Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion

June 4, 2008 updated by: University Health Network, Toronto

A prolonged elevation of plasma free fatty acids (FFA) impairs glucose stimulated insulin secretion. The concept of fatty acid impairment of glucose stimulated insulin secretion (lipotoxicity) has now been well accepted. Increased free fatty acid flux from adipose tissue to non-adipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the metabolic derangements that are characteristic of insulin resistance syndrome and type 2 diabetes.

Lipotoxicity is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. This area of research is now focused on determining the mechanisms whereby FFAs impair b-cell function. There is some evidence to suggest that lipotoxicity could be mediated through induction of reactive oxygen species (ROS). N-acetylcysteine (NAC) is a known potent antioxidant and has been used experimentally in a number of medical conditions in humans for its protective antioxidant effects. The investigators now plan to administer NAC orally to humans for 48 hours to examine the effects of antioxidant therapy in ameliorating the deleterious effects of FFAs on pancreatic beta cell function. NAC is currently approved for the treatment of acetaminophen overdose and is also used as a mucolytic agent. The investigators are now using NAC as an antioxidant to determine whether it protects the pancreatic beta cell against the toxic effects of FFAs, as outlined in the detailed study protocol. This is a proof-of-principle study and is not designed to develop n-acetylcysteine for therapeutic use.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Free fatty acids will be elevated approximately 2-fold for 48 hours by intravenous infusion of Intralipid and heparin. 15 abdominally obese insulin resistant, but otherwise healthy, non-diabetic men will be studied on three occasions each, in random order, 4 weeks apart. We have chosen to study abdominally obese, insulin resistant individuals rather than lean healthy controls because we have previously shown that these individuals are more susceptible to lipotoxicity and we are therefore more likely to see differences between the interventions if differences indeed exist. Informed written consent will be obtained from all participants in accordance with the guidelines of the Human Subjects Review Committee of the University Health Network.

Subjects will be hospitalized in the Metabolic Investigation Unit (MIU) of the Toronto General Hospital for each of their three studies, which will be performed in random order 4 to 6 weeks apart. On one occasion a saline control study will be performed, on a second occasion Intralipid (20% solution @ 40ml/hr) and heparin (250u/hr) will be infused for 48 hours as previously described and on a third occasion NAC will be administered orally concurrently with the Intralipid and heparin. The dose of NAC will be the same as that recommended for acetaminophen overdose. An initial loading dose of 140mg/kg NAC followed by a maintenance dose of 70mg/kg every 4 hours during the 48 hour infusion of Intralipid and heparin. On day three, testing of glucose-stimulated insulin secretion (GSIS) will occur as outlined below. Subjects will be provided with an isocaloric diet consisting of 50% calories derived from carbohydrates, 30% fat and 20% protein during the 48 hour infusions and will fast from midnight for the testing of pancreatic beta cell function on day three.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 2C4
        • University Health Network

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

31 years to 61 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

The following criteria will be used for the selection of insulin resistant non-diabetic men aged 35-65 years:

  1. Written informed consent obtained
  2. Body mass index (BMI) > 27 kg/m2
  3. Fasting triglycerides > 2 mmol/l and < 5 mmol/l
  4. Waist circumference > 90 cm
  5. Fasting blood glucose < 7 mmol/l
  6. In order to keep the number of study subjects to a minimum (n=15), in view of the cost of these labor-intensive metabolic studies, the investigators will be studying males only 35 to 65 years of age. This will allow them to study as homogeneous a group of subjects as possible. If significant protective effects of NAC on beta cell function are detected, they will study women using a similar protocol at a later stage.
  7. Hemoglobin above 130 g/L

Exclusion Criteria:

  1. Patient has a history of hepatitis/hepatic disease that has been active within the previous two years
  2. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr > 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic BP > 100 or systolic > 180) or proliferative retinopathy
  3. Fasting blood glucose > 7 mmol/l or known diabetes
  4. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmias or conduction delays on ECG, unstable angina, or decompensated heart failure
  5. Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l
  6. Known or suspected allergy to the medication or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions
  7. Current addiction to alcohol or substances of abuse as determined by the investigator
  8. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
  9. Any lipid lowering or hypoglycemic agents
  10. Previous history of asthma
  11. Will not donate blood three months prior to and three months post study procedures

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
To determine whether the FFA-induced impairment of pancreatic b-cell function can be ameliorated or prevented by administration of the antioxidant, NAC
Time Frame: 2 years
2 years
Assessment of insulin sensitivity
Time Frame: 2 years
2 years
To determine whether administration of NAC, an antioxidant, prevents FFA-mediated impairment of GSIS in healthy humans.
Time Frame: 2 years
2 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
assessment of glucose stimulated insulin secretion
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Health Network, Toronto

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Gary F. Lewis, MD, University Health Network, Toronto

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2004

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2007

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2008

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 12, 2005

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 12, 2005

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 16, 2005

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 5, 2008

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 4, 2008

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 03-0871-A
  • CDA Grant 777508221

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Insulin Resistance Syndrome X

Clinical Trials on N-acetylcysteine, intralipid, heparin

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings