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Sponsored by: |
University Health Network, Toronto |
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Information provided by: | University Health Network, Toronto |
ClinicalTrials.gov Identifier: | NCT00188773 |
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.
Condition | Intervention | Phase |
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Insulin Resistance Syndrome X Pancreatic Beta Cell Function |
Drug: N-acetylcysteine, intralipid, heparin |
Phase IV |
Study Type: | Interventional |
Study Design: | Diagnostic, Randomized, Open Label, Placebo Control, Single Group Assignment, Pharmacokinetics Study |
Estimated Enrollment: | 15 |
Study Start Date: | January 2004 |
Study Completion Date: | January 2008 |
Primary Completion Date: | August 2007 (Final data collection date for primary outcome measure) |
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.
Ages Eligible for Study: | 35 Years to 65 Years |
Genders Eligible for Study: | Male |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
The following criteria will be used for the selection of insulin resistant non-diabetic men aged 35-65 years:
Exclusion Criteria:
Canada, Ontario | |
University Health Network | |
Toronto, Ontario, Canada, M5G 2C4 |
Principal Investigator: | Gary F. Lewis, MD | University Health Network, Toronto |
Responsible Party: | University Health Network ( Dr. Gary Lewis ) |
Study ID Numbers: | 03-0871-A, CDA Grant 777508221 |
Study First Received: | September 12, 2005 |
Last Updated: | June 4, 2008 |
ClinicalTrials.gov Identifier: | NCT00188773 |
Health Authority: | Canada: Health Canada |
n-acetylcysteine, free fatty acid, glucose stimulated insulin secretion, |
insulin resistance syndrome antioxidant therapy Insulin Resistance |
Metabolic Syndrome X Metabolic Diseases Insulin Calcium heparin Hyperinsulinism Syndrome X Acetylcysteine |
Insulin Resistance Glucose Metabolism Disorders Metabolic disorder Heparin Abdominal obesity metabolic syndrome N-monoacetylcystine |
Respiratory System Agents Anti-Infective Agents Anticoagulants Disease Antioxidants Molecular Mechanisms of Pharmacological Action Hematologic Agents Physiological Effects of Drugs Fibrinolytic Agents Cardiovascular Agents |
Antiviral Agents Protective Agents Pharmacologic Actions Fibrin Modulating Agents Pathologic Processes Syndrome Expectorants Therapeutic Uses Free Radical Scavengers Antidotes |