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

• Status: Completed
• Trial end date: 2010-03-01
• Target enrollment: 0
• Participant gender: Male

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.

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

Details

• Lead Sponsor: University Health Network, Toronto
• Treatments: 4-phenylbutyric acid; Insulin

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