Incorporation of Oxidized Phenylalanine Derivatives into Insulin Signaling Relevant Proteins May Link Oxidative Stress to Signaling Conditions Underlying Chronic Insulin Resistance.
Judit Mohás-CsehGergő Attila MolnárMarianna PapBoglárka LaczyTibor VasMelinda KertészKrisztina NémethCsaba HetényiOrsolya CsikósGábor K TóthAttila ReményiIstván WittmannPublished in: Biomedicines (2022)
A link between oxidative stress and insulin resistance has been suggested. Hydroxyl free radicals are known to be able to convert phenylalanine (Phe) into the non-physiological tyrosine isoforms ortho- and meta-tyrosine (o-Tyr, m-Tyr). The aim of our study was to examine the role of o-Tyr and m-Tyr in the development of insulin resistance. We found that insulin-induced uptake of glucose was blunted in cultures of 3T3-L1 grown on media containing o- or m-Tyr. We show that these modified amino acids are incorporated into cellular proteins. We focused on insulin receptor substrate 1 (IRS-1), which plays a role in insulin signaling. The activating phosphorylation of IRS-1 was increased by insulin, the effect of which was abolished in cells grown in m-Tyr or o-Tyr media. We found that phosphorylation of m- or o-Tyr containing IRS-1 segments by insulin receptor (IR) kinase was greatly reduced, PTP-1B phosphatase was incapable of dephosphorylating phosphorylated m- or o-Tyr IRS-1 peptides, and the SH2 domains of phosphoinositide 3-kinase (PI3K) bound the o-Tyr IRS-1 peptides with greatly reduced affinity. According to our data, m- or o-Tyr incorporation into IRS-1 modifies its protein-protein interactions with regulating enzymes and effectors, thus IRS-1 eventually loses its capacity to play its role in insulin signaling, leading to insulin resistance.
Keyphrases
- type diabetes
- insulin resistance
- glycemic control
- oxidative stress
- adipose tissue
- induced apoptosis
- high fat diet
- amino acid
- protein protein
- skeletal muscle
- polycystic ovary syndrome
- dna damage
- diabetic rats
- small molecule
- signaling pathway
- blood glucose
- cell proliferation
- weight loss
- blood pressure
- tyrosine kinase
- drug induced
- heat stress
- data analysis
- type iii