Metabolic Actions of Insulin-Like Growth Factor-I in Normal Physiology and Diabetes
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
References (104)
- et al.
The roles of tyrosines 24, 31, and 60 in the high-affinity binding of insulin-like growth factor-I to the type 1 insulin-like growth factor receptor
J Biol Chem
(1990) - et al.
Molecular regulation of insulin-like growth factor-I and its principal binding protein, IGFBP-3
Prog Nucleic Acid Res Mol Biol
(1998) - et al.
Resistance training, and IGF involvement in the maintenance of muscle mass during the aging process
Ageing Res Rev
(2006) Skeletal muscle hypertrophy and atrophy signaling pathways
Int J Biochem Cell Biol
(2005)- et al.
Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology
Cell Immunol
(2008) - et al.
Impaired metabolic response to recombinant insulin-like growth factor-1 in dialysis patients
Kidney Int
(1995) - et al.
Specific binding of human growth hormone but not insulin-like growth factors by human adipocytes
FEBS Lett
(1986) - et al.
Increased p85alpha potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess
J Biol Chem
(2005) Free insulin-like growth factors—measurements and relationships to growth hormone secretion and glucose homeostasis
Growth Horm IGF Res
(2004)- et al.
Measurement of growth hormone, insulin-like growth factor I and their binding proteins: the clinical aspects
Clin Chim Acta
(2001)
Regulation of IGFBP-1 in humans
Prog Growth Factor Res
Low levels of insulin-like growth factor binding protein-1 (IGFBP-1 ) are prospectively associated with the incidence of type 2 diabetes and impaired glucose tolerance (IGT): the Soderakra Cardiovascular Risk Factor Study
Diabetes Metab
C-reactive protein and the insulin-like growth factor (IGF) system in relation to risk of cardiovascular disease in different ethnic groups
Atherosclerosis
Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study
Lancet
Maternal plasma concentrations of IGF-1, IGFBP-1, and C-peptide in early pregnancy and subsequent risk of gestational diabetes mellitus
Am J Obstet Gynecol
Insulin-like growth factor (IGF) axis, inflammation, and glucose intolerance among older adults
Growth Horm IGF Res
Insulin-like growth factor I (rhIGF-I) as a therapeutic agent for hyperinsulinemic insulin resistant diabetes mellitus
Diabetes Res Clin Pract
Rh/IGF/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose
Growth Horm IGF Res
Competition for binding to insulin-like growth factor (IGF) binding protein-2, 3, 4, and 5 by the IGFs and IGF analogs
Endocrinology
Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity
EMBO J
The growth hormone receptor: mechanism of activation and clinical implications
Nat Rev Endocrinol
Dietary components that regulate serum somatomedin-C concentrations in humans
J Clin Invest
Hormonal and nutritional regulation of IGF-I and its binding proteins
Horm Res
Normal growth and development in the absence of hepatic insulin-like growth factor I
Proc Natl Acad Sci U S A
Effect of insulin on the insulin-like growth factor system in children with new onset dependent diabetes
J Clin Endocrinol Metab
Regulation by fasting of insulin-like growth factor I and its receptor: effects on gene expression and binding
J Clin Invest
The role of insulin-like growth factor binding proteins
Neuroendocrinol
The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system
J Endocrinol
Free rather than total circulating insulin-like growth factor-I determines the feedback on growth hormone release in normal subjects
J Clin Endocrinol Metab
Insulin signal transduction and the IRS proteins
Annu Rev Pharmacol
AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation
Mol Endocrinol
Role of the insulin-like growth factor-I decline in the induction of atrogin-1/MAFbx during fasting and diabetes
Endocrinol
rhIGF-I enhances whole body protein anabolism and significantly diminishes the protein-catabolic effects of prednisone in humans, without a diabetogenic effect
J Clin Endocrinol Metab
Recombinant human IGF-I has significant anabolic effects in adults with GH receptor deficiency: studies on protein, glucose and lipid metabolism
J Clin Endocrinol Metab
IGF-I and GH treatment in GH deficient humans: differential effects on protein, glucose, lipid and calcium metabolism
J Clin Endocrinol Metab
Anabolic effect of insulin-like growth factor in combination with insulin-like growth factor binding protein-3 in severely burned adults
J Trauma
Testosterone deficiency in young men: marked alterations in whole body protein kinetics strength and adiposity
J Clin Endocrinol Metab
Insulin-like growth factor-I stimulates both cell growth and lipogenesis during differentiation of human mesenchymal stem cells into adipocytes
J Clin Endocrinol Metab
Insulin-like growth factor I and growth hormone (GH) treatment in GH-deficient humans: differential effects on protein, glucose, lipid, and calcium metabolism
J Clin Endocrinol Metab
Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes
Genes Dev
Muscle-specific overexpression of CD36 reverses the insulin resistance and diabetes of MKR mice
Endocrinol
Therapeutic aspect of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adults
Diabetes Obes Metab
Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism of growth hormone-mediated insulin resistance
Diabetes
Insulin-like growth factor I circumvents defective insulin action in human myotonic dystrophy skeletal cells
Endocrinol
Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects
Diabetes
Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus
Endocrinol
Inactivation of muscle insulin and IGF-I receptors and insulin responsiveness
Curr Opin Clin Nutr Metab Care
Liver-specific Igf-1 gene deletion leads to muscle insulin insensitivity
Diabetes
IGF-I/IGF-binding protein-3 combination improves insulin resistance by GH-dependent and independent mechanisms
J Clin Endocrinol Metab
Growth hormone replacement therapy for adults: into the new millennium
Growth Horm IGF Res
Cited by (0)
This work is supported by a grant from the National Institutes of Health AGO2331.
Conflict of interest: None.