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 Central Insulin Signaling Is Attenuated by Long-Term Insulin Exposure via Insulin Receptor Substrate-1 Serine Phosphorylation, Proteasomal Degradation, and Lysosomal Insulin Receptor Degradation

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Christopher M. Mayer ◽  
Denise D. Belsham
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Time Course ◽  
Proteasomal Degradation ◽  
Serine Phosphorylation ◽  
Neuronal Function ◽  
Protein Levels ◽  
Phosphorylated Akt

Abstract Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.

scholarly journals Age and tissue specific differences in the development of acute insulin resistance following injury

2009 ◽  
Vol 203 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Lidong Zhai ◽  
Joseph L Messina
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Intracellular Signaling ◽  
Male Rats ◽  
Hepatic Insulin Resistance ◽  
Surgical Trauma ◽  
Induce Insulin Resistance ◽  
Old Rats ◽  
Effect Of Age

Injuries, hemorrhage, sepsis, burn, and critical illnesses all induce insulin resistance, and insulin resistance is strongly associated with advancing age. However, the effect of age on injury induced insulin resistance is not well studied. We performed surgical trauma in male rats of three different ages (3-, 6-, and 10-weeks old). Rats were either hemorrhaged to a mean arterial pressure of 35–40 mmHg and subsequently maintained at that pressure for up to 90 min, or maintained without hemorrhage as controls. Results indicate that insulin-induced intracellular signaling was diminished in liver and skeletal muscle of 6- and 10-week old rats following trauma and hemorrhage. In even younger rats, immediately post-weaning (∼3 weeks of age), insulin signaling was lost in liver, but not in skeletal muscle. Glucocorticoids can play a role in the chronic development of insulin resistance. Our results demonstrate that corticosterone levels were increased in 6- and 10-week old animals following hemorrhage, but little change was measured in 3-week old animals. Blockade of glucocorticoid synthesis prevented the development of insulin resistance in skeletal muscle, but not in liver of 6- and 10-week old rats. Moreover, skeletal muscle glucocorticoid receptor levels increased dramatically between 3 and 6 weeks of age. These results indicate that trauma and hemorrhage-induced hepatic insulin resistance occurs at all ages tested. However, there is no development of insulin resistance following trauma and hemorrhage in skeletal muscle of post-weaning rats. In skeletal muscle of 6- and 10-week old rats, inhibition of glucocorticoid levels prevents the development of insulin resistance.

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.

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.

scholarly journals Chronic Tumor Necrosis Factor-α Treatment Causes Insulin Resistance via Insulin Receptor Substrate-1 Serine Phosphorylation and Suppressor of Cytokine Signaling-3 Induction in 3T3-L1 Adipocytes

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2994-3003 ◽  
Author(s):  
Ken Ishizuka ◽  
Isao Usui ◽  
Yukiko Kanatani ◽  
Agussalim Bukhari ◽  
Jianying He ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Serine Phosphorylation ◽  
Cytokine Signaling ◽  
Insulin Receptor Substrate ◽  
Signal Transducer ◽  
Suppressor Of Cytokine Signaling ◽  
Transcription 3

Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFα-induced insulin resistance in 3T3-L1 adipocytes. TNFα transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFα treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFα. TNFα stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFα treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFα. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFα or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFα may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.

scholarly journals Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2035
Author(s):  
Almudena Gómez-Hernández ◽  
Natalia de las Heras ◽  
Andrea R. López-Pastor ◽  
Gema García-Gómez ◽  
Jorge Infante-Menéndez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gene Therapy ◽  
Insulin Receptor ◽  
Vascular Dysfunction ◽  
Hepatic Insulin Resistance ◽  
Specific Gene ◽  
Mrna Levels ◽  
Hepatic Expression ◽  
Specific Insulin

Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.

scholarly journals Serine Phosphorylation Proximal to Its Phosphotyrosine Binding Domain Inhibits Insulin Receptor Substrate 1 Function and Promotes Insulin Resistance

2004 ◽  
Vol 24 (21) ◽  
pp. 9668-9681 ◽  
Author(s):  
Yan-Fang Liu ◽  
Avia Herschkovitz ◽  
Sigalit Boura-Halfon ◽  
Denise Ronen ◽  
Keren Paz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Treatment ◽  
Binding Domain ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Control Mechanisms ◽  
Insulin Receptor Substrate 1 ◽  
Phosphotyrosine Binding Domain

ABSTRACT Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-17A), unlike wild-type IRS-1 (IRS-1WT), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-17A to remain complexed with the insulin receptor (IR), unlike IRS-1WT, which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-17A and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.

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