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Insulin Pathway (insulin + pathway)
Selected AbstractsUpdating the effects of fatty acids on skeletal muscleJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2008Leonardo R. Silveira In this review we updated the fatty acid (FA) effects on skeletal muscle metabolism. Abnormal FA availability induces insulin resistance and accounts for several of its symptoms and complications. Efforts to understand the pathogenesis of insulin resistance are focused on disordered lipid metabolism and consequently its effect on insulin signaling pathway. We reviewed herein the FA effects on metabolism, signaling, regulation of gene expression and oxidative stress in insulin resistance. The elevated IMTG content has been associated with increased intracellular content of diacylglycerol (DAG), ceramides and long-chain acyl-coenzyme A (LCA-CoA). This condition has been shown to promote insulin resistance by interfering with phosphorylation of proteins of the insulin pathway including insulin receptor substrate-1/2 (IRS), phosphatidylinositol-3-kinase, (PI3-kinase) and protein kinase C. Although the molecular mechanism is not completely understood, elevated reactive oxygen (ROS) and nitrogen species (RNS) are involved in this process. Elevated ROS/RNS activates nuclear factor-kappaB (NFkB), which promotes the transcription of proinflammatory tumoral necrosis factor alpha (TNF,), decreasing the insulin response. Therefore, oxidative stress induced by elevated FA availability may constitute one of the major causes of insulin resistance in skeletal muscle. J. Cell. Physiol. 217: 1,12, 2008. © 2008 Wiley-Liss, Inc. [source] Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient miceAGING CELL, Issue 1 2005Christine Farrar Summary Protein l -isoaspartate (d -aspartate) O -methyltransferase is an enzyme that catalyses the repair of isoaspartyl damage in proteins. Mice lacking this enzyme (Pcmt1,/, mice) have a progressive increase in brain size compared with wild-type mice (Pcmt1+/+ mice), a phenotype that can be associated with alterations in the PI3K/Akt signal transduction pathway. Here we show that components of this pathway, including Akt, GSK3, and PDK-1, are more highly phosphorylated in the brains of Pcmt1,/, mice, particularly in cells of the hippocampus, in comparison with Pcmt1+/+ mice. Examination of upstream elements of this pathway in the hippocampus revealed that Pcmt1,/, mice have increased activation of insulin-like growth factor-I (IGF-I) receptor and/or insulin receptor. Western blot analysis revealed an approximate 200% increase in insulin receptor protein levels and an approximate 50% increase in IGF-I receptor protein levels in the hippocampus of Pcmt1,/, mice. Higher levels of the insulin receptor protein were also found in other regions of the adult brain and in whole tissue extracts of brain, liver, heart and testes of both juvenile and adult Pcmt1,/, mice. There were no significant differences in plasma insulin levels for adult Pcmt1,/, mice during glucose tolerance tests. However, they did show higher peak levels of blood glucose, suggesting a mild impairment in glucose tolerance. We propose that Pcmt1,/, mice have altered regulation of the insulin pathway, possibly as a compensatory response to altered glucose uptake or metabolism or as an adaptive response to a general accumulation of isoaspartyl protein damage in the brain and other tissues. [source] Disruption of insulin pathways alters trehalose level and abolishes sexual dimorphism in locomotor activity in DrosophilaDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2006Yesser Hadj Belgacem Abstract Insulin signaling pathways are implicated in several physiological processes in invertebrates, including the control of growth and life span; the latter of these has also been correlated with juvenile hormone (JH) deficiency. In turn, JH levels have been correlated with sex-specific differences in locomotor activity. Here, the involvement of the insulin signaling pathway in sex-specific differences in locomotor activity was investigated in Drosophila. Ablation of insulin-producing neurons in the adult pars-intercerebralis was found to increase trehalosemia and to abolish sexual dimorphism relevant to locomotion. Conversely, hyper-insulinemia induced by insulin injection or by over-expression of an insulin-like peptide decreases trehalosemia but does not affect locomotive behavior. Moreover, we also show that in the head of adult flies, the insulin receptor (InR) is expressed only in the fat body surrounding the brain. While both male and female InR mutants are hyper-trehalosemic, they exhibit similar patterns of locomotor activity. Our results indicate that first, insulin controls trehalosemia in adults, and second, like JH, it controls sex-specific differences in the locomotor activity of adult Drosophila in a manner independent of its effect on trehalose metabolism. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevityAGING CELL, Issue 4 2009Ludmila Pawlikowska Summary The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan , 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan , 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68,0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15,1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan. [source] | ||||||||||