Insulin Resistance in Human Preeclamptic Placenta Is Mediated by Serine Phosphorylation of Insulin Receptor Substrate-1 and -2

Scioscia, Marco; Gumaa, K.A.; Kunjara, Sirilaksana; Paine, Malcolm A.; Selvaggi, Luigi; Rodeck, Charles H.; Rademacher, Thomas W.

doi:10.1210/jc.2005-1965

Cited by 67 publications

(56 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This likely results in aberrant serine phosphorylation and consequently decreased tyrosine phosphorylation of IRS-2. Similar patterns of aberrant IRS-2 phosphorylation have been noted in other insulin resistance states (36).…”

Section: Discussionsupporting

confidence: 73%

Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-Extracellular nucleotides are important mediators of inflammatory responses and could also impact metabolic homeostasis. Type 2 purinergic (P2) receptors bind extracellular nucleotides and are expressed by major peripheral tissues responsible for glucose homeostasis. CD39/ENTPD1 is the dominant vascular and immune cell ectoenzyme that hydrolyzes extracellular nucleotides to regulate purinergic signaling. RESEARCH DESIGN AND METHODS-We have studiedCd39/Entpd1-null mice to determine whether any associated changes in extracellular nucleotide concentrations influence glucose homeostasis.RESULTS-Cd39/Entpd1-null mice have impaired glucose tolerance and decreased insulin sensitivity with significantly higher plasma insulin levels. Hyperinsulinemic-euglycemic clamp studies indicate altered hepatic glucose metabolism. These effects are mimicked in vivo by injection into wild-type mice of either exogenous ATP or an ecto-ATPase inhibitor, ARL-67156, and by exposure of hepatocytes to extracellular nucleotides in vitro. Increased serum interleukin-1␤, interleukin-6, interferon-␥, and tumor necrosis factor-␣ levels are observed in Cd39/Entpd1-null mice in keeping with a proinflammatory phenotype. Impaired insulin sensitivity is accompanied by increased activation of hepatic c-Jun NH 2 -terminal kinase/ stress-activated protein kinase in Cd39/Entpd1 mice after injection of ATP in vivo. This results in decreased tyrosine phosphorylation of insulin receptor substrate-2 with impeded insulin signaling. CONCLUSIONS-CD39/Entpd1is a modulator of extracellular nucleotide signaling and also influences metabolism. Deletion of Cd39/Entpd1 both directly and indirectly impacts insulin regulation and hepatic glucose metabolism. Extracellular nucleotides serve as "metabolokines," indicating further links between inflammation and associated metabolic derangements. Diabetes 57:2311-2320, 2008 P urinergic signaling elements comprise a ubiquitous sensing network within the extracellular environment. In this system, extracellular nucleotides, such as ATP, ADP, and UTP, and extracellular nucleosides, such as adenosine, trigger differential cellular responses (1,2). Purinergic signaling pathways require extracellular nucleotide release mechanisms, purinergic receptors for these mediators (type 2 purinergic [P2] receptors), and regulated expression of ectonucleotidases that hydrolyze extracellular nucleotides to generate adenosine (3-5). Extracellular nucleotides are provided by the secretion/release of intracellular substrates, and levels are increased in hypoxia, injury, mechanical stress, and inflammation.Several reports suggest roles for extracellular nucleotides and nucleosides in glucose homeostasis (e.g., stimulation of insulin secretion from islets [6 -8], modulation of glucose uptake [9,10]). P2 receptors are expressed by insulin-sensitive tissues and also by immune cells. Extracellular nucleotides activate inflammatory pathways, inducing expression of proinflammatory cytokines including interleukin-1 (11), interferon-␥ (12), and...

show abstract

Section: Discussionsupporting

confidence: 73%

Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Similar findings were reported by Shashkin et al in type II diabetic patients compared with control subjects (61). Scoscia et al studied placental membranes from women with preeclampsia, a disease with insulin resistance, compared with controls (60). With administered insulin in vitro, re- Plus-minus values are mean ± SEM.…”

Section: Inositol Imbalance and Insulin Resistancesupporting

confidence: 75%

“…Baillargeon et al (59) studied women with polycystic ovary syndrome (PCOS) and Scoscia et al (60) studied women with preeclampsia. Both diseases are associated with insulin resistance.…”

Section: Inositol Imbalance and Insulin Resistancementioning

confidence: 99%

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

Larner

Brautigan

Thorner

2010

Mol Med

151

152

View full text Add to dashboard Cite

SYNTHESISInsulin stimulates both glucose transport and glycogen synthesis; however, these actions sometimes occur in a disconnected manner. Current models for the mechanism of action for insulin, for which the dominant paradigm involves the activity of the insulin receptor Tyr kinase and its primary Tyr phosphorylated substrates-the insulin receptor substrate (IRS) family of proteins (1), are inadequate to account for these historical observations. Under certain conditions, control of glucose transport by insulin is observed in the absence of an effect on glycogen synthesis, whereas under other conditions, control of glycogen synthesis by insulin is observed in the absence of an effect on glucose transport. For example, application of insulin during perfusion of the rat heart stimulated glucose transport, but did not activate glycogen synthase (GS) (2). On the other hand, when the rat diaphragm was treated with N-ethylmaleimide, to test the effect of this sulfhydryl reagent on metabolism, no effect of insulin was observed on glucose transport, but insulin-activated GS and glycogen synthesis (3). Thus, insulin signaling proceeded along one pathway while another pathway was unaffected, suggesting the possibility that no single pathway accounts for events downstream of the IR, but parallel signaling connects the IR to activation of glucose transport and glucose metabolism. These considerations led us to the concept that a cytoplasmic second messenger was generated in parallel with the phosphorylation events initiated by the receptor Tyr kinase (4). We have emphasized the hypothesis that the phosphorylation network and the second messenger pathway operate in parallel and together are required to fully account for insulin effects on metabolic disposal of intracellular glucose (4). EVIDENCE FOR INSULIN SECOND MESSENGERSThe initial evidence to support the existence of a second messenger for insulin followed classical methods used to discover cAMP. Rats were injected with insulin and killed, and then muscle and/or liver were used to prepare heatinactivated, deproteinized extracts. The extracts from insulin-stimulated rat tissues had one or more substances that inhibited protein kinase A (PKA) and activated GS phosphatase, compared with extracts from control rats. Insulin administration maintained PKA in muscle as an inactive holoenzyme, presumably desensitized to cAMP by the soluble second D 1 6 ( 1 1 -1 2 ) 5 4 3 -5 5 1 , N Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues, the most important and relevant effects for human health. However, nonoxidative and oxidative glucose disposal by activation of glycogen synthase (GS) and mitochondrial pyruvate dehydrogenase (PDH) remain incompletely explained by current models for insulin action. Since the discovery of insulin receptor Tyr kinase activity about 25 years ago, the dominant paradigm for intracellular signaling by insulin invokes protein phosphorylation downstream of the receptor and its primar...

show abstract

“…It is well established that maternal insulin is dysregulated in pregnancies complicated by diabetes, obesity, undernutrition, and preeclampsia, and insulin resistance also occurs in the placentas from diabetic, preeclamptic, and growth-restricted pregnancies (Colomiere et al, 2009;Rademacher et al, 2007;Scioscia et al, 2006;Street et al, 2011). Maternal infection during pregnancy increases cytokines within the placenta and is predicted to disrupt insulin signaling due to the inhibitory effects of cytokines on insulin action (Aguirre et al, 2002;Sykiotis and Papavassiliou, 2001;Tanti and Jager, 2009).…”

Section: A Common Programmatic Pathwaymentioning

confidence: 99%

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

Bronson

Bale

2015

Neuropsychopharmacol

196

172

View full text Add to dashboard Cite

Adversity experienced during gestation is a predictor of lifetime neuropsychiatric disease susceptibility. Specifically, maternal stress during pregnancy predisposes offspring to sex-biased neurodevelopmental disorders, including schizophrenia, attention deficit/hyperactivity disorder, and autism spectrum disorders. Animal models have demonstrated disease-relevant endophenotypes in prenatally stressed offspring and have provided unique insight into potential programmatic mechanisms. The placenta has a critical role in the deleterious and sex-specific effects of maternal stress and other fetal exposures on the developing brain. Stress-induced perturbations of the maternal milieu are conveyed to the embryo via the placenta, the maternal-fetal intermediary responsible for maintaining intrauterine homeostasis. Disruption of vital placental functions can have a significant impact on fetal development, including the brain, outcomes that are largely sex-specific. Here we review the novel involvement of the placenta in the transmission of the maternal adverse environment and effects on the developing brain.

show abstract

Insulin Resistance in Human Preeclamptic Placenta Is Mediated by Serine Phosphorylation of Insulin Receptor Substrate-1 and -2

Cited by 67 publications

References 43 publications

Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

Contact Info

Product

Resources

About