Sitagliptin Effects on Arterial Vasculature and Inflammation in Obesity

Abdominal obesity is a major risk factor for heart attack, stroke, peripheral vascular disease, dementia, cancer and Type 2 diabetes. The central hypothesis for this proposal is that pro-atherogenic mediators emanate from inflammation in deep subcutaneous adipose tissue (dSAT) that are released into the systemic circulation and damage the arterial vasculature. The investigators postulate that inflammation of dSAT, when quantified by macrophage phenotyping/enumeration will be a) closely linked with systemic levels of pro-atherogenic mediators and b) tightly associated with endothelial dysfunction and loss of central arterial elasticity, which are highly predictive of future cardiovascular disease (CVD) complications. These relationships provide the basis for macrophage-targeted therapy to reduce obesity-related inflammation and impaired arterial vasoreactivity. The investigators will evaluate a novel approach using a dipeptidyl peptidase 4 inhibitor (DPP4i) sitagliptin, which blocks signal transduction for monocyte/macrophage activation. Thus, in abdominally obese, 18-40 years-old adults without clinical CVD, the show study is expected to show that sitagliptin versus placebo will: 1. significantly improve early measures of arterial damage (brachial artery endothelial dysfunction and reduced carotid elasticity). 2. significantly attenuate inflammation in dSAT and local production of pro-inflammatory mediators in adipose tissue, which will be associated with decreases in systemic pro-atherogenic mediators that contribute to atherogenesis. Since many obese persons fail to sustain weight loss by lifestyle interventions including diet and exercise, an important public health goal is to identify relatively safe alternative strategies that can be used pre-emptively in "asymptomatic" obese persons when arterial dysfunction and damage is still reversible before atherosclerosis progresses to serious CVD events.