Abstract 17008: Dipeptidyl peptidase-4 Inhibitor Ameliorates Stress-induced Glucose Metabolism Disorder and Prothrombotic State

Abstract

Introduction: Psychological stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state via production of coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in white adipose tissue (WAT). Hypothesis: As accumulating evidence suggests anti-inflammatory potential of dipeptidyl peptidase-4 (DPP4) inhibitors, we investigated the effects of alogliptin on stress-induced adipose tissue inflammation, insulin resistance and prothrombotic state. Methods: Mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 15 or 45 mg/kg/day alogliptin. Plasma lipids, expression of GLP-1, DPP4 activity, 8OHdG (an oxidant stress marker), monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), adiponectin, and coagulation factors (PAI-1 and TF) in blood and inguinal WAT was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests (ITT), and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Results: The stress procedure increased FFA release, 8OHdG-positive cells and monocyte accumulation in WAT, proinflammatory cytokine, and reduced adiponectin and GLP-1, followed by DPP4 activation in plasma. The stress-induced adipose inflammation increased PAI-1 and TF, and worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. The alogliptin administration suppressed stress-induced FFA release, oxidant stress production, adipose inflammation, procoagulant state in a dose dependent manner, and restored glucose metabolism in GTT and ITT. Conclusions: The results indicate that alogliptin improves stress-induced prothrombotic state, and glucose metabolism disorder. Our results suggests that alogliptin exerts additive benefits for cardiovascular complication in diabetes patients with mental stress.