Development of A Novel Anti-Hyperglycemic Agent

Inclusion Criteria:

1. History of type 2 diabetes mellitus who are na ve to hypoglycemic treatment, inadequately controlled by diet and exercise alone or oral medications.
2. Hemoglobin A1c level of 6.5 % to 8.0 % inclusive. Subjects not taking hypoglycemic drugs with HgbA1c of 6.0% to 6.5% must have a diagnosis of DM.
3. Fasting blood glucose levels reasonably stable for at least 2 months or during the two-week lead-in-period.
4. Ethnicity: All ethnic groups.
5. Gender: Both men and women.
6. Female with reproductive potential must not be pregnant or lactating, and using reliable contraception methods.
7. Age >18 years old.

Exclusion Criteria:

1. Taking insulin.
2. History of diabetic ketoacidosis or hyper osmolar non-ketotic coma.

3. Diabetes Mellitus related end-organ damage:

   • Evidence of diabetic autonomic and peripheral neuropathy
   • Diabetic proliferative retinopathy, based on eye exam by ophthalmologist
   • Diabetes nephropathy defined by > 500 mg/24 hour urinary albumin excretion

4. Any disease likely to limit life span and/or increase risks of interventions:

   • Screening carotid B-mode ultrasound indicating clinically significant stenos in the common carotid arteries requiring intervention by angioplasty or resection.
   • Cancer treatment in the past 5 years, with the exception of cancers that have been cured, and carry a good prognosis.
   • Infectious disease: HIV positivity, active tuberculosis, or pneumonia.

5. Cardiovascular disease:

   • Hospitalization for treatment of heart disease in the past 12 months.
   • New York Heart Association Functional Class > 2.
   • Left Bundle branch block on EKG.
   • Third degree atrioventricular block on EKG.
   • Uncontrolled hypertension with average systolic blood pressure of > 160 mmHg on two screening visits and diastolic blood pressure > 95 mmHg on two screening visit.
   • Pulse rate > 95 beats per minute on both screening visits.
   • Stroke or transient ischemic attack in the past 12 months.

6. Gastrointestinal disease:

   • Chronic hepatitis or cirrhosis.
   • Episode of alcoholic hepatitis or alcoholic pancreatitis.
   • Inflammatory bowel disease requiring treatment in the past 12 months.
   • Recent or significant abdominal surgery (e.g. gastrectomy, gastric bypass).
7. Renal disease: Serum creatinine > 1.5 mg/dL for men, and > 1.4 mg/dL for women.

8. Lung disease:

   • Chronic obstructive airway disease or asthma requiring daily therapy.
   • Use of home oxygen.
9. Anemia: Hematocrit of < 36.0% in men or < 33% in women.

10. Conditions or behaviors likely to affect the conduct of the study

    • Unable or unwilling to give informed consent.
    • Unable to communicate with the clinic staff.
    • Unwilling to accept treatment assignment by randomization.
    • Weight loss of > 10% in the past 6 months.
    • Unable to walk without any assisted device.
    • Major psychiatric disorder which would impede conduct of the research.
    • Excessive alcohol intake (more than 2 drinks/day)

11. Medications

    • Psychoactive agents such as Monoamine oxidase inhibitors and Antidepressive agents (lithium, prozac, zoloft, serzone, paxil, efflexor)
    • Systemic use of glucocorticoids steroids within previous 6 weeks.