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Hong Ma, Jin Yuan, Jinyu Ma, Jie Ding, Weiwei Lin, Xinlei Wang, Mingliang Zhang, Yi Sun, Runze Wu, Chun Liu, Cheng Sun and Yunjuan Gu

(IR) ( Dulloo & Montani 2012 ). IR is a hallmark of T2D, in which insulin at normal physiological concentrations fails to effectively activate its downstream signal transduction in the skeletal muscle, liver and adipose tissue ( Hartstra et al. 2015

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Daniela F Bertelli, Andressa Coope, Andrea M Caricilli, Patricia O Prada, Mario J Saad, Licio A Velloso and Eliana P Araujo

Introduction Membrane-bound phosphoinositides are molecules engaged in the transduction of signals delivered by a number of growth factors and hormones, which play a role in the control of cell growth, apoptosis, metabolism, cytoskeletal

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Raquel Barbuio, Marciane Milanski, Manoel B Bertolo, Mário J Saad and Lício A Velloso

evaluate the effect of infliximab upon liver cytokine expression, morphology, and insulin signal transduction. The results show that, after a short period of treatment, significant reductions in proinflammatory markers in the liver are accompanied by

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A Tsuchiya, T Kanno and T Nishizaki

kinase 1 (Pak1; Mao et al . 2008 ), in a PI3K-independent manner. This study was conducted to gain further insight into PI3K-induced Akt activation in the insulin signal transduction pathway. To address this, we monitored GLUT4 mobilizations, measured

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E Bottini, N Lucarini, A Amante, N Bottini and G Faggioni

The effects of 'normal' genetic variability of signal transduction on endocrine function may be more evident during stimulation tests than is observed in basal states, thereby contributing to a greater understanding of the possible role of signal transduction genetics in the pathogenesis of endocrine disorders. In the present study, we have studied the outcome of growth hormone (GH) stimulation testing by insulin in growth-retarded children in relation to the genotype of ACP1 (acid phosphatase locus 1; also referred to as cLMWPTP, cytosolic low molecular weight phosphotyrosine phosphatase). ACP1 is an enzyme, expressed as two distinct isoforms designated F and S, that down-regulates insulin receptor signal transduction and which shows a genetic polymorphism with strong quantitative enzymatic differences among genotypes. In this study, we examined 116 growth-retarded children of which 101 were genotyped for ACP1. We found that the basal level of GH is higher in ACP1 genotypes with low concentrations of the S isoform than in genotypes with high S isoform concentrations (P<0.02). Additionally, during GH stimulation with insulin, the genotypes with low S isoform concentrations were found to perform better (P<0.005) and to react more promptly than the genotypes with high S isoform concentrations (P<0.05). These findings suggest that high S isoform ACP1 activity slows down the effect of insulin, resulting in a retardation of its metabolic effect.

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A. N. Corps

The mechanism of signal transduction at the insulin receptor has long been one of the major questions of cellular endocrinology. No general relationship has been established with any of the well-known second messenger systems such as cyclic AMP, calcium or phosphoinositides (reviewed by Goldfine, 1987); a fundamentally different signalling pathway is therefore presumably involved. The same is apparently true of the stimulation of cell growth by the insulin-like growth factors (IGFs), which frequently exhibit synergy with agonists which activate the established second messenger pathways (Rozengurt, 1986).

The insulin and type-I IGF receptors are structurally-similar βααβ heterotetramers, and possess protein-tyrosine kinases in their intracellular domains (Kasuga, Karlsson & Kahn, 1982; Jacobs, Kull, Earp et al. 1983). This suggests that a cascade of regulatory phosphorylation events, initiated by the catalytic domain, might answer the question of mechanism. Many proteins do indeed undergo changes in phosphorylation in response to insulin or IGF (reviewed

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M Phillippe and E K Chien


These studies sought to test the hypothesis that potassium-stimulated phasic myometrial contractions utilize cytosolic calcium oscillation-like mechanisms comparable to those activated in response to oxytocin. Uterine tissue was obtained from pro-oestrus/oestrus Sprague-Dawley rats. In vitro isometric contraction studies were performed using longitudinal myometrial strips; computer digitalized contraction data were analyzed for contraction area, and normalized for tissue cross-section area. Dose–response studies were performed using potassium chloride with and without inhibitors of cytosolic calcium oscillation mechanisms. Qualitative inositol-phosphate production studies were performed after preloading uterine tissue with [3H]inositol; subsequently, the individual inositol-phosphates produced in response to stimulation were isolated by anion exchange chromatography. Potassium chloride over a concentration of 10 to 30 mm produced a dose-related increase in phasic contractile activity. The potassium-stimulated phasic contractions were significantly suppressed in response to inhibition of phospholipase C, stimulation of protein kinase C, inhibition of calcium-induced calcium release, and prevention of extracellular calcium influx. The qualitative inositol-phosphate production studies confirmed activation of phospholipase C in response to 20 mm potassium. These studies have provided support for the hypothesis that potassium-stimulated phasic myometrial contractions activate intracellular signal transduction mechanisms comparable to those activated in response to hormonal uterotonic agonists.

Journal of Endocrinology (1995) 146, 485–493

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Bruno C Pereira, Alisson L da Rocha, Ana P Pinto, José R Pauli, Leandro P de Moura, Rania A Mekary, Ellen C de Freitas and Adelino S R da Silva

necrosis factor alpha (TNFα) play a fundamental role in the phosphorylation (p) of IRS1 at serine 307, impairing the insulin signal transduction ( Kahn et al . 2006 , Vichaiwong et al . 2009 , Da Silva et al . 2010 , Prasannarong et al . 2012

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Gurvinder Kenth, Jennifer A Manalo Mergelas and Cynthia Gates Goodyer

. 1996 , Ballesteros et al . 2000 , Fisker et al . 2001 , 2004 , Goodyer et al . 2001 a ). These truncated receptors are capable of binding hGH with high affinity, but they do not activate intracellular signal transduction pathways and, in fact

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J Arola, P Heikkilä, R Voutilainen and A I Kahri


ACTH exerts a biphasic effect on the growth of fetal rat adrenocortical cells in primary culture when bromodeoxyuridine (BrdU) incorporation is used as an indicator of proliferation. The immediate inhibitory effect during the first 24 h of ACTH stimulation is not dependent on cyclic AMP (cAMP). Protein kinase C (PKC) inhibitors H-7 and staurosporine blocked this inhibitory effect of ACTH, whereas 12-0-tetradecanoyl phorbol-13-acetate (TPA; a PKC activator) mimicked the ACTH-induced antimitogenic effect. The stimulatory growth effect of ACTH appears after 72 h of treatment. A similar mitogenic effect is also achieved with cAMP derivative 8-bromo cAMP (8-Br cAMP). However, both ACTH- and 8-Br cAMP-induced proliferations could be reduced with H-7.

ACTH-induced corticosterone secretion was inhibited 50% with H-7 after 24 h, but 8-Br cAMP-induced secretion was unaffected. However, if the treatments were continued for 72 h, H-7 no longer reduced the steroid secretions. Reduction (50–75%) of cholesterol side-chain cleavage enzyme (P450scc) mRNA expression was also noted with H-7 in ACTH-treated cultures after 6 and 24 h. In contrast, TPA doubled the corticosterone secretion induced by 8-Br cAMP, but did not further increase the ACTH-induced secretion after 24 h. TPA alone, however, was not able to induce steroid secretion or P450scc mRNA expression. The morphological differentiation of fetal rat adrenocortical cells with ACTH or 8-Br cAMP from zona glomerulosa-like cells into zona fasciculata-like cells was not disturbed by H-7 nor was it induced by TPA alone.

These results therefore suggest that PKC- and cAMP-dependent signal transductions are involved in the ACTH-induced biphasic growth effect of fetal rat adrenocortical cells. PKC plays a role in the inhibitory growth effect, and both PKC and cAMP are involved in the stimulatory growth phase of ACTH. Both PKC and cAMP are also involved in the steroid secretion of zona glomerulosa-type cells, but differentiation into zona fasciculata-type cells and their steroid production is transduced through cAMP.

Journal of Endocrinology (1994) 141, 285–293