Mechanism of Fatty Acid-Induced Impairment of Glucose-Stimulated Insulin Secretion

• Status: Completed
• Trial end date: 2008-01-01
• Target enrollment: 0
• Participant gender: Male

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University Health Network, Toronto
• Treatments: Acetylcysteine; Calcium heparin; Heparin; Insulin; Insulin, Globin Zinc; N-monoacetylcystine; Soybean oil, phospholipid emulsion

Criteria

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