Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00188773
Status:
COMPLETED
Last Update Posted:
2008-06-05
First Post:
2005-09-12
Brief Title:
Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion
Sponsor:
University Health Network Toronto
Organization:
University Health Network Toronto
Study Overview
Official Title:
None
Status:
COMPLETED
Status Verified Date:
2007-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 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
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 40mlhr and heparin 250uhr 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 140mgkg NAC followed by a maintenance dose of 70mgkg 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
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 40mlhr and heparin 250uhr 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 140mgkg NAC followed by a maintenance dose of 70mgkg 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| CDA Grant 777508221 | None | None | None |