Insulin Resistance Syndrome X Clinical Trial
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.
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.
;
Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00474838 -
Study To Evaluate Beta Cell Function and Glycemic Outcome by Intensive Insulin Therapy
|
Phase 4 |