Disease relevance of Irs2

• The data revealed that the administration of a high dose (0.1 mg/kg body weight/day) of DEX (HDEX) attenuated insulin signaling in the cerebral cortex and hypothalamus, whereas exercise potentiated their insulin signaling along with induction of IRS2 expression [1].
• Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease [2].
• Tumor necrosis factor alpha (TNFalpha) or chronic hyperinsulinemia that induce insulin resistance trigger increased Ser/Thr phosphorylation of the insulin receptor (IR) and of its major insulin receptor substrates, IRS-1 and IRS-2 [3].
• Insulin-stimulated insulin receptor substrate 2 and Akt-2 phosphorylation were significantly blunted in IUGR rats [4].
• Insulin in UW solution exacerbates hepatic ischemia / reperfusion injury by energy depletion through the IRS-2 / SREBP-1c pathway [5].

High impact information on Irs2

• We show that secreted insulin acts via beta-cell insulin receptors and up-regulates insulin gene transcription by signaling through the IRS-2/PI-3 kinase/p70 s6k and CaM kinase pathways [6].
• The IRS-2 promoter is activated by forkhead proteins through an insulin response element (IRE) [7].
• Insulin-induced tyrosine phosphorylation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) and their protein levels were decreased in the aorta of obese rats compared with lean rats [8].
• In euglycemic clamp studies, insulin infusion greatly increased tyrosine phosphorylation of IRbeta- and IRS-2-associated PI 3-kinase activity in the aorta of lean rats, but only slight increases were observed in obese rats [8].
• Given that 1 and 7 days after PH isolated hepatocytes responded similarly to insulin in terms of induced cell proliferation, a compensatory role is proposed for IRS-2/4 induction [9].

Biological context of Irs2

• In contrast, there was a high level of IRS-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust PI3K binding and activation, which may enhance hepatocyte survival during the rapid growth phase of the liver [10].
• CONCLUSIONS: The IRS-1 signal transduction pathway does not play a major role in fetal liver growth because IRS-2 functions as the major insulin responsive molecule in early development [10].
• Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2 [11].
• However, increased IRS-2 expression augmented glucose/IGF-1 induced beta-cell growth mitogenesis and decreased apoptosis due to glucose-deprivation [12].
• Hepatic insulin resistance could be attributed to impaired insulin-stimulated IRS-1 and IRS-2 tyrosine phosphorylation [13].

Anatomical context of Irs2

• In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2 [14].
• IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells [12].
• Furthermore, the differential response of IRS-1 and IRS-2 to exercise suggests that these molecules have specialized, rather than redundant, roles in insulin signaling in skeletal muscle [15].
• High fat feeding in rats increased both protein and mRNA levels of IRS-3 but decreased those of IRS-1 and IRS-2 in epididymal adipocytes [16].
• Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells [17].

Associations of Irs2 with chemical compounds

• In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h [14].
• Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002 [18].
• Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (approximately 50%; P < 0.001 vs. control) and doubled IRS-2 pY (P < 0.01 vs. insulin) [11].
• Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats [19].
• IRS-2- and phosphotyrosine-associated PI3K activity were increased 3.5- and 4.8-fold, respectively, by insulin in glycerol-infused rats but only 1.6- and 2.3-fold in lipid-infused rats [20].

Physical interactions of Irs2

• We have previously shown that IRS-1 and IRS-2 interact with the juxtamembrane (JM) but not with the carboxyl-terminal (CT) region of the insulin receptor (IR) in vitro [21].
• Both IRS-1 and IRS-2 co-immunoprecipitate with calmodulin from insulin target tissues in rats [22].

Regulatory relationships of Irs2

• Physiological leptin concentrations (0.1-5 nmol/liter) stimulated the tyrosine phosphorylation (pY) of insulin receptor substrate-2 (IRS-2) (280-954%; P < 0.05) and its associated phosphatidylinositol-3 kinase activity (122-621%; P < 0.003) [11].
• AT2 receptor stimulation did not change insulin-induced tyrosine phosphorylation of IRS-2 or its association with the p85alpha subunit of PI3K, but led to a significant reduction of insulin-induced p85alpha phosphorylation [23].
• In contrast, cAMP pretreatment potentiated the tyrosine phosphorylation of IRS-2 induced by IGF-I, but did not affect the amount of IRS-2 [24].
• In contrast, RSG did not affect the increased PTP1B levels and activities or the already reduced insulin-stimulated glycogen synthesis and tyrosine phosphorylation of IRbeta-subunits and IRS-2 in livers of diabetic rats [25].
• PRL-induced IRS-2 phosphorylation and its association with PI 3-kinase did not add to the effect of insulin [26].

Other interactions of Irs2

• In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway [11].
• Increased beta-cell proliferation was associated with the induction of insulin receptor substrate-2 and pancreatic homeodomain protein-1 via the activation of the cAMP response element binding protein [19].
• Grb2 and phosphatidylinositol 3-kinase association to IRS-1 and IRS-2 reflected the phosphorylation levels of the two IRSs [27].
• Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosine-phosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons [28].
• AT2 receptor stimulation increased the association of a protein tyrosine phosphatase, SHP-1, with IRS-2 [23].

Analytical, diagnostic and therapeutic context of Irs2

• Finally, by immunoprecipitation, the detection of insulin-stimulated IRS-2 phosphorylation followed the same pattern as that for IRS-1 in both liver of 2- and 20-month-old rats [29].
• Semiquantitative RT-PCR analysis showed that insulin (10(4) microU/ml) alone or in combination with glucose (15 mm) markedly suppressed IRS-2 gene expression, whereas IRS-1 mRNA was unaffected by the culture conditions [30].
• Impairment of glucose uptake capacity after treatment with high glucose and insulin was most pronounced after 3 h, whereas IRS-1 and IRS-2 protein levels were unaffected up to 6 h but were reduced after 16 h [30].
• Moreover, denervation reduced insulin-induced association between IRS1/IRS2 and p85/phosphatidylinositol (PI) 3-kinase [31].
• Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase [32].

References