Effect of the Anti-oxidant N-acetylcysteine on Beta-cell Function in Type 2 Diabetes

Beta-cell dysfunction is a critical feature of type 2 diabetes (T2DM). High glucose levels
can exacerbate beta-cell dysfunction with oxidative stress proposed as a major mediator of
this "glucotoxic" effect. High glucose levels have also been shown to contribute to vascular
dysfunction and inflammation and these adverse responses decreased with the use of
antioxidants. The hypothesis is that antioxidants improve beta-cell function in individuals
with elevated glucose levels by decreasing oxidative stress. In this study the investigators
will specifically test whether the antioxidant N-acetylcysteine (NAC) can improve beta-cell
function in individuals with type 2 diabetes by decreasing oxidative stress.

This initial study will be a dose finding study to determine the tolerability of 600 mg
versus 1200 mg twice a day of NAC and the effects of NAC treatment on beta-cell function,
glucose tolerance and oxidative stress markers in persons with type 2 diabetes. Study
procedures will include a fasting urine sample and performance of a 2 hour 75 gram oral
glucose tolerance test at baseline, after 2 weeks on 600 mg twice daily NAC and again after
2 more weeks on 1200 mg NAC twice a day.

Inclusion Criteria:

- Type 2 diabetes

Exclusion Criteria:

- Pregnant or lactating females

- Uncontrolled diabetes mellitus with severe hyperglycemia (hemoglobin A1C ≥ 9%)

- Patients with diabetes mellitus who are taking insulin or glucose-lowering agents
other than metformin

- Chronic oral or parenteral corticosteroid treatment (>7 consecutive days of
treatment) within 8 weeks prior to screening

- Use of HIV protease inhibitors or niacin

- Chronic inflammatory diseases or use of anti-inflammatory drugs.

- Thyroid abnormalities (thyroid-stimulating hormone [TSH] <0.5 or >5 µU/ml)

- Creatinine >1.5 in men and >1.3 mg/dl in women

- History of dysphagia, gastroparesis, gastric ulcer, malabsorption, swallowing
disorders or intestinal motility disorder

- Gastroesophageal reflux disease (heartburn) requiring treatment.

- Active cancer

- Clinical hepatic disease or ALT greater than ≥ 1.5 times upper limit of normal within
60 days preceding the first dose of the study drug

- Weight loss of >5% body weight within the last 6 months, or starting an intensive
exercise program within 4 weeks of study initiation

- Smoke or use tobacco

- Excessive alcohol consumption (>2 drinks a day)

- Use of any investigational drug in the last 30 days

- Anemia (hematocrit <33%), donation of one unit (500 ml) or more of blood, significant
blood loss equaling at least one unit of blood within the past 2 weeks or a blood
transfusion within 8 weeks prior to screening

- Employment by the research center