Reduced Insulin Resistance Contributes to the Beneficial Effect of Protein Tyrosine Phosphatase-1B Deletion in a Mouse Model of Sepsis

Abstract

Hyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multiorgan failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. To evaluate the potential therapeutic effect of PTP1B blockade on glucose metabolism and insulin resistance in an experimental model of sepsis, we assessed the effect of PTP1B gene deletion in a cecal ligation and puncture (CLP) model of sepsis. PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation. These effects were associated with a reduction of sepsis-induced endothelial dysfunction/impaired NO production and especially of insulin-mediated dilatation. This modulation of insulin resistance may contribute to the beneficial effect of PTP1B blockade in septic shock, especially in terms of inflammation and cardiac metabolism.

Gene Expression of Protein Tyrosine Phosphatase 1B and Endoplasmic Reticulum Stress During Septic Shock

“…Inflammation can directly contribute to insulin resistance by disrupting the insulin signaling pathway, in part via PTP1B activation. In a previous experimental study, we demonstrated that PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation (9). In the present work, we did not find any link between PTPN1 levels and HOMA-IR index, glycemia, glycemia variation or insulin consumption.…”

“…Moreover, it has been shown that, in a rat model of sepsis, PTP1B induced brain mitochondrial dysfunction associated with overproduction of reactive oxygen species (24). In animal models, genetic or pharmacological inhibition of PTP1B enhanced endothelial cell proliferation and NO production, and could also reverse septic endothelial dysfunction (5, 6, 9, 25). We have shown a correlation between variations in SOFA score and PTPN1 expression.…”

“…We found that a variation in PTPN1 expression was correlated with a variation in ET1 expression. PTP1B is involved in endothelial dysfunction and it is known that PTP1B inhibition reduces sepsis-induced endothelial dysfunction and impaired NO production (9). There is no work studying the link between ET1 and PTP1B but, more than a direct link between these two markers, since ET1 is a marker of septic endothelial lesion, it is likely that the observed correlation could reflect the relationship between PTPN1 expression and septic endothelial dysfunction.…”

“…The septic inflammatory process also causes serious disturbances in the insulin signaling pathway (7, 8). We previously demonstrated that PTP1B gene ( Protein Tyrosine Phosphatase Non-Receptor Type 1 ( PTPN1 )) deletion significantly limits cecal ligation and puncture (CLP) -induced insulin resistance, improves insulin receptor signal transduction and reduces sepsis-induced endothelial dysfunction/impaired NO production (9). Multiple disturbances observed during sepsis can result in a dysfunction of the ER, leading to the accumulation of unfolded proteins within the lumen of the ER, known as ER stress (ERS) (10).…”

The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance

“…These studies point out the potential of targeting PTP1B to improve vascular inflammation, a major contributor to atherogenesis. The role of PTP1B in inflammation was further harnessed in a cecal ligation and puncture sepsis mouse model, where PTP1B deletion prevented the enhanced release of TNF-α, IL-6 and IL-1β compared to wild type mice [84]. Further providing a clear link between PTP1B and inflammation, Zabolotny et al [85], has shown that the overexpression of PTP1B was regulated by inflammation, where TNF-α increased PTP1B mRNA and protein expression through the activation of nuclear factor (NF)-κB pro-inflammatory transcription factor [85].…”