© 2004 Prime Health Consultants, Inc.
Insulin and the insulin-like growth factor (IGF)-II both bind the A isoform of the insulin receptor (IR-A); how do the 2 hormones achieve specificity in responses? Pandini et al used microarray technology to test the hypothesis that the hormones affect different patterns of gene expression. They studied IGF-I receptor (IGF-1R)-deficient murine fibroblasts (R¯cells) to isolate the effects on the IR from possible IGF-1R cross-reactivity. Some R¯ cells were transfected with human IR-A cDNA (R¯/IR-A cells; ~ 5 X 10 5 IR’s/cell) for comparison with the R¯ cells (~5 X 10 3 native IRs/cell), and gene expression profiles were compared following exposure to insulin or IGF-II. Two hundred fourteen transcripts were similarly regulated by the 2 hormones, and 45 were differentially transcribed. Expression patterns are summarized in the Table.
To validate the microarray data, changes in 12 genes belonging to different functional categories were confirmed by real-time PCR. Surprisingly, the different gene profiles of the 2 hormones did not fit neatly with the original functional dichotomy. For example, 3 genes selectively up-regulated by insulin were involved in regulating angiogenesis and differentiation, and 3 genes up-regulated longer after IGF-II than insulin were involved in metabolism (cholesterol metabolism, phosphate transport, and selenium supply/oxidative stress prevention). The authors concluded that these studies provided a molecular basis for the biological differences between insulin and IGF-II.
Editors Comments: The somatomedins were renamed the insulin-like growth factors (IGFs) for their primary structural homology to pro-insulin. Because of their different functions, the IGF and insulin systems were believed to be separate; IGF-I and IGF-II both stimulate cell survival and proliferation through the type 1 IGF receptor (IGF-1R), while insulin affects metabolism through the IR. The IGF-IIR, which is identical to the mannose 6-phosphate receptor, serves to clear IGF-II from the circulation.
Then things became more complicated. Not only do the ligands share structural homology, but the receptors are also very similar and they overlap in function. Both IGF-1R and IR are transmembrane a 2 b 2 aggregates with autocatalytic tyrosine kinase activity, and both receptors activate signaling cascades in common (MAP kinase pathway and PI3 kinase/Akt pathways). The IGFs and insulin can have similar metabolic effects; IGF-II over expression by tumors may cause hypoglycemia, and insulin is recognized as a growth-promoting hormone (best exemplified by the macrosomy of infants of diabetic mothers and babies with congenital hyperinsulinism).
In addition to the IR found in metabolically responsive adult tissues—fat, liver, and muscle (the IR-B isoform)—there is also a shorter IR-A isoform (12 amino acids omitted from the a-subunit by skipping exon 11). IR-A is the predominant isoform in fetal tissues and binds both insulin and IGF-II with high affinity. 1 IR-A is also over-expressed in cancers. Hybrid receptors, composed of an IR hemireceptor combined with an IGF-1R hemireceptor, have also been identified and implicated in neoplasia. These hybrid receptors are not just structural mistakes; they have been shown to bind IGF-I (but not insulin) with high affinity and contribute to IGF-stimulated cell growth. 2
Thus, the question now is no longer, are the IGF and insulin systems truly related, but rather, how do they achieve specificity in response? One possible mechanism involves differential expression profiles of the various receptors that are cell-type– and ontogeny–dependent. Another involves differences in relative ligand concentrations, ligand binding affinities, and receptor densities. A third possibility evokes different downstream targets.
This paper is an important contribution to the field. Unfortunately, by providing a novel glimpse into the system, it makes it all seem a bit more complicated still.
Adda Grimberg, MD
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