Mechanism of Fatty Acid-induced Impairment of Glucose-simulated Insulin Secretion - Effect of Buphenyl

Each subject will undergo 4 studies, 4 weeks apart. Each study will consist of a 2 week treatment period with either Buphenyl or placebo, followed by 48 hour hospital stay to test insulin sensitivity and insulin secretion. The four studies are as follows: 1. 2-week placebo tablets followed by in hospital 48-hour infusion of normal saline prior to testing of insulin secretion and insulin sensitivity (CONTROL study), 2. 2-week placebo treatment followed by 48 hour infusion of intralipid and heparin to raise plasma free fatty acids 2-fold prior to testing of insulin secretion and insulin sensitivity (PLACEBO-INTRALIPID+HEPARIN study), 3. 2-week Buphenyl treatment followed by 48-hr infusion of intralipid and heparin to raise plasma free fatty acids 2-fold prior to testing of insulin secretion and insulin sensitivity (BUPOHENYL+INTRALIPID+HEPARIN study), 4. 2-week Buphenyl treatment followed by 48-hr infusion of normal saline prior to testing of insulin secretion and insulin sensitivity (BUPHENYL+SALINE study).

For two weeks prior to each admission to hospital and during each hospital admission subjects will ingest 5 tablets 3 times per day with meals (total of 15 tablets per day). For two of the 4 studies the tablet will contain Buphenyl (total of 15 tablets per day, each tablet of Buphenyl contains 500mg, total 7.5grams per day), whereas for the other two studies the tablet will be a placebo, containing no active ingredient. The study will be conducted as a single blind study, with the subject not knowing whether they are receiving a placebo or biphenyl. For safety reasons and since it will not influence the results of this study it will not be conducted as a double blind study. On each of four occasions, 4 weeks apart, after taking the tablets for 2 weeks, the subject will fast overnight for 12-hours prior to their admission to the Toronto General Hospital metabolic research ward for 48 hours to undergo testing as follows.

On the morning they are admitted an intravenous (iv) line will be placed in a superficial vein (under the skin) of each forearm (2 iv's, one iv in each arm). These intravenous lines will be used for blood sampling at regular intervals throughout the study and to infuse solutions. Blood samples will be drawn painlessly through the IV at timed intervals for the first two days. The total amount of blood to be taken for each of the three study periods will be less than 250 ml per visit i.e. less than the amount given when donating blood (a total amount of 1,000 ml over the entire study, which usually takes about 4 months to complete). During two of the four admissions to hospital they will receive a 48-hour infusion of intralipid (40 ml/hr of a 20% fat solution) and Heparin (250U/hr)) to raise plasma FFAs approximately 2-fold as we have previously described (8;54) whereas on the two other occasions they will receive an infusion of saline (salt water) for 48 hours in hospital. Heparin is stimulates an important enzyme involved in the breakdown of fat particles (lipoprotein lipase) and is used for this purpose in this study. Intralipid is a fat emulsions that supplies the synthetic triglycerides as substrate for LPL in order to raise plasma FFAs. Subjects will be permitted to eat and drink and will be provided with regular low fat meals during the 48 hours of the study.