Why there is an IRS.

Abstract

Insulin regulates the expression of at least 100 genes (1). This major action of the hormone is important for normal metabolism but gains added significance in view of the fact that insulin resistance is the cornerstone of genetic diseases such as noninsulin-dependent diabetes mellitus and obesity. The possibility that faulty regulation of gene expression by insulin could result in disease is now given credence by the observations reported by Li et al. (2) in this issue of The Journal.Hypertriglyceridemia (HTG) is a risk factor for coronary heart disease. Plasma triglycerides are carried mainly in VLDL and chylomicrons, both of which contain apo CIII as a major protein constituent; several studies have suggested that the overexpression of apo CIII causes some forms of HTG (3). Perhaps most convincing is the observation that overexpression of human apo CIII in transgenic mice results in HTG (4).Chen et al. (5) showed that transcription of the hepatic apo CIII gene is increased in diabetic mice and that insulin treatment reduces apo CIII gene transcription to basal levels. In addition, a reporter gene containing the apo CIII promoter sequence from -854 to + 22 is inhibited by insulin (5), thus the DNA sequence responsible for the insulin effect must be in that segment. Recently, Dammerman et al. (3) identified five polymorphisms in this region of the apo CIII promoter. Li et al. (2) now show that single base pair changes at either of two of the five variant sites (at -482 and -455) abolish the repression of apo CIII gene transcription by insulin, an observation that reveals why these mutations lead to apo CIII overexpression. The functional significance of the nucleotide changes in the other three variant sites is unclear but is not related to regulation of apo CIII gene expression by insulin. Moreover, the increased susceptibility to HTG associated with the mutation at -482 is dependent on the presence of a particular polymorphism in the apo CIII 3' UTR, suggesting that other factors are important in vivo.The region containing the variant sites at -482 and -455 is sufficient to confer an inhibitory effect of insulin on reporter gene expression when ligated to a minimal apo CIII promoter (Leff, T., personal communication) and therefore represents an insulin response sequence (IRS) (1). This observation may have broader significance because within this region (between -460 and -456) is found the same T(G/A)TTll motif that has been identified as the core IRS in the phosphoenolpyruvate carboxykinase (PEPCK), insulin-like growth factor binding protein-I (IGFBP-I), and (probably) tyrosine aminotransferase (TAT) genes (6-9). Hepatic nuclear factor-3 (HNF-3) binds to the IRS in all three genes but does not appear to be the protein through which insulin manifests its inhibitory action on gene transcription (7). Rather, HNF-3 acts as an accessory factor required for the full induction of the transcription of all three genes by glucocorticoids (7,9

Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA levels in human muscle.

“…We have identified two important genes, (namely, Rad and the p85 ␣ regulatory subunit of phosphatidylinositol-3-kinase) that can be added to the growing list of the genes controlled by insulin. Since the products of these genes, in particular PI-3K, play a crucial role in the insulin mechanism of action, our findings strengthen the possibility that altered regulation of gene expression by insulin could result in insulin resistance (39). The methodology developed here allowing a wide screening of mRNA levels represents a valuable tool to test this hypothesis.…”

SIRT1 Regulates Adiponectin Gene Expression through Foxo1-C/Enhancer-binding Protein α Transcriptional Complex

“…Scanning this region revealed three putative Foxo1 binding sites (core motif T(G/A)TTT) (Fig. 3A), which are usually named insulin response sequences (IRSs) (18,31). The results of the transient transfection study showed that mutation of IRS1 or IRS3 significantly decreased the basal adiponectin promoter activity (Fig.…”