Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion
Condition: Insulin Resistance Syndrome X; Pancreatic Beta Cell Function
MeSH terms: Insulin Resistance; Metabolic Syndrome
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): N-acetylcysteine, intralipid, heparin
Intervention type(s): Drug
Intervention description(s): 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
Intervention MeSH terms: Acetylcysteine; Heparin; Soybean oil, phospholipid emulsion; N-monoacetylcystine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: n-acetylcysteine,; free fatty acid,; glucose stimulated insulin secretion,; insulin resistance syndrome; antioxidant therapy; Insulin Resistance