Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion
Status:
Completed
Trial end date:
2008-01-01
Target enrollment:
Participant gender:
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.