Several studies have demonstrated that therapeutic agents used to reduce glucose levels and/or weight can delay the onset of type 2 diabetes. Intriguingly, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) also result in reduction in the onset of type 2 DM. The most striking effect was found with Ramipril in the HOPE study. The onset of new type 2 DM was reduced by 34% (p<0.001) as compared to placebo. Furthermore, the results of the DREAM trial demonstrate that Ramipril at a dose of 15 mg can significantly reverse impaired glucose tolerance. However, the mechanisms underlying Ramipril effects to delay type 2 diabetes are not known.

The proposal will be focused on determining the integrated in-vivo mechanisms responsible for Ramipril’s effects on delaying type 2 DM and restoring normal glycemia in patients with impaired glucose tolerance.

The specific aims of the project are:

• to determine the effect of Ramipril on insulin resistance at the level of the liver and peripheral tissues,

• to determine the effect of Ramipril on endothelial function,

• to determine the effects of Ramipril on insulin secretion, and

• to determine the effects of Ramipril on substrate flux, lipolysis and inflammatory cytokines.

Inclusion:

• 48 (24 male / 24 female) with impaired glucose tolerance.

• Impaired blood glucose values as outlined by the American Diabetes Association guideline. Fasting plasma glucose between 100 and 126 mg/dl or 2 hour post prandial glucose between 140 and 200 mg/dl

• BMI > 25 kgM2

• Age: 20-65 years

• Treated or Untreated hypertension defined as measurement of seated BP at screening visit of systolic BP 120 to 150 and/ or diastolic BP 80 to 100.

Exclusion:

• Patients receiving agents that can increase or lower blood glucose, i.e., metformin, thiazolidinediones, sulfonylureas, glitinides, acarbose, GLP-1 receptor agonists

• Untreated or treated while seated Systolic Blood pressure >150and/or Diastolic Blood pressure >100

• Taking hypertensive medications of HCTZ or ACE/ARB

• Allergy to HCTZ, heparin, nitroglycerin or lidocaine

• History of allergy or unacceptable side effects from ACE inhibitors

• Pregnancy or intent to become pregnant during the study

• Smoking

• Subject unable to give voluntary informed consent

Physical Exam Exclusion Criteria

• Clinically significant Cardiac Abnormalities (e.g. Heart Failure, Arrhythmia) from history or ECG in subjects > 40 years old

• Pneumonia

• Hepatic Failure/Jaundice

• Renal Failure

• Acute Cerebrovascular/ Neurological deficit

• Fever greater than 38.0 C

Screening Laboratory Tests Exclusion Criteria according to protocol