Sitagliptin Effects on Arterial Vasculature and Inflammation in Obesity

APPROACH: Overview of Study Design: This is a double-masked, randomized, placebo-controlled pilot study of treatment sitagliptin (100mg/day) to suppress monocyte/macrophage activation in obese non-diabetic participants. 16 abdominally obese18-40 year-old largely minorities will be randomized 3:1 to receive sitagliptin (N=12) or matching placebo (N=4) daily for 28 days. Eligibility Criteria for the Study Cohort: Based on prior studies conducted by the investigators, approximately 60-70% of participants enrolled will be Hispanics and African Americans. Both minorities have increased prevalence of insulin resistance (IR) at young ages. In their prior studies, insulin resistance (HOMA-IR\* ≥3.0) had a predictive value of 88% for crown like structure in abdominal fat (a surrogate for fat inflammation); the inclusion criterion for IR will assure that most study subjects will have abdominal fat inflammation. \* homeostatic method of analysis-insulin resistance Inclusion Criteria 1. Age 18-40 years of age 2. Stable weight (no change \>3% in prior 6 months) 3. Waist circumference ≥102cm for men; ≥88cm for women 4. Fasting plasma glucose 100-125, HgbA1C 5.7-6.4% or HOMA-IR\* ≥3.0 Exclusion Criteria: 1. Regular use of a non-steroidal anti-inflammatory drug (NSAID); unwilling to stop NSAID drug 2. On statin or other prescription anti-inflammatory drugs 3. Diabetes or clinically evident cardiovascular disease 4. Smoking daily or consuming \>200g alcohol/day Study participants will be adults 18-40 years of age to exclude older persons with irreversible atherosclerosis (e.g. calcified, stenotic plaque) or subclinical arterial thrombus which release inflammatory mediators. Persons with Type 2 diabetes (a myocardial infarction equivalent) and those receiving "statins" (also potent anti-inflammatory drugs) will be excluded, thereby further excluding participants with advanced atherosclerosis. The goal is to identify and study persons with abdominal obesity and inflammation at a younger age as a potential target population for pre-emptive anti-inflammatory therapy to prevent serious CVD events over ensuing years. Outcome Measures: 1. Change in arterial vasoreactivity measured and quantified by ultrasound assessment of brachial artery flow mediated dilation and carotid stiffness (elasticity and distensibility). 2. Change in measures of inflammation in intra-abdominal adipose tissue: 1. M1 pro-inflammatory macrophages and M2 anti-inflammatory macrophages by fluorescent activated cell sorting. 2. Ex vivo secretion of inflammatory mediators from macrophages fractions. 3. Change in systemic pro-inflammatory/pro-atherogenic markers and insulin resistance.