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

• ClinicalTrials.gov Identifier: NCT01394510
• Recruitment Status: Completed
• First Posted: July 14, 2011
• Results First Posted: June 17, 2016
• Last Update Posted: June 17, 2016
• Sponsor: Utzschneider, Kristina, M.D.
• Collaborator: VA Puget Sound Health Care System
• Information provided by (Responsible Party): Kristina Utzschneider, MD, Utzschneider, Kristina, M.D.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes; Oxidative Stress	Drug: N-acetylcysteine	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Effect of Anti-oxidants on Beta-cell Function in Humans
• Study Start Date: June 2011
• Actual Primary Completion Date: September 2014
• Actual Study Completion Date: December 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: N-acetylcysteine dose study; 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; 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.; Other Name: NAC

Outcome Measures

Primary Outcome Measures :

1. Fasting Urine F2 Alpha Isoprostane Levels [ Time Frame: 4 weeks ]
   Change in fasting urine isoprostane levels at 4 weeks vs baseline as a marker of oxidative stress

Secondary Outcome Measures :

1. Area Under the Curve for Glucose (AUCg) [ Time Frame: 4 weeks ]
   Change in AUCg from 0-120 minutes during the oral glucose tolerance test at 4 weeks compared to baseline
2. Oral Disposition Index [ Time Frame: 4 weeks ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Washington

VA Puget Sound Health Care System

Seattle, Washington, United States, 98108

Sponsors and Collaborators

Utzschneider, Kristina, M.D.

VA Puget Sound Health Care System

Investigators

• Principal Investigator: Kristina Utzschneider, MD; VA Puget Sound Health Care System

More Information

Publications of Results:

Szkudlinska MA, von Frankenberg AD, Utzschneider KM. The antioxidant N-Acetylcysteine does not improve glucose tolerance or β-cell function in type 2 diabetes. J Diabetes Complications. 2016 May-Jun;30(4):618-22. doi: 10.1016/j.jdiacomp.2016.02.003. Epub 2016 Feb 5.

• Responsible Party: Kristina Utzschneider, MD, Associate Professor of Medicine, Utzschneider, Kristina, M.D.
• ClinicalTrials.gov Identifier: NCT01394510
• Other Study ID Numbers: NACStudy001
• First Posted: July 14, 2011
• Results First Posted: June 17, 2016
• Last Update Posted: June 17, 2016
• Last Verified: May 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: The study sample size is very small. The data will be made available upon request.

Keywords provided by Kristina Utzschneider, MD, Utzschneider, Kristina, M.D.:

insulin secretion; beta-cell function; oxidative stress; type 2 diabetes

Additional relevant MeSH terms:

Diabetes Mellitus, Type 2; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Acetylcysteine; N-monoacetylcystine; Antiviral Agents; Anti-Infective Agents; Expectorants; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Antidotes