This study evaluates exenatide, sitagliptin, and glimepiride for the treatment of high blood sugar in patients with impaired fasting glucose or early type 2 diabetes. The purpose of this study is to determine if exenatide and sitagliptin increase the amount of insulin made by the pancreas compared to glimepiride. It is hypothesized that exenatide or sitagliptin will sustain or increase the amount of insulin made by the pancreas in comparison to glimepiride.

The incidence of type 2 diabetes (T2D) has reached epidemic proportions throughout the world. In the United States more than 1.5 million new cases of diabetes were diagnosed in 2005, and the estimated prevalence of the disease was over 20 million. Another 54 million Americans are believed to have impaired fasting glucose, which represents a "pre-diabetic" state at increased risk for progression to overt diabetes. T2D ultimately results from an inadequate mass of functional beta-cells, where insufficient beta-cell compensation for insulin resistance leads to the development of impaired glucose tolerance and eventually diabetes. Autopsy studies have demonstrated a decreased beta-cell mass occurring with fasting glucose > 110 mg/dl, consistent with functional studies that demonstrate decreased beta-cell (insulin) secretory capacity beginning in the range of impaired fasting glucose. Strategies that might preserve or expand functional beta-cell mass in vivo would be expected to reverse the progressive deterioration in blood glucose control seen with diabetes. One such strategy involves the incretin hormone glucagon-like peptide-1 (GLP-1), which is trophic for islet beta-cells, having both pro-proliferative and anti-apoptotic effects. However, it is not known whether increasing GLP-1 effects can preserve or enhance functional beta-cell mass in humans. This proposal will determine the effect of increasing GLP-1 levels on functional beta-cell mass in human subjects with impaired fasting glucose (fasting glucose 110 - 126 mg/dl) or early T2D (fasting glucose 127 - 149 mg/dl) where a critical window exists for reversing further beta-cell deterioration. GLP-1 effects will be promoted by administration of either the GLP-1 analog, exenatide, or by increasing endogenous GLP-1 levels through administration of the oral dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin for a 6-month period. To control for the effect of exenatide and sitagliptin on normalization of blood glucose, subjects will be randomized to receive exenatide, sitagliptin or the sulfonylurea glimepiride, the latter being a first-line anti-diabetogenic agent that will serve as an active comparator.

Inclusion Criteria:

1. Male and female patients age 18 to 70 years.
2. Ability to provide written informed consent
3. Mentally stable and able to comply with the procedures of the study protocol
4. Clinical history compatible with impaired fasting glucose or early T2D as defined by a plasma glucose concentration between 110-159 mg/dl following a 12 hour overnight fast performed off any anti-diabetogenic agent for at least 2 weeks (6 weeks for thiazolidinediones)
5. Stable body weight (+ 5%) for at least 2 weeks
6. Female Patients: Agree to use adequate contraception if reproductively capable. Adequate contraception includes either a hormonal or barrier method, or surgical sterilization.

Exclusion Criteria:

1. Diagnosis of type 1 diabetes
2. Receiving insulin, exenatide (Byetta®), or sitagliptin (Januvia®) treatment or taking > 2 oral anti-diabetogenic agents for the treatment of diabetes
3. BMI > 44 kg/m2
4. Allergy to any sulfa-containing compounds
5. Uncontrolled hypertension (Systolic Blood Pressure >160 or Diastolic Blood Pressure > 100 mmHg)
6. Uncontrolled hyperlipidemia (triglycerides > 500 or LDL > 160 mg/dl)
7. Elevation of liver function tests > 2 times the upper limit of normal
8. Estimated Glomerular Filtration Rate (GFR) < 55 ml/min/1.73m2 (46)
9. Hyperkalemia (serum potassium > 5.5 mmol/L)
10. Moderate anemia (hemoglobin concentration < 12 g/dl in men and < 11 g/dl in women)
11. Female patients: pregnant or lactating
12. Hepatic cirrhosis
13. Known active alcohol or substance abuse
14. Active cardiovascular disease
15. Use of any investigational agent within 6 weeks of the baseline visit
16. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial