• To determine whether the FFA-induced impairment of pancreatic b-cell function can be ameliorated or prevented by administration of the antioxidant, NAC [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  
• Assessment of insulin sensitivity [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  
• To determine whether administration of NAC, an antioxidant, prevents FFA-mediated impairment of GSIS in healthy humans. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  

• assessment of glucose stimulated insulin secretion [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  

Drug: N-acetylcysteine, intralipid, heparin
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

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.

Inclusion Criteria:

The following criteria will be used for the selection of insulin resistant non-diabetic men aged 35-65 years:

1. Written informed consent obtained
2. Body mass index (BMI) > 27 kg/m2
3. Fasting triglycerides > 2 mmol/l and < 5 mmol/l
4. Waist circumference > 90 cm
5. Fasting blood glucose < 7 mmol/l
6. In order to keep the number of study subjects to a minimum (n=15), in view of the cost of these labor-intensive metabolic studies, the investigators will be studying males only 35 to 65 years of age. This will allow them to study as homogeneous a group of subjects as possible. If significant protective effects of NAC on beta cell function are detected, they will study women using a similar protocol at a later stage.
7. Hemoglobin above 130 g/L

Exclusion Criteria:

1. Patient has a history of hepatitis/hepatic disease that has been active within the previous two years
2. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr > 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic BP > 100 or systolic > 180) or proliferative retinopathy
3. Fasting blood glucose > 7 mmol/l or known diabetes
4. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmias or conduction delays on ECG, unstable angina, or decompensated heart failure
5. Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l
6. Known or suspected allergy to the medication or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions
7. Current addiction to alcohol or substances of abuse as determined by the investigator
8. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
9. Any lipid lowering or hypoglycemic agents
10. Previous history of asthma
11. Will not donate blood three months prior to and three months post study procedures