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neurons against focal ischemia/reperfusion in rats ( Miao et al . 2007 ). The phosphatidylinositol-3-kinase (PI3K)/Akt and ERK1/2 pathways have been implicated in the regulation of cell survival ( Datta et al . 1999 , Pearson et al . 2001 ). Previous
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Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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Insulin receptor substrate (IRS)-1 and IRS-2 are the major substrates that mediate insulin action. Insulin itself regulates the expression of the IRS protein in the liver, but the underlying mechanisms of IRS-1 and IRS-2 regulation are not fully understood. Here we report that insulin suppressed the expression of both IRS-1 and IRS-2 proteins in Fao hepatoma cells. The decrease in IRS-1 protein occurred via proteasomal degradation without any change in IRS-1 mRNA, whereas the insulin-induced suppression of IRS-2 protein was associated with a parallel decrease in IRS-2 mRNA without changing IRS-2 mRNA half-life. The insulin-induced suppression of IRS-2 mRNA and protein was blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, LY294002, but not by the MAP kinase-ERK kinase (MEK) inhibitor, PD098059. Inhibition of Akt by overexpression of dominant-negative Akt also caused complete attenuation of the insulin-induced decrease in IRS-2 protein and partial attenuation of its mRNA down-regulation. Some nuclear proteins bound to the insulin response element (IRE) sequence on the IRS-2 gene in an insulin-dependent manner in vitro, and the binding was also blocked by the PI 3-kinase inhibitor. Reporter gene assay showed that insulin suppressed the activity of both human and rat IRS-2 gene promoters through the IRE in a PI 3-kinase-dependent manner. Our results indicate that insulin regulates IRS-1 and IRS-2 through different mechanisms and that insulin represses IRS-2 gene expression via a PI 3-kinase/Akt pathway.
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In the rat, dexamethasone treatment during late pregnancy leads to intrauterine growth retardation and is used as a model of early programming of adult onset disease. The present study investigated whether pre-natal dexamethasone treatment modifies cardiac glucose transporter (GLUT) protein expression in adulthood and identified signalling pathways involved in the response. Dexamethasone (100 microg/kg body wt per day) administered via an osmotic pump to pregnant rats (day 15 to day 21; term=22 to 23 days) reduced fetal weight at day 21 and caused hypertension, hyperinsulinaemia and elevated corticosterone levels in the adult (24-week-old) male offspring. Cardiac GLUT1 protein expression was selectively up-regulated (2.5-fold; P<0.001), in the absence of altered cardiac GLUT4 protein expression, in adult male offspring of dexamethasone-treated dams. Maternal dexamethasone treatment did not influence cardiac GLUT1 protein expression during fetal or early post-natal life. We examined potential regulatory signalling proteins that might mediate up-regulation of cardiac GLUT1 protein expression in adulthood. We observed marked (2.2-fold; P<0.01) activation of Akt/protein kinase B (PKB), together with modest activation of the anti-apoptotic protein kinase C (PKC) isoforms PKC alpha (88%, P<0.05) and PKC epsilon (56%, P<0.05) in hearts of the early-growth-retarded male offspring. These effects were, however, observed in conjunction with up-regulation of cardiac protein expression of PKC beta(1) (191%, P<0.01), PKC beta(2) (49%, P<0.05) and PKC delta (35%; P<0.01), effects that may have adverse consequences. Maternal dexamethasone treatment was without effect on cardiac extracellular signal-related kinase (ERK) 1 or ERK2 activity in adulthood. In conclusion, our data demonstrate an effect of maternal dexamethasone treatment to up-regulate cardiac GLUT1 protein expression in early-growth-retarded, hypertensive, hyperinsulinaemic adult male offspring, an effect observed in conjunction with activation of Akt/PKB.
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Neonatology Division, Diabetes Division, Geriatric Research, Barshop Institute for Longevity and Aging Studies, Department of Obstetrics, Department of Pediatrics
Neonatology Division, Diabetes Division, Geriatric Research, Barshop Institute for Longevity and Aging Studies, Department of Obstetrics, Department of Pediatrics
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administered in late gestation, whereas AKT (protein kinase B) and mTOR pathway molecules were only increased in the muscle of those fetuses exposed to cortisol infusion but not GCs ( Jellyman et al . 2012 ). Extremely low birth weight (ELBW) infants (<1000 g
Babu Banarasi Das University, BBD City, Lucknow, India
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Academy of Scientific and Innovative Research, CSIR-IITR, Lucknow, India
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Babu Banarasi Das University, BBD City, Lucknow, India
Academy of Scientific and Innovative Research, CSIR-IITR, Lucknow, India
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insulin action ( Copps & White 2012 ). Newton’s group first claimed the identification of a protein phosphatase, PHLPP, while searching for a mechanism of AKT dephosphorylation and signal termination (Newton et al . 2005). PHLPP directly dephosphorylates
Taichung Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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Taichung Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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Taichung Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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Taichung Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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the effects of IGF-I and insulin on FOXO are mediated through phosphatidylinositol 3-kinase (PI3-K) and protein kinase B/Akt ( Hribal et al. 2003 , Stitt et al. 2004 ). Upon activation of PI3-K and Akt, IGF-I and insulin suppress FOXO1 by
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) and Akt inhibitor VIII was procured from Santa Cruz Biotechnology (Santa Cruz, CA, USA). All tissue culture reagents were obtained from Gibco/Invitrogen, and all other reagents were obtained from Sigma unless otherwise indicated. Adult rat hippocampal
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
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Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil
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recruits and activates downstream molecules, including serine-threonine kinases, tyrosine kinases, GTPases, and others. Protein kinase B (PKB)/Akt is one key downstream target of PI 3-kinase, activated by serine and threonine phosphorylation. Akt is
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recruit PDK1 that can phosphorylate AKT at its threonine 308 residue ( Alessi et al . 1997 ). This, in turn, leads to mechanistic target of rapamycin complex 2 (MTORC2) phosphorylating AKT at serine 473 ( Sarbassov et al . 2005 ), resulting in a
