Insulin Resistance Syndrome XPhase 4NCT00188773
Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion
A Phase 4 study testing N-acetylcysteine, intralipid, heparin in people with Insulin Resistance Syndrome X and Pancreatic Beta Cell Function, run by University Health Network, Toronto at 1 site in Canada.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 35 to 65 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Insulin Resistance Syndrome X, Pancreatic Beta Cell Function
- What is being tested?
- N-acetylcysteine, intralipid, heparin
- How many people
- 15 participants
- Where
- 1 siteCanada
- Study dates
- Jan 2004to Jan 2008
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 65 years
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- The following criteria will be used for the selection of insulin resistant non-diabetic men aged 35-65 years:
- Written informed consent obtained
- Body mass index (BMI) > 27 kg/m2
- Fasting triglycerides > 2 mmol/l and < 5 mmol/l
- Waist circumference > 90 cm
- Fasting blood glucose < 7 mmol/l
- 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.
- Hemoglobin above 130 g/L
Who cannot join
- Patient has a history of hepatitis/hepatic disease that has been active within the previous two years
- 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
- Fasting blood glucose > 7 mmol/l or known diabetes
- 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
- Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l
- 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
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- Current addiction to alcohol or substances of abuse as determined by the investigator
- Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
- Any lipid lowering or hypoglycemic agents
- Previous history of asthma
- Will not donate blood three months prior to and three months post study procedures
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Being tested
- N-acetylcysteine, intralipid, heparin
- Keywords
- n-acetylcysteine,, free fatty acid,, glucose stimulated insulin secretion,, insulin resistance syndrome, antioxidant therapy, Insulin Resistance
- Medical subject headings
- Metabolic Syndrome, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-acetylcysteine, intralipid, heparinDrug
One visit subject will receive N-acetylcysteine plus intralipid and heparin, another visit n-acetylcyksteine plus saline, another visit intralipid and heparin and another visit saline alone
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine whether the FFA-induced impairment of pancreatic b-cell function can be ameliorated or prevented by administration of the antioxidant, NAC
Measured: 2 years
Assessment of insulin sensitivity
Measured: 2 years
To determine whether administration of NAC, an antioxidant, prevents FFA-mediated impairment of GSIS in healthy humans.
Measured: 2 years
Secondary outcomes (1)
assessment of glucose stimulated insulin secretion
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2005 (estimated)
- Study startJan 2004
- Primary completionAug 2007
- Study completionJan 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Insulin Resistance Syndrome XStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Investigators
- Gary F. Lewis, MD, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00188773
- Sponsor's protocol ID
- 03-0871-A
- Other IDs
- CDA Grant 777508221
- Status last verified
- Jun 2007
- First submitted
- 12 Sep 2005
- Last updated
- 5 Jun 2008
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Jun 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion
- ClinicalTrials.gov ID
- NCT00188773
- Acronym / sponsor ID
- 03-0871-A
- Keywords
- n-acetylcysteine,, free fatty acid,, glucose stimulated insulin secretion,, insulin resistance syndrome, antioxidant therapy, Insulin Resistance
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (estimated)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- Jan 2004
- Primary completion
- Aug 2007 (actual)
- Study completion
- Jan 2008 (actual)
- First posted
- 16 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 35 to 65 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- The following criteria will be used for the selection of insulin resistant non-diabetic men aged 35-65 years:
- Written informed consent obtained
- Body mass index (BMI) > 27 kg/m2
- Fasting triglycerides > 2 mmol/l and < 5 mmol/l
- Waist circumference > 90 cm
Key exclusion criteria (11 listed)
- Patient has a history of hepatitis/hepatic disease that has been active within the previous two years
- 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
- Fasting blood glucose > 7 mmol/l or known diabetes
- 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
- Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| N-acetylcysteine, intralipid, heparinOne visit subject will receive N-acetylcysteine plus intralipid and heparin, another visit n-acetylcyksteine plus saline, another visit intralipid and heparin and another visit saline alone | Drug | – |
Primary outcome
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
Assessment of insulin sensitivity
Time frame: 2 years
To determine whether administration of NAC, an antioxidant, prevents FFA-mediated impairment of GSIS in healthy humans.
Time frame: 2 years
1 secondary outcome
assessment of glucose stimulated insulin secretion
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jun 2008.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gary F. Lewis, MD principal investigator
University Health Network, Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing N-acetylcysteine, intralipid, heparin in people with Insulin Resistance Syndrome X and Pancreatic Beta Cell Function, run by University Health Network, Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Jun 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2008.