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

• Sponsor: Utzschneider, Kristina, M.D. (Other)
• Overall Status: Completed
• CT.gov ID: NCT01394510
• Collaborator: VA Puget Sound Health Care System (U.S. Fed)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 54
• Patients Per Site Per Month: 0.2

Study Details

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	N/A

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
• 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: Jun 1, 2011
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Dec 1, 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 Names: NAC

Outcome Measures

Primary Outcome Measures

1. Fasting Urine F2 Alpha Isoprostane Levels [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) [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 [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

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kristina Utzschneider, MD, Associate Professor of Medicine, Utzschneider, Kristina, M.D.
• ClinicalTrials.gov Identifier: NCT01394510
• Other Study ID Numbers: NACStudy001
• First Posted: Jul 14, 2011
• Last Update Posted: Jun 17, 2016
• Last Verified: May 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Kristina Utzschneider, MD, Associate Professor of Medicine, Utzschneider, Kristina, M.D.: insulin secretion; beta-cell function; oxidative stress; type 2 diabetes
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

Arm/Group Title	N-acetylcysteine Dose Study
Arm/Group Description	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. 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.
Period Title: Overall Study
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	N-acetylcysteine Dose Study
Arm/Group Description	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. 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.
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.9 (11.7)
Sex: Female, Male (Count of Participants)
Female	7 53.8%
Male	6 46.2%
body mass index (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	37.3 (10.1)
HbA1c (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	6.17 (2.05)
metformin (participants) [Number]
Number [participants]	6 46.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Change in urine F2 alpha isoprostanes/mg urine creatinine. Urine isoprostanes were only measured in a subset of participants due to lack of effect of the intervention on glucose tolerance.

Arm/Group Title	N-acetylcysteine Dose Study
Arm/Group Description	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. 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.
Measure Participants	9
Mean (Standard Deviation) [ng/ml]	-0.089 (1.28)

2. Secondary Outcome

Title	Area Under the Curve for Glucose (AUCg)
Description	Change in AUCg from 0-120 minutes during the oral glucose tolerance test at 4 weeks compared to baseline
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine Dose Study
Arm/Group Description	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. 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.
Measure Participants	13
Mean (Standard Deviation) [mg/dl x 120 minutes]	-1011 (10922)

3. Secondary Outcome

Title	Oral Disposition Index
Description	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.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine Dose Study
Arm/Group Description	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. 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.
Measure Participants	12
Mean (Standard Deviation) [mg/dl]	-0.08 (0.18)

Adverse Events

Time Frame	4 weeks
Arm/Group Title	N-acetylcysteine Dose Study
Arm/Group Description	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. 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.
All Cause Mortality
	N-acetylcysteine Dose Study
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	N-acetylcysteine Dose Study
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	N-acetylcysteine Dose Study
	Affected / at Risk (%)	# Events
Total	0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.