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FP Dominici, D Cifone, A Bartke and D Turyn

Growth hormone (GH) excess is associated with secondary hyperinsulinemia, but the molecular mechanism and consequences of this alteration are poorly understood. To address this problem we have examined the levels and phosphorylation state of the insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1), the association between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) as well as the PI 3-kinase activity in the livers of GH-transgenic mice. As expected, IR levels were reduced in the liver of GH-transgenic mice (55% of normal values) as determined by immunoblotting with an anti-IR beta-subunit antibody. IR and IRS-1 phosphorylation as determined by immunoblotting with antiphosphotyrosine antibody were increased in basal conditions by 315% and 560% respectively. After a bolus administration of insulin in vivo, IR phosphorylation increased by 40% while IRS-1 phosphorylation did not change. Insulin administration to control (normal) mice produced 670% and 300% increases in the IR and IRS-1 phosphorylation respectively. In the GH-transgenic animals, basal association of PI 3-kinase with IRS-1 as well as PI 3-kinase activity in liver was increased by 200% and 280% respectively, and did not increase further after administration of insulin in vivo, indicating a complete insensitivity to insulin at these levels. In conclusion, GH excess and the resulting secondary hyperinsulinemia were associated with alterations at the early steps of insulin action in liver. IR concentration was reduced, while IR and IRS-1 phosphorylation, IRS-1/PI 3-kinase association, and PI 3-kinase activity appeared to be maximally activated under basal conditions, thus making this tissue insensitive to further stimulation by exogenous insulin in vivo.

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S Matthaei, B Trost, A Hamann, C Kausch, H Benecke, H Greten, W Höppner and H H Klein


To examine the effect of thyroid hormone status on insulin action in isolated rat adipocytes, age- and weight-matched Sprague–Dawley rats were rendered hypothyroid (h) by i.p. injection of 2 mCi [131I]/kg. Another group of rats was made hyperthyroid (H) by i.p. injection of 500 μg l-thyroxine/kg/day for 7 days. The T4 levels in experimental groups were: controls, 33·5±0·95; h, 12·3±1·59: H, 133·2±8·8 μg/l. Adipocytes were isolated and 3-O-methylglucose transport (GT), insulin binding (IB) and insulin receptor kinase activity (IRKA) were determined. Subcellular membrane fractions (low-density microsomes, plasma membranes) were prepared and GLUT1 and GLUT4 glucose transporter immunodetected.

Hyperthyroidism caused no significant effect on either IB or IRKA but increased insulin-stimulated GT by 43·6%. This increase of GT was associated with an increase of primarily GLUT4 glucose transporters. Hypothyroidism was associated with both increased insulin receptor affinity and enhanced IRKA. Despite a marked reduction of primarily GLUT4 glucose transporters, basal and insulinstimulated GT was not reduced when compared with control.

These results suggest that (1) in hyperthyroidism, increased insulin-stimulated glucose transport is associated with an increase of primarily GLUT4 glucose transporters, which may be responsible for the increment of peripheral glucose utilization in hyperthyroidism, and (2) the effect of hypothyroidism on insulin action in adipocytes is characterized by a state of increased insulin sensitivity, as indicated by the increase in insulin receptor affinity and tyrosine kinase activity. Despite the marked reduction of primarily GLUT4 glucose transporters, insulin-stimulated glucose transport is not diminished, which may suggest that functional activity of plasma membrane glucose transporters is enhanced in hypothyroidism.

Journal of Endocrinology (1995) 144, 347–357

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Cid Pitombo, Eliana P Araújo, Cláudio T De Souza, José C Pareja, Bruno Geloneze and Lício A Velloso

. 2002 ). Acting on insulin sensitive tissues, pro-inflammatory cytokines can impair insulin signal transduction by promoting the serine phosphorylation of key elements of the insulin signaling pathway ( Hotamisligil 2003 ). This inhibitory effect

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Eliana H Akamine, Anderson C Marçal, João Paulo Camporez, Mara S Hoshida, Luciana C Caperuto, Estela Bevilacqua and Carla R O Carvalho

Introduction Insulin signaling begins when insulin binds and activates its receptor, resulting in tyrosine phosphorylation of several substrates, including the insulin receptor substrate (IRS) 1–4. IRS proteins, in turn, bind and activate the enzyme

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Hongying An and Ling He

, the importance of the gut–brain–liver axis in chronic metformin action remains to be determined. Metformin alleviates hyperglycemia in T2D through the improvement of insulin signaling: an indirect pathway of metformin action Even though metformin

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Jose A Viscarra, Cory D Champagne, Daniel E Crocker and Rudy M Ortiz

gluconeogenesis (the generation of glucose from non-carbohydrate substrates), and free fatty acids, which decrease insulin sensitivity by inhibiting intracellular insulin signaling and glucose uptake, are increased in the circulation, contributing to continuation

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Myat Theingi Swe, Laongdao Thongnak, Krit Jaikumkao, Anchalee Pongchaidecha, Varanuj Chatsudthipong and Anusorn Lungkaphin

renal gluconeogenesis in an obese condition where insulin signaling is compromised is interesting. The sodium-dependent glucose cotransporters, SGLT1 and 2, in the renal proximal tubule reabsorb nearly all filtered glucose. SGLT2 is responsible for

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Kok Lim Kua, Shanming Hu, Chunlin Wang, Jianrong Yao, Diana Dang, Alexander B Sawatzke, Jeffrey L Segar, Kai Wang and Andrew W Norris

on insulin action and signaling. To accomplish our aim, we developed in vivo techniques to study rodent fetus glucose disposition, insulin sensitivity and insulin signaling. We examined three distinct aspects of fetal diabetes exposure: fetal

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Paolo Comeglio, Ilaria Cellai, Tommaso Mello, Sandra Filippi, Elena Maneschi, Francesca Corcetto, Chiara Corno, Erica Sarchielli, Annamaria Morelli, Elena Rapizzi, Daniele Bani, Daniele Guasti, Gabriella Barbara Vannelli, Andrea Galli, Luciano Adorini, Mario Maggi and Linda Vignozzi

.0001). The intracellular localization of the insulin-regulated glucose transporter GLUT4 and of the small GTP-binding protein RhoA, involved in insulin signaling, were assessed by Western blot analysis ( Fig. 4C and D , respectively). In VAT extracts, HFD