Phosphorylation of insulin receptor substrates (IRS-1 and IRS-2) is attenuated following cecal ligation and puncture in mice

Molecular Medicine

Research Article

Ana Nedeljkovic-Kurepa¹  Deepa Mathew¹  Mabel Abraham¹  Julia Barillas-Cerritos²  Clifford S. Deutschman³  Matthew D. Taylor³ 

[1] Department of Pediatrics, Cohen Children’s Medical Center, Lake Success, NY, USA;Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, 11030, Manhasset, NY, USA;Department of Pediatrics, Cohen Children’s Medical Center, Lake Success, NY, USA;Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, 11030, Manhasset, NY, USA;Pediatric Endocrinology, Metabolism and Diabetes, Winthrop Pediatrics Associates, Mineola, NY, USA;Department of Pediatrics, Cohen Children’s Medical Center, Lake Success, NY, USA;Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, 11030, Manhasset, NY, USA;Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA;

关键词: Sepsis;    Cecal ligation and puncture;    CLP;    Insulin;    Insulin receptor substrate;    Tyrosine phosphorylation;    Hypoglycemia;    Insulin resistance;    Liver;    Skeletal muscle;   

DOI  :  10.1186/s10020-023-00703-9

 received in 2023-02-28, accepted in 2023-07-18,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSepsis is characterized as an insulin resistant state. However, the effects of sepsis on insulin’s signal transduction pathway are unknown. The molecular activity drivinginsulin signaling is controlled by tyrosine phosphorylation of the insulin receptor β-subunit (IRβ) and of insulin receptor substrate molecules (IRS) -1 and IRS-2.HypothesisCecal ligation and puncture (CLP) attenuates IRβ, IRS-1 and IRS-2 phosphorylation.MethodsIACUC-approved studies conformed to ARRIVE guidelines. CLP was performed on C57BL/6 mice; separate cohorts received intraperitoneal insulin at baseline (T0) or at 23 or 47 h. post-CLP, 1 h before mice were euthanized. We measured levels of (1) glucose and insulin in serum, (2) IRβ, IRS-1 and IRS-2 in skeletal muscle and liver homogenate and (3) phospho-Irβ (pIRβ) in liver and skeletal muscle, phospho-IRS-1 (pIRS-1) in skeletal muscle and pIRS-2 in liver. Statistical significance was determined using ANOVA with Sidak’s post-hoc correction.ResultsCLP did not affect the concentrations of IRβ, IRS-1or IRS-2 in muscle or liver homogenate or of IRS-1 in liver. Muscle IRS-1 concentration at 48 h. post-CLP was higher than at T0. Post-CLP pIRS-1 levels in muscle and pIRβ and pIRS-2 levels in liver were indistinguishable from T0 levels. At 48 h. post-CLP pIRβ levels in muscle were higher than at T0. Following insulin administration, the relative abundance of pIRβ in muscle and liver at T0 and at both post-CLP time points was significantly higher than abundance in untreated controls. In T0 controls, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was higher than in untreated mice. However, at both post-CLP time points, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was not distinguishable from the abundance in untreated mice at the same time point. Serum glucose concentration was significantly lower than T0 at 24 h., but not 48 h., post-CLP. Glucose concentration was lower following insulin administration to T0 mice but not in post-CLP animals. Serum insulin levels were significantly higher than baseline at both post-CLP time points.ConclusionsCLP impaired insulin-induced tyrosine phosphorylation of both IRS-1 in muscle and IRS-2 in liver. These findings suggest that the molecular mechanism underlying CLP-induced insulin resistance involves impaired IRS-1/IRS-2 phosphorylation.

【 授权许可】

CC BY   
© The Feinstein Institute for Medical Research 2023

【 图 表 】

Fig. 5