Abstract 14392: Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus are Reduced by Liraglutide
Prior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues in patients with diabetes mellitus (DM). Initially, ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in human diabetes remains incompletely defined. To characterize vascular ER stress, we isolated venous endothelial cells (EC) from 20 patients with Type 2 DM and 17 non-diabetic subjects. EC from patients with DM displayed higher levels of ER stress markers compared to non-diabetic controls. Both the early adaptive response, evidenced by higher phosphorylated protein kinase-like ER kinase and inositol requiring kinase 1 (p-IRE1) (P=0.03, P<0.001), and the chronic ER stress response evidenced by higher C/EBPα-homologous protein (CHOP) (P=0.01) were activated in patients with DM. The GLP-1 analogue, liraglutide, has been used to reduce glucose levels in DM, and recently has been shown to downregulate high glucose-induced ER stress in cultured EC. Acute treatment with liraglutide (100nM, 45’) significantly reduced p-IRE1 (P=0.02) (Figure), and the activation of its downstream target JNK (P=0.04) in EC from diabetic patients Furthermore, impaired eNOS activation after insulin stimulation in diabetic patients was restored by liraglutide treatment (P<0.001). In summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further we have demonstrated that liraglutide ameliorates ER stress, decreases JNK activation and restores of insulin response in EC from patients with DM.
Author Disclosures: R. Breton-Romero: None. M. Holbrook: None. J.L. Fetterman: None. E.A. Linder: None. R.M. Weisbrod: None. M.D. Caitlin: None. B. Feng: None. E. Inagaki: None. N. Gokce: None. N.M. Hamburg: None.
- © 2016 by American Heart Association, Inc.