The purpose of this investigation is to evaluate whether exenatide, a type 2 diabetes medication, will improve the function of the innermost part of the arterial wall called the endothelium after a fat-enriched meal and to determine how this occurs. The results of this study will help to determine and understand a novel action of this group of diabetes medications based on the action of naturally occuring gut substances called incretins. This may have a significant impact on cardiovascular health in patients with early and longstanding diabetes.

Two independent, double-blinded, crossover substudies will be conducted to test the effect of exenatide on daylong post-meal and fasting endothelial function. We will measure endothelial function measured by peripheral arterial tonometry (EndoPAT2000, Itamar Inc.). Patients with recent onset (<3 years) or established (>5 years, Substudy 1 only) diabetes and impaired sugar tolerance (Substudy 2 only) will be studied. The plan is to complete studies in 75 patients (40 in Substudy 1 and 35 in Substudy 2).

In Substudy 1 patients will get twice a day a skin injection of exenatide (Byetta) or identically looking placebo for 10 days, separated by 14-day period. On the next day after each treatemnt period (day 11), they get just one injection and eat a fat-enriched breakfast. A fatty lunch of similar caloric content will be given 4 hours following the breakfast. Endothelial function will be measured just prior to the injection and every 2 hours for total 8 hours.

In Substudy 2, patients on 3 different days will get infusion of exenatide withg or without a blocking drug exendin-9, and a control test with placebo without exendin-9. Endothelial function will be measured before the infusion and 2 hours later during the final 15 minutes of the infusion cocktails. Patients will not eat any meal during the test visits.

Inclusion Criteria:

• US Veterans
• type 2 diabetes mellitus (T2D) diagnosed within 3 years with good glycemic control on diet, metformin, or sulfonylurea agents or combinations of these agents (HbA1c ≤8.0%)
• T2D diagnosed ≥ 5 years prior to study enrollment
• Impaired glucose tolerance

Exclusion Criteria:

• T2D not meeting inclusion above criteria for duration of diabetes or HbA1c values
• known or suspected T1D (early onset age, low body mass index, lack of family history)
• TZD use in the prior 3 months
• prior regular use of insulin
• Creatinine >2.0 mg/dl or other laboratory or clinical evidence of kidney disease
• anemia
• known active liver disease or hepatic enzyme elevation two-and-a half times above normal
• acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
• stable or unstable angina or other major illness in the past 6 months
• Raynaud's disease or any rheumatic disease affecting fingers
• current regular use of anti-inflammatory medications or antioxidants, including over the counter medications and high dose salicylates (>1 g/day);
• subjects receiving lipid lowering or anti-hypertension medications must be on stable doses for at least 2 months prior to participation.