Novel Function for Endothelial Protease-Activated Receptors in Modulating Insulin Receptor Activity With Implications...

Area of Science:

• Endocrinology
• Vascular Biology
• Metabolic Diseases

Background:

• Thrombin, a serine protease, exhibits heightened activity in diabetes and signals via protease-activated receptors (PARs) 1 and 4 on endothelial cells (ECs).
• PAR1 and PAR4 function differently on ECs: PAR1 is high-affinity/low-potency, while PAR4 is low-affinity/high-potency.
• Understanding endothelial PAR roles is crucial for elucidating diabetic pathology.

Purpose of the Study:

• To investigate the influence of endothelial PAR1 and PAR4 on diabetic pathology.
• To explore the relationship between endothelial PARs and insulin sensitivity.
• To identify potential therapeutic targets for diabetes.

Main Methods:

• Generated mice with inducible deletion of PAR1/4 in ECs (Par1/4iECko).
• Induced diabetes using streptozotocin and assessed glucose/insulin levels and tolerance.
• Examined insulin receptor (IR) activity, phosphorylation, and insulin transcytosis in cultured ECs lacking PARs.

Main Results:

• Par1/4iECko mice showed increased insulin sensitivity and protection against streptozotocin-induced diabetes.
• ECs lacking PAR1/4 exhibited enhanced basal IR activity and phosphorylation, and improved insulin transcytosis.
• Elevated IR activity in these ECs was linked to reduced PTP1B activity, a key regulator of IR.

Conclusions:

• Endothelial PAR signaling is a novel regulator of insulin sensitivity.
• ECs play a critical role in maintaining metabolic homeostasis.
• Targeting endothelial PARs may offer a new therapeutic strategy for diabetes.