scholarly journals Role of Insulin Receptor Substrate-1 Serine 307 Phosphorylation and Adiponectin in Adipose Tissue Insulin Resistance in Late Pregnancy

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5933-5942 ◽  
Author(s):  
Julio Sevillano ◽  
Javier de Castro ◽  
Carlos Bocos ◽  
Emilio Herrera ◽  
M. Pilar Ramos
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Late Pregnancy ◽  
Serine Phosphorylation ◽  
Pregnant Rats

Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy.

scholarly journals Implication of Low Level Inflammation in the Insulin Resistance of Adipose Tissue at Late Pregnancy

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4094-4105 ◽  
Author(s):  
J. de Castro ◽  
J. Sevillano ◽  
J. Marciniak ◽  
R. Rodriguez ◽  
C. González-Martín ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
P38 Mapk ◽  
Physiological Role ◽  
Late Pregnancy ◽  
Serine Phosphorylation ◽  
Low Grade ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pregnant Rats ◽  
Low Grade Inflammation

Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1β, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance.

Role of O-GlcNAcylation and endoplasmic reticulum stress on obesity and insulin resistance

2019 ◽  
Vol 44 (5) ◽  
pp. 599-610 ◽  
Author(s):  
Benan Pelin Sermikli ◽  
Gulizar Aydogdu ◽  
Afsar Abbasi Taghidizaj ◽  
Erkan Yilmaz
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Western Blot ◽  
Er Stress ◽  
Insulin Receptor ◽  
Serine Phosphorylation ◽  
Wild Type ◽  
Adipose Tissues ◽  
Insulin Resistant

Abstract Background Obesity is a global public health problem. Obesity closely associated with various metabolic diseases such as; insulin resistance, hypertension, dyslipidemia and cardiovascular diseases. Endoplasmic reticulum (ER) stress is a critical factor for insulin resistance. O-linked N-acetyl-glucosamine (O-GlcNAc); is the post-translational modification which is has a vital role in biological processes; including cell signaling, in response to nutrients, stress and other extracellular stimuli. Materials and methods In this study, we aimed to investigate the role of O-GlcNAc modification in the context of obesity and obesity-associated insulin resistance in adipose tissue. For this purpose, first, the visceral and epididymal adipose tissues of obese and insulin resistant C57BL/6 Lepob/Lepob and wild-type mice were used to determine the O-GlcNAc modification pattern by western blot. Secondly, the external stimulation of O-GlcNAc modification in wild-type mice achieved by intraperitoneal 5 mg/kg/day glucosamine injection every 24 h for 5 days. The effect of increased O-GlcNAc modification on insulin resistance and ER stress investigated in adipose tissues of glucosamine challenged wild-type mice through regulation of the insulin signaling pathway and unfolded protein response (UPR) elements by western blot. In addition to that, the O-GlcNAc status of the insulin receptor substrate-1 (IRS1) investigated in epididymal and visceral adipose tissues of ob/ob, wild-type and glucosamine challenged mice by immunoprecipitation. Results We found that reduced O-GlcNAc levels in visceral and epididymal adipose tissues of obese and insulin-resistant ob/ob mice, although interestingly we observed that increased O-GlcNAc modification in glucosamine challenged wild-type mice resulted in insulin resistance and ER stress. Furthermore, we demonstrated that the IRS1 was modified with O-GlcNAc in visceral and epididymal adipose tissues in both ob/ob mice and glucosamine-injected mice, and was compatible with the serine phosphorylation of this modification. Conclusion Our results suggest that O-GlcNAcylation of proteins is a crucial factor for intracellular trafficking regulates insulin receptor signaling and UPR depending on the cellular state of insulin resistance.

Reversion of insulin resistance in the rat during late pregnancy by 72-h glucose infusion

1995 ◽  
Vol 269 (5) ◽  
pp. E858-E863 ◽  
Author(s):  
P. Ramos ◽  
E. Herrera
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Utilization ◽  
Late Pregnancy ◽  
Glucose Infusion ◽  
Continuous Intravenous Infusion ◽  
Pregnant Rats ◽  
Bidistilled Water ◽  
Insulin Responsiveness

To determine whether sustained exaggerated hyperinsulinemia in normoglycemic rats modifies insulin responsiveness during pregnancy, 17-day-pregnant and virgin rats were studied after receiving a continuous intravenous infusion (35 ml/day) of either 50% glucose or bidistilled water (controls) for 72 h. Plasma glucose was unchanged, whereas insulin was highly increased, and the effect was more marked in pregnant than in virgin rats. Insulin responsiveness, estimated under the hyperinsulinemic euglycemic clamp with 0.8 IU insulin.h-1.kg-1, was lower in control pregnant than in virgin rats but higher in pregnant than in virgin rats in those that had received the glucose infusion. The tissue glucose utilization metabolic index (GUI) was estimated with 2-deoxy-D-[1-3H]glucose in the clamped rats. The GUI was lower in heart, white- and red-fiber skeletal muscle, and adipose tissue in control pregnant rats than in control virgin rats, and, although the glucose infusion decreased that index in both red-fiber muscle and adipose tissue in virgin rats, glucose increased the index in red-fiber muscle in pregnant rats to the level found in virgin controls. Results therefore show that, when unaccompanied by hypoglycemia, sustained exaggerated hyperinsulinemia decreases insulin responsiveness in virgin rats but reverts insulin resistance in late-pregnant rats.

scholarly journals Mechanisms of Hemorrhage-Induced Hepatic Insulin Resistance: Role of Tumor Necrosis Factor-α

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5168-5176 ◽  
Author(s):  
Yuchen Ma ◽  
Balazs Toth ◽  
Adam B. Keeton ◽  
LaWanda T. Holland ◽  
Irshad H. Chaudry ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Burn Injury ◽  
Serine Phosphorylation ◽  
Hepatic Insulin Resistance ◽  
Surgical Trauma ◽  
Hepatic Expression ◽  
Protein Levels ◽  
Induce Insulin Resistance

Abstract Hemorrhage, sepsis, burn injury, surgical trauma and critical illness all induce insulin resistance. Recently we found that trauma and hemorrhage acutely induced hepatic insulin resistance in the rat. However, the mechanisms of this hemorrhage-induced acute hepatic insulin resistance are unknown. Here we report on the mechanisms of this hepatic insulin resistance. Protein levels and phosphorylation of the insulin receptor and insulin receptor substrate-1/2 (IRS-1/2) were measured, as was the association between IRS-1/2 and phosphatidylinositol 3-kinase (PI3K). Also examined were the hepatic expression of TNFα and TNFα-induced serine phosphorylation of IRS-1. Insulin receptor and IRS-1/2 protein levels and insulin-induced tyrosine phosphorylation of the insulin receptor were unaltered. In contrast, insulin-induced tyrosine phosphorylation of IRS-1/2 and association between IRS-1/2 and PI3K were dramatically reduced after hemorrhage. Hepatic levels of TNFα mRNA and protein were increased as was phosphorylation of IRS-1 serine 307 after hemorrhage. Our data provide the first evidence that compromised IRS-1/2 tyrosine phosphorylation and their association with PI3K contribute to hemorrhage-induced acute hepatic insulin resistance. Increased local TNFα may play a role in inducing this hepatic insulin resistance after trauma and hemorrhage.

scholarly journals Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 24-32 ◽  
Author(s):  
Li Li ◽  
LaWanda H. Thompson ◽  
Ling Zhao ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Rapid Development ◽  
Serine Phosphorylation ◽  
Synthesis Inhibitor ◽  
Adult Rats ◽  
Counterregulatory Hormones

Acute insulin resistance occurs after injury, hemorrhage, infection, and critical illness. However, little is known about the development of this acute insulin-resistant state. In the current study, we found that insulin resistance develops rapidly in skeletal muscle, with the earliest insulin signaling defects at 60 min. However, defects in insulin signaling were measurable even earlier in liver, by as soon as 15 min after hemorrhage. To begin to understand the mechanisms for the development of acute insulin resistance, serine phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun N-terminal kinase phosphorylation/activation was investigated. These markers (and possible contributors) of insulin resistance were increased in the liver after hemorrhage but not measurable in skeletal muscle. Because glucocorticoids are important counterregulatory hormones responsible for glucose homeostasis, a glucocorticoid synthesis inhibitor, metyrapone, and a glucocorticoid receptor antagonist, RU486, were administered to adult rats prior to hemorrhage. In the liver, the defects of insulin signaling after hemorrhage, including reduced tyrosine phosphorylation of the insulin receptor and IRS-1, association between IRS-1 and phosphatidylinositol 3-kinase and serine phosphorylation of Akt in response to insulin were not altered by pretreatment of rats with metyrapone or RU486. In contrast, hemorrhage-induced defects in insulin signaling were dramatically reversed in skeletal muscle, indicating a prevention of insulin resistance in muscle. These results suggest that distinct mechanisms for hemorrhage-induced acute insulin resistance are present in these two tissues and that glucocorticoids are involved in the rapid development of insulin resistance in skeletal muscle, but not in the liver, after hemorrhage. Glucocorticoids play a major role in the development of acute insulin resistance following hemorrhage in skeletal muscle, but not in the liver.

scholarly journals Molecular Mechanisms of Hypothalamic Insulin Resistance

2019 ◽  
Vol 20 (6) ◽  
pp. 1317 ◽  
Author(s):  
Hiraku Ono
Keyword(s):  
Insulin Resistance ◽  
Central Nervous System ◽  
Nervous System ◽  
Insulin Receptor ◽  
Molecular Mechanisms ◽  
Saturated Fatty Acids ◽  
Saturated Fat ◽  
Serine Phosphorylation ◽  
Obesity And Diabetes ◽  
The Central Nervous System

Insulin exists in the central nervous system, where it executes two important functions in the hypothalamus: the suppression of food intake and the improvement of glucose metabolism. Recent studies have shown that both are exerted robustly in rodents and humans. If intact, these functions exert beneficial effects on obesity and diabetes, respectively. Disruption of both occurs due to a condition known as hypothalamic insulin resistance, which is caused by obesity and the overconsumption of saturated fat. An enormous volume of literature addresses the molecular mechanisms of hypothalamic insulin resistance. IKKβ and JNK are major players in the inflammation pathway, which is activated by saturated fatty acids that induce hypothalamic insulin resistance. Two major tyrosine phosphatases, PTP-1B and TCPTP, are upregulated in chronic overeating. They dephosphorylate the insulin receptor and insulin receptor substrate proteins, resulting in hypothalamic insulin resistance. Prolonged hyperinsulinemia with excessive nutrition activates the mTOR/S6 kinase pathway, thereby enhancing IRS-1 serine phosphorylation to induce hypothalamic insulin resistance. Other mechanisms associated with this condition include hypothalamic gliosis and disturbed insulin transport into the central nervous system. Unveiling the precise molecular mechanisms involved in hypothalamic insulin resistance is important for developing new ways of treating obesity and type 2 diabetes.

Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling

2003 ◽  
Vol 31 (6) ◽  
pp. 1152-1156 ◽  
Author(s):  
Y. Le Marchand-Brustel ◽  
P. Gual ◽  
T. Grémeaux ◽  
T. Gonzalez ◽  
R. Barrès ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor α, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307 as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser307 phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.

scholarly journals Interleukin-1α Inhibits Insulin Signaling with Phosphorylating Insulin Receptor Substrate-1 on Serine Residues in 3T3-L1 Adipocytes

2006 ◽  
Vol 20 (1) ◽  
pp. 114-124 ◽  
Author(s):  
Jianying He ◽  
Isao Usui ◽  
Ken Ishizuka ◽  
Yukiko Kanatani ◽  
Kazuyuki Hiratani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Proinflammatory Cytokines ◽  
Insulin Signaling ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Akt Phosphorylation ◽  
Iκb Kinase ◽  
Serine Kinases

Abstract Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1α is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1α may also cause insulin resistance. Here, we investigated the effects of IL-1α treatment on insulin signaling in 3T3-L1 adipocytes. IL-1α treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1α stimulation, when several serine kinases, IκB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1α-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1α. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1α in the presence of IL-6. Taken together, short-term IL-1α treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1α may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.

scholarly journals Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRβ/IRS-1 and Akt and insulin resistance in muscle of mice

2006 ◽  
Vol 291 (3) ◽  
pp. E476-E482 ◽  
Author(s):  
Marco A. Carvalho-Filho ◽  
Mirian Ueno ◽  
José B. C. Carvalheira ◽  
Lício A. Velloso ◽  
Mario J. A. Saad
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Tissue Expression ◽  
Inos Expression ◽  
Serine Phosphorylation ◽  
Insulin Signal Transduction ◽  
Diet Induced Obesity ◽  
Oxide Synthase ◽  
Lps Treatment

We have previously demonstrated that the insulin resistance associated with inducible nitric oxide synthase (iNOS) induction in two different models of obesity, diet-induced obesity and the ob/ ob mice, is mediated by S-nitrosation of proteins involved in insulin signal transduction: insulin receptor β-subunit (IRβ), insulin receptor substrate 1(IRS-1), and Akt. S-nitrosation of IRβ and Akt impairs their kinase activities, and S-nitrosation of IRS-1 reduces its tissue expression. In this study, we observed that LPS-induced insulin resistance in the muscle of wild-type mice, as demonstrated by reduced insulin-induced tyrosine phosphorylation of IRβ and IRS-1, reduced IRS-1 expression and reduced insulin-induced serine phosphorylation of Akt. This resistance occurred in parallel with enhanced iNOS expression, which was accompanied by S-nitrosation of IRβ/IRS-1 and Akt. In the muscle of iNOS−/− mice, we did not observe enhanced iNOS expression or any S-nitrosation of IRβ/IRS-1 and Akt after LPS treatment. Moreover, insulin resistance was not present. The preservation of insulin-induced tyrosine phosphorylation of IRβ and IRS-1, of IRS-1 protein expression, and of insulin-induced serine phosphorylation of Akt observed in LPS-treated iNOS−/− mice strongly suggests that the insulin resistance induced by LPS is iNOS mediated, probably through S-nitrosation of proteins of early steps of insulin signaling.

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