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

BACKGROUND

Thrombin, a serine protease with increased activity in people with diabetes, signals through PAR (protease-activated receptor) 1 and 4 on endothelial cells (ECs). On these cells, PAR1 is a high-expressing, high-affinity, low-potency thrombin receptor, whereas PAR4 is a low-expressing, low-affinity, high-potency receptor. This study aims to determine how endothelial PARs influence diabetic pathology, thereby providing deeper insights into the roles and relationships between these receptors.

METHODS

We generated mice with inducible deletion of in ECs () and induced diabetes with streptozotocin treatment. Blood glucose and insulin levels were assessed after streptozotocin administration. In addition, we measured insulin and glucose tolerance in mice. Lastly, we measured how the loss of endothelial PARs in cultured primary ECs affected IR (insulin receptor) activity/phosphorylation, and insulin transcytosis.

RESULTS

Although studying the roles of endothelial PAR1/4 in diabetic pathology, we found that mice displayed increased insulin sensitivity and were protected against streptozotocin-induced diabetes. Concordantly, we found that cultured primary ECs with PAR1/4 deficiency exhibited increased basal activity and phosphorylation of IR, as well as enhanced insulin transcytosis. This elevated IR activity correlated with reduced activity of PTP1B (protein tyrosine phosphatase 1B), a negative regulator of IR. Lastly, mice with additional deletion of 1 allele of the endothelial IR gene demonstrated restoration of diabetic phenotypes after streptozotocin treatment, indicating that insulin sensitivity in mice was driven by heightened IR activity in ECs.

CONCLUSIONS

These findings establish a novel link between endothelial PAR signaling and IR regulation, underscoring the critical role of ECs in metabolic homeostasis and identifying a potential therapeutic target for diabetes.