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

This study has been completed.
Sponsor:
Information provided by:
University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT00533559
First received: September 19, 2007
Last updated: June 24, 2010
Last verified: August 2007
  Purpose

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.


Condition Intervention Phase
Diabetes
Insulin Resistance
Drug: sodium phenylbutyrate
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Health Services Research
Official Title: Mechanism of Fatty Acid-induced Impairment of Glucose-stimulated Insulin Secretion - Effect of Buphenyl

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • we will measure insulin secretion, calculate disposition index and insulin clearance during a hyperglycemic clamp. We will also measure insulin sensitivity during a euglycemic hyperinsulinemic clamp [ Time Frame: one year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • During the hyperglycemic clamp we will also measure Free Fatty Acid, C-peptide and triyglycerides. During the euglycemic hyperinsulinemic clamp we will determine the insulin sensitivity index and the disposition index. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Enrollment: 10
Study Start Date: September 2007
Study Completion Date: March 2010
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: buphenyl Drug: sodium phenylbutyrate
buphenyl, 7.5 gm/day for two weeks for two studies, one with saline and one admission with intralipid and heparin
Other Name: sodium phenylbutyrate
Placebo Comparator: Placebo Drug: Placebo
Placebo comparator

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.

  Eligibility

Ages Eligible for Study:   35 Years to 60 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Body mass index (BMI) > 27kg/m2. Fasting triglycerides > 2 mmol/l and < 5mmol/l Waist circumference > 90 cm Fasting blood glucose < 7 mmol/l Hemoglobin above 130g/L.

Exclusion Criteria:

  • History of hepatitis/hepatic disease that has been active within the previous two years
  • any significant aactive disease of the gastrointestinal, pulmonary, neurological, renal, genitourinary,hematological systems or has severe uncontrolled treated or untreated hypertension or proliferative retinopathy
  • fasting blood glucose > 7mmol/l or known diabetes
  • History of MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or hkeart failure
  • any laboratory values>2x the upper limit of normal
  • known or suspected allergy to the mediction or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions, History of hypersensitivity to heparin
  • current addiction to alcohol or substances of abuse as determined by the investigator
  • Metal incapacity, unwillingness or language barrier precdluding adequate understanding or cooperation
  • any lipid lowering or hypoglycemic agents
  • previous history of asthma
  • will not donate blood thre months prior to and three months post study procedures thrombocytopenis
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00533559

Locations
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada, M5G 2C4
Sponsors and Collaborators
University Health Network, Toronto
Investigators
Principal Investigator: Gary F. Lewis, MD University Health Network, Toronto General Hospital
  More Information

No publications provided

Responsible Party: Dr. Gary Lewis, University Health Network
ClinicalTrials.gov Identifier: NCT00533559     History of Changes
Other Study ID Numbers: 07-0274-B, Canadian Diabetes Association
Study First Received: September 19, 2007
Last Updated: June 24, 2010
Health Authority: Canada: Health Canada

Keywords provided by University Health Network, Toronto:
type 2 diabetes
free fatty acids
insulin resistance
beta cell lipotoxic effect

Additional relevant MeSH terms:
Insulin Resistance
Glucose Metabolism Disorders
Hyperinsulinism
Metabolic Diseases
4-phenylbutyric acid
Insulin
Antineoplastic Agents
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014