Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling

doi:10.1016/S0003-4266(04)95629-6

Annales d'Endocrinologie

Volume 65, Issue 1, February 2004, Pages 43-48

https://doi.org/10.1016/S0003-4266(04)95629-6 Get rights and content

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. 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 “diabetogenic” factors such as FFA, TNFα, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser^307/612/632 as phosphorylated sites. Moreover, several kinases able to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tissues. Identifying the pathways by which “diabetogenic” factors activate IRS-1 kinases and defining the precise role of serine phosphorylation events in IRS-1 regulation represent important goals. Such studies may enable rational drug design to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.

La résistance à l’insuline, combinée avec un défaut de sécrétion d’insuline, contribues au développement du diabète de type 2. L’insulinorésistance se caractérise par une diminution de l’effet de l’insuline sur le transport de glucose dans les muscles et les adipocytes. La phosphorylation d’IRS-1 (substrat majeur du récepteur de l’insuline) sur des résidus de tyrosine et sa liaison à la phosphatidylinositol 3-kinase sont nécessaires à la stimulation du transport de glucose par l’insuline. Des modifications du niveau de phosphorylation d’IRS-1 sur des résidus de sérine est un des mécanismes pouvant conduire à une diminution de sa phosphorylation sur des résidus de tyrosine et à une diminution du transport de glucose. Des facteurs diabètogènes comme les acides gras libres, le TNFa, l’hyperinsulinémie et différents stress, augmentent la sérine phosphorylation d’IRS-1 sur 3 résidus différents : les sérines 307, 612 et 632. De plus de nombreuses sérine/thréonine kinases phosphorylent ces trois résidus de sérine. Ces résultats récents suggèrent qu’une augmentation de la sérine phosphorylation d’IRS-1 puisse être une caractéristique des états d’insulinorésistance. Une meilleure compréhension du rôle de cette phosphorylation sur la fonction d’IRS-1 ainsi que des mécanismes employés par les facteurs diabètogénes pour activer les IRS-1 kinases représente de nouvelles voies de recherche. Ces études devraient permettre de définir de nouvelles approchent pharmacologiques pour le traitement du diabète de type 2.

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Fagiolo et al. (1993) recorded that cytokine production elevated with age. Moreover, the administration of LPS in rodents has been reported to elevate triglyceride levels by de novo fatty acids synthesis, which have been shown to increase the sein phosphorylation of IRS-1) (Feingold et al., 1992; Tanti et al., 2004) (Fig. 2). Therefore, the gut microbiota appeared to link LPS of plasma, cytokine, inflammation, fatty acids, and insulin resistance.
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However, at the molecular level, inhibitory phosphorylation of IRS1 at serine 307 (pIRS1Ser307) represents an early hallmark of insulin resistance leading to impairment of IRS1 ability to activate downstream kinase and transduce insulin signal (Sykiotis and Papavassiliou, 2001). It was previously shown that “diabetogenic” factors such as fatty acids and proinflammatory cytokines may lead to increased inhibitory serine Ser307 phosphorylation of IRS1 (Tanti et al., 2004). The underlying mechanism that links hippocampal insulin resistance and altered behavior could be impaired plasticity of neuronal networks and reduced hippocampal neurogenesis, since insulin is involved in regulation of these processes (Blazquez et al., 2014).
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The results showed that MIF^−/− mice exhibit emphasized anxiety-like behaviors, as well as impaired recognition memory, which may be hippocampus-dependent. This behavioral phenotype was associated with impaired systemic insulin sensitivity and attenuated hippocampal insulin sensitivity, characterized by increased inhibitory Ser³⁰⁷ phosphorylation of insulin receptor substrate 1 (IRS1). Finally, MIF^−/− mice displayed a decreased hippocampal PSA-NCAM level and unchanged Bdnf, NT-3, NT-4 and Igf-1 mRNA levels.
The results suggest that the lack of MIF leads to disturbances of systemic and hippocampal insulin sensitivity, which are possibly responsible for memory deficits and anxiety, most likely through decreased PSA-NCAM-mediated neuroplasticity rather than through neurotrophic factors.
Gut microbiota and immune crosstalk in metabolic disease
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Innate immune cells infiltrate the tissues through a mechanism requiring the expression of the C–C motif chemokine receptor-2 (CCR2) by the circulating monocytes tissue macrophages and the production of chemokine ligand-2 (CCL2) and MCP1 by adipose tissue derived cells [27]. Activated M1 macrophages produce large amounts of TNFα, IL-1β, and IL-6, which contribute to insulin resistance by phosphorylating the c-Jun amino terminal kinase (JNK) and inhibitor of nuclear factor kappa B kinase subunit β (IKK-β) responsible for the phosphorylation of serine of IRS-1 [28,29]. Serine phosphorylation inactivates the IRS, which reduces insulin signaling and triggers insulin resistance.
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In vivo, ectopic accumulation of fatty acids in muscles leads to alterations in insulin signaling at both the IRS1 and Akt steps. However, in vitro treatments with saturated fatty acids or their derivative ceramide demonstrate an effect only at the Akt step. In this study, we adapted our experimental procedures to mimic the in vivo situation and show that the double-stranded RNA-dependent protein kinase (PKR) is involved in the long-term effects of saturated fatty acids on IRS1. C2C12 or human muscle cells were incubated with palmitate or directly with ceramide for short or long periods, and insulin signaling pathway activity was evaluated. PKR involvement was assessed through pharmacological and genetic studies. Short-term treatments of myotubes with palmitate, a ceramide precursor, or directly with ceramide induce an inhibition of Akt, whereas prolonged periods of treatment show an additive inhibition of insulin signaling through increased IRS1 serine 307 phosphorylation. PKR mRNA, protein, and phosphorylation are increased in insulin-resistant muscles. When PKR activity is reduced (siRNA or a pharmacological inhibitor), serine phosphorylation of IRS1 is reduced, and insulin-induced phosphorylation of Akt is improved. Finally, we show that JNK mediates ceramide-activated PKR inhibitory action on IRS1. Together, in the long term, our results show that ceramide acts at two distinct levels of the insulin signaling pathway (IRS1 and Akt). PKR, which is induced by both inflammation signals and ceramide, could play a major role in the development of insulin resistance in muscle cells.
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Wistar rats received during 21 days a commercial diet or the same diet supplemented with 10% fructose in drinking water without/with R/S-α-lipoic acid injection. After this period, we measured a) serum glucose, triglyceride, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), insulin glucose ratio (IGR) and Matsuda indexes and b) liver oxidative stress, inflammatory markers and insulin signaling pathway components.
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Session 2Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signallingAnomalies dans l’action de l’insuline : rôle de la sérine phosphorylation d’IRS-1 dans la régulation négative du signal insulinique

J Biol Chem

J Biol Chem

Curr Opin Pharmacol

J Biol Chem

J Biol Chem

J Biol Chem

Diabetes Metab

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Trends Cell Biol

Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes

Diabetes

Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression

Diabetes

Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes

N Engl J Med

Session 2
Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signallingAnomalies dans l’action de l’insuline : rôle de la sérine phosphorylation d’IRS-1 dans la régulation négative du signal insulinique