Disease relevance of Insr

• Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles the human syndrome of leprechaunism [1].
• Insr ablation in 98% of cells, while resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia [1].
• The very pronounced hyperglycemia in Insr-/- mice could result in an increased plasma insulin level of up to approximately 300 microU/ml, as compared with approximately 25 microU/ml for normal littermates [2].
• The Insulin Receptor (IR) is a potential oncogene for mammary epithelial cells since its content is increased in most human breast cancer specimens, and both ligand-dependent malignant transformation and ligand-dependent enhanced growth occurs in cultured breast cells overexpressing the IR [3].
• Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles [4].

High impact information on Insr

• Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival [5].
• Insulin receptor tyrosine kinase is defective in skeletal muscle of insulin-resistant obese mice [6].
• Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR) [7].
• IR gene regulation of the response to trinitrophenyl-polysaccharides. Two independent genes are required for antibody production [8].
• The mechanisms of action of antibody to IR gene products in autoimmune disease are discussed [9].

Chemical compound and disease context of Insr

• Subsequently, these cells were infected with adenovirus encoding cre recombinase to delete insulin receptor (beta-IR(-/-)). beta-Cells expressed insulin and Pdx-1 mRNA in response to glucose [10].

Biological context of Insr

• Analyses of protein expression indicated that L1 mice had modestly reduced Insr content but normal insulin-stimulated Akt phosphorylation in the liver [11].
• To examine this question, we generated mice with variable cellular mosaicism for null Insr alleles [1].
• The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11 [12].
• Insulin receptor transphosphorylates several immediate substrates, resulting in modulation of a cascade of downstream signal transduction molecules [13].
• We investigated the molecular mechanism involved and characterized two RNA-splicing events that could account for the decrease in IGF-IR [14].

Anatomical context of Insr

• Partial restoration of insulin receptor Insr expression in brain, liver, and pancreatic beta cells is sufficient for rescuing Insr knockout mice from neonatal death, preventing diabetes ketoacidosis, and normalizing life span and reproductive function [11].
• Conversely, L1 mice had a near complete ablation of Insr protein product in the arcuate and paraventricular nuclei of the hypothalamus, which was associated with a failure to undergo insulin-dependent Akt phosphorylation in the hypothalamus [11].
• Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II [12].
• Electron microscopy analysis detected all stages of differentiation of the adipocyte precursor in IR-/- mice, suggesting that lack of insulin receptors is not associated with selective impairment of the adipocyte differentiation process [15].
• Histological, immunohistochemical, and ultrastructural analyses of white dermal adipose tissue were performed in newborn IR-/- mice, as well as normal (IR +/+ ) and heterozygous controls (IR+/-) [15].

Associations of Insr with chemical compounds

• Insr+/- mice were normal as shown by glucose tolerance tests [2].
• In concordance with these increases by LPS, tyrosine phosphorylation of the insulin receptor (IR) is partially impaired and phosphorylation of the insulin receptor substrate (IRS) proteins is almost completely suppressed [16].
• This effort led to the identification of a nonpeptidyl, small molecule, insulin-mimetic compound (demethylasterriquinone B-1, DMAQ-B1) that was isolated from a mixture of metabolites produced by a tropical endophytic fungus, Pseudomassaria sp. This compound induced human IRTK activation and increased tyrosine phosphorylation of IR beta subunit [13].
• Treatment with metformin was able to increase the tyrosine phosphorylation of IR and IRS-1 by 100 and 90% respectively [17].
• Both insulin (100 nM) and pervanadate (100 microM), a protein tyrosine phosphatase inhibitor, induced a marked increase in the phosphorylation at tyrosine residues of IR and insulin receptor substrate 1 (IRS-1) and in 2-deoxyglucose uptake in 3T3-L1 adipocytes [18].

Physical interactions of Insr

• In most cells and tissues, IR binds IGF-II with relatively low affinity [12].
• Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha [19].

Enzymatic interactions of Insr

• The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro [20].

Regulatory relationships of Insr

• However, IR could replace IGF-IR if efficiently activated by IGF-II [21].
• Only the A isoform of the insulin receptor (IR) can induce IRS-1 nuclear translocation, which is significant when the receptor is over-expressed [22].
• The observed reduction in endogenous IGF-IR expression was sufficient to inhibit IGF-I-stimulated cell proliferation [23].
• The partial differentialPHPTB IRS-2 protein is dependent for its effect on an activated IGF-IR, is cytoplasmic, binds to the beta-subunit of the IGF-IR, and requires for its action the presence of phosphatidylinositol 3-kinase binding sequences [24].
• Two closely-related protein tyrosine phosphatases, PTP1B and TCPTP both showed abilities to negatively regulate insulin receptor signaling [25].

Other interactions of Insr

• Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity [26].
• Unlike the liver, which is mostly unaffected by changes in IGF-I level, skeletal muscles express high levels of IGF-I receptor (IGF-IR) [27].
• Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells [12].
• The role of caveolin 1 in the Insulin Receptor (IR) signalling has been well investigated [28].
• Insulin receptor alpha-subunit protein content and beta-subunit tyrosine kinase activity remained unchanged upon insulin stimulation, regardless of the lack of IRS-1 [29].

Analytical, diagnostic and therapeutic context of Insr

• RT-PCR analysis also showed IGF-IR mRNA throughout the estrous cycle [30].
• Insulin receptor content was measured by a specific radioimmunoassay [3].
• Using immunohistochemistry, IGF-IR immunostaining was detected throughout the estrous cycle and on days 2-7 of gestation, but was restricted to the glandular epithelium [30].
• IR and IRS-1 phosphorylation as determined by immunoblotting with antiphosphotyrosine antibody were increased in basal conditions by 315% and 560% respectively [31].
• Gene targeting was used to characterize the physiological role of growth factor receptor-bound (Grb)14, an adapter-type signalling protein that associates with the insulin receptor (IR) [32].

References