Mechanism of Fatty Acid-induced Impairment of Glucose-simulated Insulin Secretion - Effect of Buphenyl
Condition: Diabetes; Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Interventional
Phase: Phase 4

Summary: 
      An increase of plasma free fatty acids impairs insulin secretion and insulin sensitivity,
      thereby playing an important role in causing type 2 diabetes. Lipotoxicity plays an important
      role in the progression from normal glucose tolerance to fasting hyperglycemia and coversion
      to frank type 2 diabetes. A recent publication in the journal Science showed that buphenyl,
      when given to obese diabetic mice, resulted in normalization of hyperglycemia, restoration of
      systemic insulin sensitivity, resolution of fatty liver disease and inhancement of insulin
      action in liver, muscle and adipose tissue. the mechanism of action is believed to be due to
      reduction of endoplasmic reticulum (ER) stress. Buphenyl is currently approved for the
      treatment of rare inherited disorders of the urea cycle. We plan to administer Buphenyl
      orally to humans at a dose far lower than that used for the treatment of urea cycle disorders
      for 2 weeks prior to the testing of pancreatic function. One potential mechanism whereby
      chromically elevated plasma FFAs and glucose impairment beta cell function and insuln
      sensitivity is by ER stress and this can be prevented by administeration of buphenyl.
    

Detailed description: 
      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.
    

Intervention name(s): sodium phenylbutyrate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): buphenyl, 7.5 gm/day for two weeks for two studies, one with saline and one admission with intralipid and heparin; Placebo comparator
Intervention MeSH terms: 4-phenylbutyric acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Health Services Research
Keywords: type 2 diabetes; free fatty acids; insulin resistance; beta cell lipotoxic effect