A NEW study has shed light on a potential pathway for combating insulin resistance, a key contributor to Type 2 diabetes mellitus, by targeting the degradation of the insulin receptor β subunit (InsRβ) in skeletal muscle cells.
Researchers have discovered that the activation of peroxisome proliferator-activated receptor (PPAR)β/δ helps to maintain InsRβ levels by alleviating endoplasmic reticulum (ER) stress and reducing lysosomal degradation. The findings could pave the way for new therapeutic approaches in the fight against insulin resistance and Type 2 diabetes.
The study, conducted using both genetically modified mice and cultured muscle cells, examined how PPARβ/δ regulates InsRβ levels under ER stress conditions. Researchers compared wild-Type (WT) mice with genetically altered Ppard−/− mice, which lack the PPARβ/δ gene, and found that the latter exhibited significantly lower InsRβ levels in skeletal muscle. However, when WT mice were treated with GW501516, a PPARβ/δ agonist, InsRβ levels increased.
Further experiments in C2C12 myotubes, a type of skeletal muscle cell, exposed to the ER stressor tunicamycin demonstrated that treatment with GW501516 partially reversed the stress-induced decline in InsRβ levels. This was achieved by reducing ER stress markers and suppressing excessive lysosomal activity, a process known to accelerate InsRβ degradation.
The study also identified ephrin receptor B4 (EphB4) as a key player in this mechanism. EphB4, which binds to InsRβ and promotes its degradation, was found to be elevated in Ppard−/− mice. However, treatment with GW501516 reduced EphB4 levels, suggesting that PPARβ/δ activation counteracts the receptor’s breakdown by modulating EphB4 expression.
These findings highlight PPARβ/δ as a promising target for preserving InsRβ function, offering a potential strategy to mitigate insulin resistance. By addressing ER stress and lysosomal degradation, PPARβ/δ activation could play a crucial role in future diabetes treatments. Researchers hope that further studies will explore the clinical applications of these findings in human patients.
Victoria Antoniou, EMJ
Reference
Wang JR et al. PPARβ/δ upregulates the insulin receptor β subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels. Cell Commun Signal. 2024;22(1):595.
