SUN-651 Murine Cecal Ligation and Puncture (CLP) Perturbs Phosphorylation of Insulin Receptor Substrate 2 (IRS-2)

Abstract Hyperglycemia is a characteristic finding in sepsis, and its presence worsens outcome (1). Patients with sepsis need larger doses of insulin to reduce glucose levels. This abnormality has been termed “insulin resistance” but the molecular mechanism by which sepsis attenuates the insulin signaling pathway is unknown. Previous work has shown impairment of phosphorylation in several intracellular signaling pathways following CLP, a well-validated murine model of sepsis (2). Phosphorylation of tyrosine in IRS-2 is essential for functional insulin signaling in hepatocytes (3). Therefore the aim of this study was to investigate the effects of CLP on IRS-2 phosphorylation. Hypothesis: CLP attenuates phosphorylation of IRS-2. Methods: All studies were approved by the Feinstein IACUC and conformed to ARRIVE guidelines. CLP was performed on C57Bl6 mice. Before CLP, animals were identified for sacrifice at specific post-procedure time points. To stimulate phosphorylation of IRS-2, insulin was injected in control and CLP mice at 24 and 48 hours post CLP. Following sacrifice, protein was isolated from liver tissue. Protein abundance was determined using immunoblotting. The detection of the phosphorylated form of these proteins was determined by enzyme-linked immunosorbent assay (ELISA) with a phospho-insulin receptor antibody. Statistical significance was determined using ANOVA for repeated measures with a Sidak post-hoc correction. Results: Relative to the control, tyrosine phosphorylation of IRS-2 was significantly (p<0.05) reduced at 24 and 48 hours following CLP. Conclusions: Tyrosine phosphorylation of hepatic IRS2 is attenuated at early time points following CLP. These results are consistent with other studies examining the effects of CLP on intra-cellular signal transduction pathways (1). Further, these results provide evidence that changes in the insulin signaling transduction underlie CLP-induced “insulin resistance”. References: (1) Abcejo et al., Crit Care Med. 2009;37(5):1729-1734. (2) van den Berghe et al, NEngl J Med. 2001;345(19):1359-1367. (3) Valverde et al., Diabetes 2003 Sep; 52(9): 2239-2248.

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Effect of Subtoxic DDT Exposure on Glucose Uptake and Insulin Signaling in Rat L6 Myoblast-Derived Myotubes

International Journal of Toxicology ◽

10.1177/1091581819850577 ◽

2019 ◽

Vol 38 (4) ◽

pp. 303-311 ◽

Cited By ~ 2

Author(s):

Vijay Kumar Singh ◽

Sajib Kumar Sarkar ◽

Alpana Saxena ◽

Bidhan Chandra Koner

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Tyrosine Phosphorylation ◽

Insulin Signaling ◽

Messenger Rna ◽

Insulin Receptors ◽

Serine Phosphorylation ◽

Enzyme Linked Immunosorbent Assay ◽

Antioxidant Content ◽

L6 Myoblast

Exposure to persistent organic pollutants including dichlorodiphenyltrichloroethane (DDT) induces insulin resistance. But the mechanism is not clearly known. The present study was designed to explore the effect of subtoxic DDT exposure on (1) insulin-stimulated glucose uptake, (2) malondialdehyde (MDA) level and total antioxidant content, (3) activation of redox sensitive kinases (RSKs), and (4) insulin signaling in rat L6 myoblast-derived myotubes. Exposure to 30 mg/L and 60 mg/L of DDT for 18 hours dose dependently decreased glucose uptake and antioxidant content in myotubes and increased MDA levels. The exposures did not alter tumor necrosis factor α (TNF-α) level as determined by enzyme-linked immunosorbent assay, despite decreased messenger RNA expression following DDT exposures. Phosphorylation of c-Jun N-terminal kinases and IκBα, an inhibitory component of nuclear factor κB (NFκB), was increased, suggesting activation of RSKs. The level of tyrosine phosphorylation of insulin receptor substrate 1 and serine phosphorylation of protein kinase B (Akt) on insulin stimulation decreased in myotubes with exposure to subtoxic concentrations of DDT, but there was no change in tyrosine phosphorylation level of insulin receptors. We conclude that subtoxic DDT exposure impairs insulin signaling and thereby induces insulin resistance in muscle cells. Data show that oxidative stress-induced activation of RSKs is responsible for impairment of insulin signaling on DDT exposure.

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

Molecular Endocrinology ◽

10.1210/me.2005-0107 ◽

2006 ◽

Vol 20 (1) ◽

pp. 114-124 ◽

Cited By ~ 69

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.

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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 ◽

10.1210/en.2006-1702 ◽

2007 ◽

Vol 148 (6) ◽

pp. 2994-3003 ◽

Cited By ~ 39

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.

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Impaired insulin signaling in the liver of transgenic rats with low circulating growth hormone levels

Journal of Endocrinology ◽

10.1677/joe.0.1720127 ◽

2002 ◽

Vol 172 (1) ◽

pp. 127-136 ◽

Cited By ~ 4

Author(s):

Y Furuhata ◽

T Yonezawa ◽

M Takahashi ◽

M Nishihara

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Insulin Signaling ◽

Gh Deficiency ◽

Pi3 Kinase ◽

The Body ◽

Transgenic Rat ◽

Insulin Stimulation ◽

Transgenic Rats

GH is known to regulate glucose and lipid metabolism as well as body growth. Controversy exists as to whether GH-deficient adults are indeed insulin sensitive or insulin resistant. In GH-deficient animal models, however, no clear observation indicating insulin resistance has been made, while increased insulin sensitivity has been reported in those animals. We have produced human GH (hGH) transgenic rats characterized by low circulating hGH levels and virtually no endogenous rat GH secretion. Although the body length of the transgenic rat is normal, they develop massive obesity and insulin resistance, indicating that the transgenic rat is a good model for the analysis of insulin resistance under GH deficiency. In this study, we have examined how GH deficiency affects the early steps of insulin signaling in the liver of the transgenic rat. Circulating glucose and insulin concentrations were significantly higher in the transgenic rats than in their littermates. In addition, impaired glucose tolerance was observed in the transgenic rat. The amount of insulin receptor was smaller in the liver of the transgenic rat, resulting in decreased tyrosine phosphorylation in response to insulin stimulation. The amounts of insulin receptor substrate-1 and -2 (IRS-1 and -2) and insulin-stimulated phosphorylation of IRSs were also smaller in the transgenic rat. Despite the decrease in tyrosine phosphorylation levels of IRSs being mild to moderate (45% for IRS-1 and 16% for IRS-2), associated phosphatidylinositol 3-kinase (PI3-kinase) activity was not increased by insulin stimulation at all in the transgenic rat. To elucidate whether this discrepancy resulted from the alteration in binding of the p85 subunit of PI3-kinase to phosphotyrosine residues of the IRSs, we determined the amount of p85 subunit in the immunocomplexes with anti-phosphotyrosine antibody. Insulin did not affect the amount of p85 subunit associated with phosphotyrosine in the transgenic rats, while it significantly increased in the controls, indicating that alteration may have occurred at the sites of phosphorylated tyrosine residues in IRSs. These results suggest that GH deficiency in the transgenic rat leads to impairment in at least the early steps of insulin signaling in the liver with a resultant defect in glucose metabolism.

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Adolescent Pitcher Fatigue: Ulnar Collateral Ligament Stress, Flexor-Pronator Mass Energy Depletion, and Correlation to Pitch Count

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967121s00247 ◽

2021 ◽

Vol 9 (7_suppl4) ◽

pp. 2325967121S0024

Author(s):

Manuel Schubert ◽

Tariq Awan ◽

Aaron Sciascia ◽

Emily Pacheco ◽

Jennifer DeMink ◽

...

Keyword(s):

Grip Strength ◽

Muscle Glycogen ◽

Repeated Measures ◽

Statistical Significance ◽

Ulnar Collateral Ligament ◽

Glycogen Storage ◽

Collateral Ligament ◽

Time Points ◽

Subjective Fatigue ◽

Forearm Flexor

Objectives: There has been a rise in elbow ulnar collateral ligament (UCL) injuries in youth pitchers over recent years. With forearm flexor-pronator mass fatigue, the dynamic stability provided could be diminished placing greater stress on the UCL. Pitch count limits have been instituted in an attempt to help curtail this rise in throwing injuries, especially in youth athletes. In order to provide more objective data regarding current pitch count limits for youth pitchers, the purpose of this pilot study was to evaluate for potential fatigue of the flexor-pronator mass by assessing changes in medial elbow laxity, noninvasively characterizing changes in muscle glycogen storage within the forearm flexor-pronator mass, and evaluating changes in subjective fatigue, strength, range of motion (ROM), pitching velocity, and accuracy with increasing number of pitches thrown by 10-year-old pitchers up to their recommended 75 pitch count limit. Methods: After appropriate power analysis, male pitchers 10 years of age were recruited for the study (n=22). Pitchers threw a total of 75 pitches divided into sets of 25 pitches, with standardized periods of rest in between throws and sets to best simulate a game. Bilateral medial elbow laxity was measured by applying 10 decanewtons of valgus force with a standardized stress device and utilizing ultrasound imaging (Figures 1A-B) prior to pitching and after each pitching set. The change in medial ulnohumeral joint distance (Figure 1C) after stress was applied was calculated from baseline without stress. Relative changes in muscle glycogen storage, detected as changes in echogenicity, within the flexor carpi radialis (FCR) and the flexor digitorum superficialis (FDS)/flexor carpi ulnaris (FCU) muscles were measured non-invasively with ultrasound-based software (Figures 1D-E) and recorded as fuel percentile. Repeated measures analysis of variance and post-hoc testing were used to determine statistical significance (alpha=0.05). Results: There were no significant differences in medial elbow laxity between arms or time points. There was a trend for similar decline in FCR fuel percentile values between each arm, indicating relative decreases in glycogen storage bilaterally. However, only the throwing arm demonstrated a statistically significant decline in fuel percentile from baseline to after 75 pitches (p=0.05). There were no statistically significant differences across time points for FDS/FCU fuel percentile values. Fatigue measurements for both arms were significantly higher at all time points compared to baseline (p≤0.03). Grip strength of the dominant arm after 75 pitches was significantly decreased compared to after 25 pitches (p=0.02). There were no statistically significant changes in other strength measurements, ROM, velocity, or accuracy between all time points. Conclusions: By the recommended 75 pitch count limit in 10-year-olds, subjective fatigue and a decrease in grip strength had occurred. Furthermore, relative glycogen storage of the flexor-pronator mass of the throwing arm decreased between pitching 50 to 75 pitches, but without an increase in medial elbow gapping. This study provides a foundation and raises questions for further objective testing of physiologic changes that occur throughout increasing pitching to better guide pitch count limits and ensure the safety of young athletes

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

Molecular and Cellular Biology ◽

10.1128/mcb.24.21.9668-9681.2004 ◽

2004 ◽

Vol 24 (21) ◽

pp. 9668-9681 ◽

Cited By ~ 83

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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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 ◽

10.1210/en.2009-0838 ◽

2010 ◽

Vol 151 (1) ◽

pp. 75-84 ◽

Cited By ~ 38

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.

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Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e1014 ◽

1997 ◽

Vol 273 (5) ◽

pp. E1014-E1023 ◽

Cited By ~ 17

Author(s):

Jacob E. Friedman ◽

Tatsuya Ishizuka ◽

Sha Liu ◽

Craig J. Farrell ◽

David Bedol ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Glucose Intolerance ◽

Leptin Receptor ◽

Spontaneously Hypertensive Rat ◽

Regulatory Subunit ◽

Oral Glucose ◽

Spontaneously Hypertensive

Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3- O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85α regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.

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

Journal of Endocrinology ◽

10.1677/joe-09-0269 ◽

2009 ◽

Vol 203 (3) ◽

pp. 365-374 ◽

Cited By ~ 10

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.

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Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

10.21203/rs.3.rs-483980/v1 ◽

2021 ◽

Author(s):

Qian Zhou ◽

Wan-Wan Sun ◽

Jia-Cong Chen ◽

Huilu Zhang ◽

Jie Liu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Amino Acids ◽

Insulin Receptor ◽

Glucose Uptake ◽

Insulin Signaling ◽

Trna Synthetase ◽

Blood Samples ◽

Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

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