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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Oxidative Stress
• Intervention / Treatment: Drug: N-acetylcysteine

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 Type: Interventional
• Enrollment (Actual): 13
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: NAC

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Utzschneider, Kristina, M.D.
• Collaborators: VA Puget Sound Health Care System
• Investigators: Principal Investigator: Kristina Utzschneider, MD, VA Puget Sound Health Care System

Publications and helpful links

General Publications

• Szkudlinska MA, von Frankenberg AD, Utzschneider KM. The antioxidant N-Acetylcysteine does not improve glucose tolerance or beta-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.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: July 12, 2011
• First Submitted That Met QC Criteria: July 13, 2011
• First Posted (Estimate): July 14, 2011

Study Record Updates

• Last Update Posted (Estimate): June 17, 2016
• Last Update Submitted That Met QC Criteria: May 10, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: type 2 diabetes; oxidative stress; insulin secretion; beta-cell function
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: NACStudy001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The study sample size is very small. The data will be made available upon request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No