Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene Transcription

Abstract

Insulin and insulin-like growth factor-1 (IGF-1) act on highly homologous receptors, yet in vivo elicit distinct effects on metabolism and growth. To investigate how the insulin and IGF-1 receptors exert specificity in their biological responses, we assessed their role in the regulation of gene expression using three experimental paradigms: 1) preadipocytes before and after differentiation into adipocytes that express both receptors, but at different ratios; 2) insulin receptor (IR) or IGF1R knock-out preadipocytes that only express the complimentary receptor; and 3) IR/IGF1R double knock-out (DKO) cells reconstituted with the IR, IGF1R, or both. In wild-type preadipocytes, which express predominantly IGF1R, microarray analysis revealed ϳ500 IGF-1 regulated genes (p < 0.05). The largest of these were confirmed by quantitative PCR, which also revealed that insulin produced a similar effect, but with a smaller magnitude of response. After differentiation, when IR levels increase and IGF1R decrease, insulin became the dominant regulator of each of these genes. Measurement of the 50 most highly regulated genes by quantitative PCR did not reveal a single gene regulated uniquely via the IR or IGF1R using cells expressing exclusively IGF-1 or insulin receptors. Insulin and IGF-1 dose responses from 1 to 100 nM in WT, IRKO, IGFRKO, and DKO cells re-expressing IR, IGF1R, or both showed that insulin and IGF-1 produced effects in proportion to the concentration of ligand and the specific receptor on which they act. Thus, IR and IGF1R act as identical portals to the regulation of gene expression, with differences between insulin and IGF-1 effects due to a modulation of the amplitude of the signal created by the specific ligandreceptor interaction.Insulin and insulin-like growth factor-1 (IGF-1) 2 are closely related hormones that control different aspects of growth and metabolism in many organisms. They act on specific tyrosine kinase receptors, i.e. the insulin receptor (IR) and the IGF-1 receptor (IGF1R), which, once activated, elicit the activation of a cascade of intracellular proteins leading to the regulation of gene expression, protein synthesis, cell proliferation or death, and glucose and lipid metabolism. Insulin and IGF-1 fully activate their own receptor, but can also bind and activate the other receptor, although with reduced affinity.In mammals, the conventional view regarding the actions of insulin and IGF-1 is that in vivo insulin mediates mainly a metabolic response, whereas IGF-1 mediates growth promoting effects (1). This is supported by the phenotypes of insulin receptor and IGF-1 receptor knock-out mice. Thus, mice lacking IGF1R display pronounced growth retardation and die shortly after birth due to respiratory insufficiency and failure to thrive (2), whereas mice with knock-out of the IR exhibit only slight growth retardation, but die during the first week of life from severe hyperglycemia and diabetic ketoacidosis (3, 4). In addition, phenotypes of the insulin and IGF-1 knock-out mice are very simila...

CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients

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Insulin and its analogues and their affinities for the IGF1 receptor

“…Although the IR and IGF1R have distinct and overlapping functions, it was recently suggested that in vivo specificity of insulin and IGF1 reflects at least in part the levels and timing of the expression of IRs and IGF1Rs in target tissues in combination with ligand concentration and availability (Boucher et al 2010). As Boucher stated: IR and IGF1R act as identical portals for the regulation of gene expression, with differences between insulin and IGF1 effects due to a modulation of the amplitude of the signal created by the specific ligand-receptor interaction (Boucher et al 2010).…”

“…As Boucher stated: IR and IGF1R act as identical portals for the regulation of gene expression, with differences between insulin and IGF1 effects due to a modulation of the amplitude of the signal created by the specific ligand-receptor interaction (Boucher et al 2010).…”

“…As previously discussed, it has been suggested that the IR and IGF1R act at identical portals to the regulation of gene expression, with differences between insulin and IGF1 effects due to a modulation of the signal created by the specific ligand-receptor interactions (Boucher et al 2010). As a consequence, it is almost impossible in most in vitro cell lines to disentangle the individual contribution of each type of receptor to the final downstream event.…”

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“…Insulin and insulin-like growth factor-1 (IGF-1) exert specificity on metabolism and growth through homologous receptors (Boucher, et al, 2010). Several studies have shown that both hormones may mediate the same physiological response.…”