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

Study Overview
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Brief Summary
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Insulin is secreted by cells in the pancreas called beta-cells. 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 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 on beta-cell function, glucose tolerance and oxidative stress markers in persons with type 2 diabetes.

Detailed Description
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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.

Official Title
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Effect of Anti-oxidants on Beta-cell Function in Humans

Conditions
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Type 2 Diabetes, Oxidative Stress

Intervention / Treatment
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* Drug: N-acetylcysteine


Participation Criteria
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Eligibility Criteria
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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 human immunodeficiency virus (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 alanine aminotransferase (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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-acetylcysteine dose study<br>Subjects will take N-acetylcysteine (NAC) 600 mg twice daily for 2 weeks, then 1200 mg twice daily for an additional 2 weeks. Study procedures will be performed at baseline, after 2 weeks and after 4 weeks. | Drug: N-acetylcysteine<br>* 600 mg N-acetylcysteine (NAC) twice daily by mouth for 2 weeks followed by 1200 mg NAC twice daily by mouth for 2 additional weeks.<br>* Other names: NAC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Urine F2 Alpha Isoprostane Levels | Change in fasting urine isoprostane levels at 4 weeks vs baseline as a marker of oxidative stress | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve for Glucose (AUCg) | Change in AUCg from 0-120 minutes during the oral glucose tolerance test at 4 weeks compared to baseline | 4 weeks | 
| Oral Disposition Index | The change in the oral disposition index defined was the change in the early insulin response divided by the change in glucose from 0-30 minutes during the oral glucose tolerance test divided by fasting insulin. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insulin secretion, beta-cell function, oxidative stress, type 2 diabetes