Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes

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