Fetal hyperinsulinemia increases farnesylation of p21 Ras in fetal tissues

Stephens, Elizabeth; Thureen, Patti J.; Goalstone, Marc L.; Anderson, Marianne; Leitner, J. Wayne; Hay, William W.; Draznin, Boris

doi:10.1152/ajpendo.2001.281.2.e217

Cited by 23 publications

(20 citation statements)

References 24 publications

(31 reference statements)

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“…Previously, we have reported insulin-induced effects on the mitogenic pathway in fetal sheep skeletal muscle, measured by increases in the activity of farnesyltransferase and in the amount of farnesylated p21 Ras after 4 h of insulin stimulation (32). The current study and a previous in vitro study (12) suggest a more rapid effect of insulin in this pathway, since the peak in downstream phosphorylated ERK proteins occurred after 2 h of insulin infusion.…”

Section: Discussionsupporting

confidence: 65%

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

Anderson

Thamotharan²,

Kao³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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. Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle. Am J Physiol Regul Integr Comp Physiol 288: R473-R481, 2005. First published November 11, 2004; doi:10.1152/ajpregu.00405.2004.-To test the effects of acute fetal hyperinsulinemia on the pattern and time course of insulin signaling in ovine fetal skeletal muscle, we measured selected signal transduction proteins in the mitogenic, protein synthetic, and metabolic pathways in the skeletal muscle of normally growing fetal sheep in utero. In experiment 1, 4-h hyperinsulinemiceuglycemic clamps were conducted in anesthetized twin fetuses to produce selective fetal hyperinsulinemia-euglycemia in one twin and euinsulinemia-euglycemia in the other. Serial skeletal muscle biopsies were taken from each fetus during the clamp and assayed by Western blot for selected insulin signal transduction proteins. Tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and the p85 subunit of phosphatidylinositol 3-kinase doubled at 30 min and gradually returned to control values by 240 min. Phosphorylation of extracellular signal-regulated kinase 1,2 was increased fivefold through 120 min of insulin infusion and decreased to control concentration by 240 min. Protein kinase B phosphorylation doubled at 30 min and remained elevated throughout the study. Phosphorylation of p70 S6K increased fourfold at 30, 60, and 120 min. In the second experiment, a separate group of nonanesthetized singleton fetuses was clamped to intermediate and high hyperinsulinemic-euglycemic conditions for 1 h. GLUT4 increased fourfold in the plasma membrane at 1 h, and hindlimb glucose uptake increased significantly at the higher insulin concentration. These data demonstrate that an acute increase in fetal plasma insulin concentration stimulates a unique pattern of insulin signal transduction proteins in intact skeletal muscle, thereby increasing pathways for mRNA translation, glucose transport, and cell growth. insulin signaling; fetal growth; glucose transporter 4 IN ADULT ANIMALS and humans, insulin has primarily a metabolic role to regulate skeletal muscle glucose uptake with less effect on skeletal muscle protein synthesis than in rapidly growing tissues. Although increased serum insulin concentration in the fetal sheep has been shown to increase fetal skeletal muscle glucose uptake, especially at pharmacological doses (17,18,20,21), insulin in the rapidly growing fetus seems to act largely as an anabolic hormone, promoting skeletal muscle protein synthesis and growth. In human fetuses, abnormal insulin concentrations contribute to variations in fetal growth; excessive insulin promotes fetal overgrowth, whereas insufficient insulin leads to fetal growth restriction. Animal studies have produced experimental deficiencies in insulin secretion in fetal lambs, resulting in fetal growth restriction and limited carcass protein accretion (27). Also, it has been shown in the neonatal pig that insulin action to promote s...

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Section: Discussionsupporting

confidence: 65%

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

Anderson

Thamotharan²,

Kao³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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“…Guanine nucleotide exchange factors promote dissociation of GDP from the inactive Ras-GDP complex, allowing Ras proteins to bind GTP, and the activation requires posttranslational modification of Ras proteins (farnesylation). The process of farnesylation of Ras is catalyzed by farnesyltransferase (42). The posttranslational modifications of Ras make it more hydrophobic, facilitating in their translocation from the cytosol to the membrane (42).…”

Section: Discussionmentioning

confidence: 99%

“…The process of farnesylation of Ras is catalyzed by farnesyltransferase (42). The posttranslational modifications of Ras make it more hydrophobic, facilitating in their translocation from the cytosol to the membrane (42). In human umbilical endothelial cells, insulin is shown to activate farnesyltransferase, and this activation is likely to augment the vascular actions of VEGF (43).…”

Section: Discussionmentioning

confidence: 99%

Potential Contributory Role of H-Ras, a Small G-Protein, in the Development of Retinopathy in Diabetic Rats

Kowluru

Chakrabarti

et al. 2004

Diabetes

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Hyperglycemia is thought to be the underlying factor in the development of diabetic retinopathy, but the mechanisms involved remain partially understood. Diabetes increases oxidative stress, and reactive oxygen species affect the interactions between a small-molecularweight G-protein, H-Ras, and several of its effector proteins. The purpose of this study was to examine the regulatory role of H-Ras in glucose-induced apoptosis of retinal endothelial cells. The expressions of H-Ras and its effector protein (Raf-1) were compared in the retina obtained from diabetic rats (2-8 months' duration) and age-matched normal rats and in retinal endothelial cells exposed to high-glucose medium. The effect of inhibition of H-Ras function on glucose-induced capillary cell death and the potential involvement of oxidative stress in diabetes-induced activation of H-Ras were also determined. The expressions of H-Ras and Raf-1 were increased in the retina in diabetes, and antioxidant therapy prevented diabetes-induced increased protein and mRNA expressions. The inhibitors of Ras farnesylation inhibited glucose-induced nitric oxides and apoptosis in isolated retinal endothelial cells. Thus, the results suggest that functional activation of H-Ras might be one of the signaling steps involved in glucoseinduced capillary cell apoptosis and supports the role of H-Ras in the development of retinopathy in diabetes.

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“…Reduction of hyperinsulinaemia by exercise training resulted in decreased amounts of farnesylated Ras in Zucker fa/fa rats [18]. Induction of fetal hyperinsulinaemia by direct infusion of insulin into the fetus and by fetal or maternal infusions of glucose resulted in significant increases in the activity of farnesyltransferase and the amounts of farnesylated Ras in fetal liver, skeletal muscle, fat and white blood cells [19]. An additional infusion of somatostatin into hyperinsulinaemic fetuses blocked fetal hyperinsulinaemia and completely prevented these increases, specifying insulin as a causative factor.…”

Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

“…Overall, the ability of insulin to potentiate action of IGF-1, EGF, PDGF and VEGF has been observed in a variety of tissues, including vascular smooth muscle cells, endothelial cells, adipocytes, fibroblasts, liver cells and breast cancer cells [9,10,13,[15][16][17][18][19][20][21]. This effect of insulin has been consistently observed whenever metabolic insulin resistance along the PI3K pathway is present.…”

Section: Merriam-webster Dictionary 11th Edition (1977)mentioning

confidence: 99%

Mitogenic action of insulin: friend, foe or ‘frenemy’?

Draznin

2009

Diabetologia

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Either endogenous or exogenous hyperinsulinaemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras proteins. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. The stimulatory effect of hyperinsulinaemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin.

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Fetal hyperinsulinemia increases farnesylation of p21 Ras in fetal tissues

Cited by 23 publications

References 24 publications

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

Potential Contributory Role of H-Ras, a Small G-Protein, in the Development of Retinopathy in Diabetic Rats

Mitogenic action of insulin: friend, foe or ‘frenemy’?

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