Abstract 685: Wnt5a/JNK Signaling Mediates Endothelial Insulin Resistance in Human Diabetes

Abstract

Diabetes mellitus (DM) is associated with endothelial dysfunction that contributes to the development of atherosclerosis and promotes cardiovascular disease. Recent work has identified the secreted Wnt5a as a pro-inflammatory mediator of metabolic dysfunction in obesity acting through a non-canonical signaling pathway involving JNK activation. In animal models, JNK activity has been widely described to be involved in systemic insulin resistance. However, the relevance of Wnt5a/JNK axis in the vasculature is unknown. Our study aimed to evaluate the involvement of Wnt5a/JNK in endothelial dysfunction, studying its potential role in altered eNOS activation and insulin signaling in patients with DM. We measured protein expression, and insulin response in freshly isolated endothelial cells (ECs) from patients with DM (n=26) and non-diabetic controls (n=32). ECs from patients with DM displayed impaired insulin-mediated eNOS activation and reduced NO release in conjunction with higher expression of Wnt5a (P=0.01). This effect was accompanied with an enhanced activation of JNK (P<0.01). In endothelial cells from non-diabetic subjects, Wnt5a treatment increased JNK activation and reduced insulin-mediated activation of eNOS (P<0.001). In ECs from patients with DM, treatment with a JNK chemical inhibitor (SP600125) restored eNOS activation and insulin response (P<0.001). In summary, our data provide evidence for the presence of altered endothelial Wnt5a and JNK activity in human diabetes, suggesting that Wnt5a/JNK signaling pathway contributes to endothelial insulin resistance in DM and support further studies of Wnt5a inhibitors to restore endothelial function.