF-I, IGF-II and proinsulin evolved from a single precursor molecule approximately 60 million years ago. The function of that single precursor molecule was to provide a chemical signal for cells within primitive organisms to establish that adequate nutrient was present not only for basal metabolic needs but also for protein synthesis and cell proliferation. At the time vertebrates appeared, this system evolved into one with more complexity to be able to store calories as fat. At that time, insulin diverged from IGF-I and the pituitary gland appeared along with growth hormone (GH). The function of these 3 hormones was linked to be able to regulate both nutrient availability during periods of starvation and repletion as well as continuing to provide adequate signals and substrate for growth. As such, the regulation of synthesis and the secretion of these 3 hormones are directly linked to nutrient intake. Because insulin, IGF-I, and IGF-II evolved from a single precursor, they continue to share significant structural homology; however, there are also distinct differences. The primary domains within IGF-I and insulin that determine receptor binding have significant amino acid differences that account for major differences in affinity for their respective receptors.1 Similarly, the IGFs have the unique characteristic of being able to bind to IGF-binding proteins (IGFBPs), which is determined by a specific amino acid sequence in positions, 3, 4, 15, 16 of N terminus of IGF-I molecule and homologous substitutions in IGF-II.2 These structural differences provide an important distinction for the regulation of IGF-I and insulin bioavailability and, thus indirectly regulate their effects on metabolism.

IGF-I and insulin have distinct receptors. Both receptors are tyrosine kinase–containing receptors and they show 48% amino acid sequence homology.3 Despite these similarities, the ligand-binding specificity is strict. The affinity of the IGF receptor is 1000 times greater for IGF-I than insulin, and the insulin receptor has a 100-fold greater affinity for insulin compared with IGF-I. Insulin and IGF-I receptor densities vary widely among cell types (ie, mature differentiated hepatocytes and adipocytes have abundant insulin receptors, whereas they have almost no IGF-I receptors). Conversely, cell types, such as vascular smooth muscle cells, have abundant IGF-I receptors and minimal insulin receptors. This difference in receptor distribution accounts for many of the differences in insulin and IGF-I actions. GH has an entirely different structure and its receptor belongs to the cytokine receptor family.4 GH has a major regulatory influence on the metabolic actions of both IGF-I and insulin and functions in several important ways that are distinct from insulin and IGF-I to modulate nutrient availability that is necessary for both balanced tissue growth and the maintenance of normal intermediary metabolism. Therefore, coordinated regulation of the metabolic actions of these 3 hormones provides an important basis for understanding their individual effects on intermediary metabolism and how they function coordinately to maintain nutrient balance.

Section snippets

Nutrient regulation of IGF-I secretion

As can be predicted from the phylogenetic development of IGF-I, the primary variable regulating plasma IGF-I concentrations is nutrient intake. Both total caloric and protein intake are important regulatory variables.5 The effect of caloric intake is such that if caloric intake is reduced by approximately 50%, there is a significant reduction in IGF-I secretion. The effects of protein are more graded in that even small reductions result in changes in IGF-I.6 For each 25% reduction in protein

Metabolic effects of IGF-I

Although IGF-I is classically considered an important growth factor because it stimulates the growth of all cell types, it has major metabolic effects. This overarching effect of IGF-I on metabolism is to provide a signal to cells that adequate nutrient is available to avoid apoptosis, enhance cellular protein synthesis, enable cells to undergo hypertrophy in response to an appropriate stimulus, and to allow stimulation of cell division. Therefore, even in cytostatic adult tissues, such as

Protein metabolism

In cells in tissue culture, IGF-I is a potent stimulant of protein synthesis. The phosphoinositide (PI)-3 kinase pathway modulates this response. Following IGF-I receptor activation, the receptor tyrosine kinase, phosphorylates tyrosines on the adaptor protein termed insulin receptor substrate-1 (IRS-1),14 which provides a binding site for the p85 subunit of PI-3 kinase, which is then activated. Activation of PI-3 kinase results in the coordinate stimulation of AKT, which then leads to the

Fat metabolism

Although mature adipocytes do not express IGF-I receptors, preadipocytes have abundant IGF-I receptors and IGF-I stimulates preadipocyte differentiation.26 However, as preadipocytes differentiate they markedly reduce their IGF-I receptor number and insulin receptors become predominant. Thus, in well-formed adipose tissue beds, physiologic concentrations of IGF-I are not effective in stimulating changes in lipid synthesis or lipolysis and IGF-I has effects on primary adipocytes only at high

Effects on carbohydrate metabolism

An understanding of the effect of IGF-I on carbohydrate metabolism depends on knowledge of its effects in modulating insulin and GH actions. IGF-I reduces serum GH concentrations and it also reduces GH’s direct effects on insulin suppression of hepatic gluconeogenesis; by increasing free fatty acid uptake in muscle, it indirectly enhances hepatic insulin action.31 In both fat and liver, GH stimulates the synthesis of the p85 subunit of PI-3 kinase.32 This relative increase in p85 leads to the

IGF-I and the metabolic syndrome

Several studies have attempted to correlate total plasma IGF-I concentrations with the presence of the metabolic syndrome. In general, patients with a low-normal IGF-I who are obese and meet other criteria for metabolic syndrome tend to have a worse cardiovascular disease outcomes than those with a midnormal to high-normal IGF-I.49 Clearly, many of these patients have insulin resistance. Whether the degree of resistance or the accompanying changes in inflammatory cytokine secretion is the

IGF-I Gene Polymorphisms and Changes in Metabolism

A polymorphism caused by a CA dinucleotide repeat in a microsatellite that is 1 kb upstream from the IGF-I transcription start site results in lower serum IGF-I levels, and some investigators have found this is associated with a lower birth weight.75 This polymorphism occurs in approximately 11% of the Dutch Caucasian population. A study of 477 Dutch patients with evidence of ischemic heart disease and 808 control subjects demonstrated an increase relative risk of 1.7:1.0 for the presence of

Summary

IGF-I is ancestrally related to proinsulin and, therefore, retains some physiologic effects that complement the ability of insulin to stimulate glucose uptake. Furthermore, the actions of IGF-I are coordinately regulated with GH, thus enabling organisms to breakdown fat and use this as a substrate to meet the energy needs that are required for growth and to coordinate their effects for stimulation of protein synthesis and an anabolic response. Therefore, IGF-I plays an integral role in

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    This work is supported by a grant from the National Institutes of Health AGO2331.

    Conflict of interest: None.

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